Giugliano Robert P, Wiviott Stephen D, Stone Peter H, Simon Daniel I, Schweiger Marc J, Bouchard Alain, Leesar Massoud A, Goulder Michael A, Deitcher Steven R, McCabe Carolyn H, Braunwald Eugene
TIMI Study Group, Boston, Massachusetts 02115, USA.
J Am Coll Cardiol. 2007 Jun 26;49(25):2398-407. doi: 10.1016/j.jacc.2007.02.065. Epub 2007 Jun 11.
We sought to evaluate the safety and efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2) in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS).
Recombinant NAPc2 is a potent inhibitor of the tissue factor/factor VIIa complex that has the potential to reduce ischemic complications mediated by thrombin generation.
A total of 203 patients were randomized 4:1 to double-blinded intravenous rNAPc2 or placebo every 48 h for a total of 1 to 3 doses in 8 ascending panels (1.5 to 10 microg/kg). All patients received aspirin, unfractionated heparin (UFH), or enoxaparin and early catheterization; clopidogrel and glycoprotein IIb/IIIa blockers were encouraged. Two subsequent open-label panels evaluated 10 mug/kg rNAPc2 with half-dose UFH (n = 26) and no UFH (n = 26). The primary end point was the rate of major plus minor bleeding. Pharmacokinetics, pharmacodynamics, continuous electrocardiography, and clinical events were assessed.
Recombinant NAPc2 did not significantly increase major plus minor bleeding (3.7% vs. 2.5%; p = NS) despite increasing the international normalized ratio in a dose-related fashion (trend p < or = 0.0001). Higher-dose rNAPc2 (> or =7.5 microg/kg) suppressed prothrombin fragment F1.2 generation compared with placebo and reduced ischemia by >50% compared to placebo and lower-dose rNAPc2. Thrombotic bailout requiring open-label anticoagulant occurred in 5 of 26 patients treated without UFH, but none in the half-dose UFH group (19% vs. 0%; p = 0.051).
In patients with nSTE-ACS managed with standard antithrombotics and an early invasive approach, additional proximal inhibition of the coagulation cascade with rNAPc2 was well tolerated. rNAPc2 doses > or =7.5 microg/kg suppressed F1.2 and reduced ischemia, though some heparin may be necessary to avoid procedure-related thrombus formation. (Anticoagulation With rNAPc2 to Eliminate MACE/TIMI 32; http://www.clinicaltrial.gov/ct/show/NCT00116012?order=1; NCT00116012).
我们旨在评估重组线虫抗凝血蛋白c2（rNAPc2）在非ST段抬高型急性冠状动脉综合征（nSTE-ACS）患者中的安全性和有效性。
重组NAPc2是组织因子/因子VIIa复合物的强效抑制剂，有可能减少由凝血酶生成介导的缺血性并发症。
总共203例患者按4:1随机分组，每48小时接受双盲静脉注射rNAPc2或安慰剂，共1至3剂，分8个递增剂量组（1.5至10微克/千克）。所有患者均接受阿司匹林、普通肝素（UFH）或依诺肝素治疗并早期进行导管插入术；鼓励使用氯吡格雷和糖蛋白IIb/IIIa阻滞剂。随后的两个开放标签组评估了10微克/千克rNAPc2联合半剂量UFH（n = 26）和不使用UFH（n = 26）的情况。主要终点是严重出血和轻微出血的发生率。评估了药代动力学、药效学、连续心电图和临床事件。
尽管rNAPc2以剂量相关方式增加国际标准化比值（趋势p≤0.0001），但并未显著增加严重出血和轻微出血的发生率（3.7%对2.5%；p = 无统计学意义）。与安慰剂相比，高剂量rNAPc2（≥7.5微克/千克）抑制凝血酶原片段F1.2的生成，与安慰剂和低剂量rNAPc2相比，缺血减少>50%。在未使用UFH治疗的26例患者中有5例需要开放标签抗凝进行血栓解救，但半剂量UFH组无1例（19%对0%；p = 0.051）。
在采用标准抗栓治疗和早期侵入性治疗方法的nSTE-ACS患者中，用rNAPc2对凝血级联进行额外的近端抑制耐受性良好。rNAPc2剂量≥7.5微克/千克可抑制F1.2并减少缺血，不过可能需要一些肝素以避免与手术相关的血栓形成。（rNAPc2抗凝以消除MACE/TIMI 32；http://www.clinicaltrial.gov/ct/show/NCT00116012?order=1；NCT00116012）
