HORIZONS AMI：A Prospective, Randomized Comparison of Bivalirudin vs.Heparin Plus Glycoprotein GPIIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction:30-Day Results

　　Dr.Gregg Stone在第19届TCT科学研讨会最新临床试验分会上，公布了关于急性心肌梗死血运重建和支架的实验结果。在这个全球性试验中，STEMI患者直接PCI后，应用直接抗凝血酶Bivalirudin可产生更好的临床效果（以死亡、MI、靶病变血运重建、中风、或大出血等来衡量）。30天心脏事件风险Bivalirudin组比肝素联合糖蛋白GP IIb/IIIa抑制剂组更低。

　　背景

　　近年来，PCI治疗急性冠脉综合征的目标是：1）减少缺血性并发症2）减少引起出血的并发症。在治疗稳定型心绞痛患者及不稳定心绞痛/非ST段抬高性心肌梗死的患者，接受介入治疗，直接凝血酶抑制剂Bivalirudi能有效地减少大出血，但出现了类似于肝素联合糖蛋白GP IIb/IIIa抑制剂产生的复合性缺血。Bivalirudin对于行直接PCI术的STEMI患者的安全性和有效性还没有进行研究。

　　研究设计

　　HORIZONS AMI试验由CRF发起，MEDICINES公司及波士顿科学公司联合赞助。它是研究直接PCI治疗STEMI患者应用抗凝药临床疗效的最大规模的试验之一。该研究入选了11个国家3，602例STEMI患者试验，是前瞻性、单盲、随机、多中心研究，。患者被随机分为Bivalirudin联合使用糖蛋白GP IIb/IIIa抑制剂组和普通肝素（UFH）联合使用GP IIb/IIIa抑制剂组，随机接受TAXUS支架和ＢＭＳ；试验仍在进行。

　　内科治疗

　　急诊室患者口服非肠溶阿司匹林324mg（或静滴500mg），后改为住院病人300～325 mg/天治疗，门诊病人以75～81 mg/天服用。急诊室给予氯吡格雷以负荷剂量300～600mg，随后至少6个月（推荐1年或更长时间）每天口服75 mg/次，1次/日。

　　静脉给予患者普通肝素60单位/kg，除非需要更多的抗凝血酶，直到手术结束。另外，UFH组患者常规给予GP IIb/IIIa抑制剂。每名患者根据规定剂量及肾功能，应用阿昔单抗12小时或埃替非巴肽18小时。Bivalirudin0.75 mg/kg静脉注射，1.75mg/kg/h滴注，持续到手术结束，除非需要更多的抗凝血酶（以0.25 mg/kg/h的剂量给予）。推荐只在大血栓或难治性Bivalirudin组发生缺血时，给予GP IIb/IIIa抑制剂，且在试验中对7.2%的患者进行给药。

　　终点

　　2个主要临床终点是大出血和不良临床事件，即30天发生联合主要不良心血管事件（死亡、再梗死、中风、靶病变血运重建）和大出血。大出血被定义为如下情况：颅内出血，眼内出血，腹膜后出血，需要进行介入/手术治疗的病变部位出血，血肿≥5cm，血色素下降<3g/dL伴明显缺血征象，血色素下降>4g/dL不伴缺血征象或需成分输血。次要临床终点是30天主要不良心血管事件。

　　结果：共有1,800例患者PCI治疗给予Bivalirudin，1,802例患者给予普通肝素联合GP IIb/IIIa抑制剂。30天结果如下：

与肝素联合GP IIb/IIIa抑制剂组相比，Bivalirudi组30天不良临床事件的发生率显著降低，降低24%（9.2% vs. 12.1%,Ｐ=0.006），显著降低大出血发生率，降低40%（4.9% vs. 8.3%,Ｐ＜0.0001这两组主要心脏不良事件的发生率没有明显差别（5.4% vs.5.5%，Ｐ=1.0）。30天随访，Bivalirudin心源性死亡的发生率降低了38%（1.8% vs. 2.9%,Ｐ=0.035）.两组30天支架内血栓发生率没有明显差别（Bivalirudin组是2.5%，肝素联合GP IIb/IIIa抑制剂组是1.9%，Ｐ=0.33）,但是24小时急性支架血栓Bivalirudin组要更高（1.3% vs. 0.3%,Ｐ=0.0009）

　　结论：在计划做PCI治疗STEMI的患者中，与肝素联合GP IIb/IIIa抑制剂组相比，使用Bivalirudin的策略，由于其能减少大出血从而降低30天联合终点事件发生率，如死亡、心肌梗死、靶病变血运重建、中风和大出血。但两者在主要不良心脏事件中没有明显差别。

HORIZONS AMI: A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction: 30-Day Results

Dr. Gregg Stone presented the results of the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial at a late-breaking session of the 19th annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium. In this global trial of STEMI patients undergoing primary percutaneous coronary intervention (PCI), the direct antithrombin bivalirudin resulted in superior net clinical benefit, defined as death, MI, ischemic target vessel revascularization (TVR), stroke, or major bleeding. At 30 days, the risk of cardiac deaths was lower in the bivalirudin group compared with UFH and GP IIb/IIIa inhibitor.

Background

Two goals of therapy for acute coronary syndromes (ACS) and PCI have emerged in recent years: 1) to reduce ischemic complications and 2) to prevent hemorrhagic complications. In patients with stable angina and UA/NSTEMI undergoing an invasive strategy, the direct thrombin inhibitor bivalirudin has shown rates of composite ischemia similar to heparin plus GP IIb/IIIa inhibitors, while significantly reducing major bleeding. Whether bivalirudin has comparable safety and efficacy in patients with STEMI undergoing primary PCI had not yet been studied.

Study Design

HORIZONS-AMI was conducted by the Cardiovascular Research Foundation and was co-funded by grants from The Medicines Company and Boston Scientific. It was one of the largest studies of anticoagulants in STEMI patients undergoing primary PCI. The trial was a prospective, single-blind, randomized, multi-center study in 3,602 patients presenting with STEMI at hospitals in 11 countries. Patients undergoing angioplasty were randomly assigned to receive either bivalirudin with provisional use of GP IIb/IIIa inhibitor or UFH plus GP IIb/IIIa inhibitor. Patients enrolled in the HORIZONS-AMI trial also were assigned randomly to receive either TAXUS drug-eluting stents or bare-metal stents; this component of the trial is still ongoing.

Medical Treatments

All patients received chewed non-enteric coated aspirin 324 mg (or 500 mg IV) in the ER, followed by 300-325 mg/day in-hospital and 75-81 mg/day as outpatients indefinitely. Clopidogrel 300 mg or 600 mg loading dose (per investigator discretion) was given in the ER, followed by 75 mg PO QD for at least 6 months (1 year or longer recommended).

Patients were randomized to receive UFH at a dose of 60 U/kg IV, with subsequent boluses titrated by nomogram to ACT 200-250 sec and terminated at procedure end unless prolonged antithrombin was needed. In addition, patients in the UFH arm were routinely given a GP IIb/IIIa inhibitor. Abciximab or double bolus eptifibatide as per investigator discretion (dosed per FDA label and adjusted for renal function) continued for 12h (abciximab) or 12-18h (eptifibatide). Bivalirudin was administered as a bolus of 0.75 mg/kg IV, infusion 1.75 mg/kg/h (not titrated to ACT), and terminated at procedure end unless prolonged antithrombin was needed (in which case a dose of 0.25 mg/kg/hr was given). GP IIb/IIIa inhibitors were recommended only for giant thrombus or refractory no reflow in the bivalirudin arm, and were used in 7.2% of patients in the trial.

Endpoints

The two primary endpoints were major bleeding and net adverse clinical events, a composite of major adverse cardiovascular events (death, reinfarction, stroke, or ischemic target vessel revascularization) and major bleeding at 30 days. Major bleeding was defined as any one of the following: intracranial bleeding, intraocular bleeding, retroperitoneal bleeding, access site bleed requiring intervention/surgery, hematoma ≥5 cm, Hgb ≥3g/dL with an overt source, Hgb ≥4g/dL without overt source, reoperation for bleeding, or blood product transfusion. The major secondary endpoint was major adverse cardiovascular events at 30 days.

Results

A total of 1800 patients were randomized to treatment during PCI with bivalirudin and 1802 to UFH plus GP IIb/IIIa inhibitor. Results at 30 days were as follows:

For the primary endpoint, the incidence of net adverse clinical events at 30 days, bivalirudin significantly reduced the composite of major adverse cardiac events or major bleeding by 24% (9.2% vs. 12.1%, p = 0.006). Bivalirudin also significantly reduced the incidence of major bleeding by 40% (4.9% vs. 8.3%, p <0.0001). There were comparable rates of major adverse cardiac events in the two groups (5.4% vs. 5.5%, p = 1.0). At 30 day follow-up, bivalirudin significantly reduced the incidence of cardiac-related mortality by 38% (1.8% vs. 2.9%, p= 0.035). There was no significant difference in stent thrombosis at 30 days between the groups (2.5% with bivalirudin vs. 1.9% with UFH plus GP IIb/IIIa inhibitor, p = 0.33), but rates of acute stent thrombosis within 24 hours were higher in the bivalirudin group (1.3% vs. 0.3%, p = 0.0009).

Conclusion

Among patients undergoing planned primary PCI for STEMI, use of a strategy of bivalirudin was associated with a reduction in the composite endpoint of death, MI, target vessel revascularization, stroke, and major bleeding at 30 days compared with UFH plus GP IIb/IIIa inhibitors, driven by a reduction in major bleeding with no difference in major adverse cardiac events.