Kereiakes D J, Kleiman N S, Ferguson J J, Masud A R, Broderick T M, Abbottsmith C W, Runyon J P, Anderson L C, Anders R J, Dreiling R J, Hantsbarger G L, Bryzinski B, Topol E J
Carl and Edyth Lindner Center for Clinical Cardiovascular Research, Health Alliance of Greater Cincinnati Cincinnati, Ohio, USA.
Circulation. 1998 Sep 29;98(13):1268-78. doi: 10.1161/01.cir.98.13.1268.
Parenteral administration of platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blockers can reduce ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers may allow more sustained receptor antagonism with the potential for long-term secondary prevention. The pharmacodynamic efficacy, clinical safety, and outcomes after prolonged receptor blockade with an orally active GP IIb/IIIa antagonist are not known. The Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis (ORBIT) Trial is a multicenter, placebo-controlled, randomized trial of xemilofiban, an oral platelet GP IIb/IIIa blocking agent, administered to patients after percutaneous coronary intervention.
After successful elective percutaneous coronary intervention, 549 patients were randomized to receive either placebo or xemilofiban in a dose of 15 or 20 mg. Stented patients randomized to placebo also received ticlopidine 250 mg orally BID for 4 weeks. Patients who received abciximab during the coronary intervention and who were randomized to receive xemilofiban were administered a reduced dosage (10 mg TID for 2 weeks) followed by the randomized maintenance dose of 15 or 20 mg BID for 2 more weeks. All patients received 325 mg aspirin PO QD. Ex vivo platelet aggregation in response to 20 micromol/L ADP and 4 microg/mL collagen was measured over time after the initial dose of study drug and at days 14 and 28 of long-term therapy in 230 patients. All patients were followed clinically for 90 days. Xemilofiban inhibited platelet aggregation to both ADP and collagen with peak levels of inhibition that were similar at 14 and 28 days of long-term oral therapy. Plasma levels of xemilofiban correlated with the degree of platelet inhibition. Peak platelet inhibition on day 1 correlated with the subsequent occurrence of insignificant or mild bleeding events. Although this study was not powered to evaluate differences in clinical outcomes, a trend (P=0.04) was observed for reduction of cardiovascular events at 3 months in patients not treated with abciximab who received the highest dose (20 mg) of xemilofiban studied.
Xemilofiban inhibited platelet aggregation and was well tolerated during 28 days of long-term oral therapy. The observed trend in reduction of cardiovascular events in follow-up awaits confirmation in the larger-scale phase III study (EXCITE trial) currently in progress.
胃肠外给予血小板糖蛋白IIb/IIIa（GP IIb/IIIa）受体阻滞剂可降低冠状动脉血管成形术的缺血性并发症。口服活性GP IIb/IIIa阻滞剂可能使受体拮抗作用更持久，具有长期二级预防的潜力。口服活性GP IIb/IIIa拮抗剂长期阻断受体后的药效学疗效、临床安全性及结果尚不清楚。口服糖蛋白IIb/IIIa受体阻断抑制血栓形成（ORBIT）试验是一项多中心、安慰剂对照、随机试验，将口服血小板GP IIb/IIIa阻断剂 xemilofiban应用于经皮冠状动脉介入治疗后的患者。
成功进行选择性经皮冠状动脉介入治疗后，549例患者被随机分为接受安慰剂或剂量为15或20 mg的xemilofiban。随机接受安慰剂的置入支架患者还口服噻氯匹定250 mg，每日2次，共4周。在冠状动脉介入治疗期间接受阿昔单抗且随机接受xemilofiban的患者，先给予减量剂量（10 mg，每日3次，共2周），随后随机给予维持剂量15或20 mg，每日2次，再持续2周。所有患者均口服325 mg阿司匹林，每日1次。在230例患者中，在给予研究药物初始剂量后及长期治疗的第14天和第28天，随时间测量对20 μmol/L ADP和4 μg/mL胶原的体外血小板聚集情况。所有患者均进行90天的临床随访。Xemilofiban抑制对ADP和胶原的血小板聚集，在长期口服治疗的第14天和第28天，抑制峰值水平相似。Xemilofiban的血浆水平与血小板抑制程度相关。第1天的血小板抑制峰值与随后发生的轻微或轻度出血事件相关。尽管本研究无足够效能评估临床结果的差异，但在未接受阿昔单抗治疗且接受研究中最高剂量（20 mg）xemilofiban的患者中，观察到3个月时心血管事件减少的趋势（P = 0.04）。
Xemilofiban抑制血小板聚集，在28天的长期口服治疗期间耐受性良好。随访中观察到的心血管事件减少趋势有待正在进行的更大规模III期研究（EXCITE试验）证实。
