抗凝药比伐卢定国外临床应用进展

比伐卢定(bivalirudin)是一种新型直接凝血酶抑制剂,2000年被FDA批准应用于临床.比伐卢定是水蛭素的衍生物,通过抑制凝血酶的活性位点而起效,国外将其与其他常用抗凝药进行了比较研究,认为比伐卢定可以作为普通肝素和血小板糖蛋白IIb/IIIa受体阻滞剂的替代药物用于手术过程中的抗凝治疗.现综述比伐卢定的药理学特点及其在经皮冠状动脉介入治疗、急性心肌梗死溶栓治疗、外周血管介入治疗、心脏外科手术、肝素诱导的血小板减少症、管内放射治疗术等方面的临床研究进展.     

比伐卢定抗凝作用的研究进展

FDA在2000年批准了一种新的直接凝血酶抑制剂比伐卢定应用于临床，该药是水蛭素的类似物，它通过抑制凝血酶的活性位点而起效。国外将其与其他常用的抗凝药进行了比较研究，认为比伐卢定可以作为普通肝素和血小板糖蛋白Ⅱb／Ⅲa拮抗剂的替代药物应用于非高危患者的经皮冠脉介入治疗。     

比伐卢定在冠心病PCI术中有效性和安全性的临床研究进展

比伐卢定是一种直接凝血酶抑制剂,能够直接地抑制凝血酶的活性,起到抗凝作用,近年在行PCI术的冠心病患者中应用得到推广。多数临床研究显示,与肝素相比,比伐卢定能够降低出血风险,甚至带来临床获益。但近期的一些大型临床研究及荟萃分析提示比伐卢定并不优于肝素,使比伐卢定的地位受到质疑。本文就近年最新的大型比伐卢定临床研究及荟萃分析进行综述。     

国产比伐卢定在老年急性心肌梗死患者急诊冠状动脉介入治疗的疗效及安全性观察

<正>比伐卢定是一个直接凝血酶抑制剂,通过直接并特异性抑制凝血酶活性发挥抗凝作用,其与凝血酶活性位点和底物识别位点可逆性结合,持续时间短,平均消除半衰期为24min[1]。目前其已广泛用于择期冠状动脉介入术(PCI)、急性冠状动脉综合征以及ST段抬高性心梗患者(STEMI)。然而,比伐卢定在老年患者STEMI中的疗效在国内还未见报道。因此,本研究的目的是评估国产比伐卢定在老年STEMI患者中     

直接凝血酶抑制剂比伐卢定的研究现状

比伐卢定在2000年经美国食品药品管理局批准上市,是直接的、特异的、可逆的凝血酶抑制剂,具有抗凝效果的可预测性、不诱导血小板减少及对纤维蛋白结合的凝血酶有效等优势,克服了肝素、水蛭素的局限性。本文对其药理学特点、药效学与药代动力学、药物相互作用、临床应用与不良反应等进行简要综述。     

抗凝药比伐卢定临床应用研究进展

比伐卢定(bivalirudin)作为一种新型凝血酶抑制剂,具有抗凝效果的可预测性、不诱导血小板减少等优势。本文收集整理了比伐卢定在经皮冠状动脉介入术、颈动脉支架、球囊主动脉瓣成形术、肝素诱导的血小板减少、体外膜肺氧合等领域的最新研究近况,深入分析了其在临床应用方面的不足,为比伐卢定在使用中的安全性及疗效提供参考依据。     

比伐卢定治疗起搏器电极导线血栓的分析与探讨

<正>比伐卢定(bivalirudin)是由水蛭素提取的直接凝血酶抑制剂,是一种新型抗凝药,2000年被美国食品和药物管理局(FDA)批准上市,应用于经皮冠状动脉介入治疗、肝素诱导血小板减少症、颈动脉支架植入等疾病的治疗~([1]),但在起搏器电极导线血栓中的应用罕见报道。临床药师参与1例临时起搏器植入术后发生电极周围血栓患者的个     

不合理使用增加抗凝药比伐卢定用药风险

抗凝药比伐卢定(bivalirudin)广泛用于经皮冠脉介入治疗(PCI)。欧洲开展了一项多国参与的比伐卢定使用情况调查研究,约35%患者在比伐卢定维持治疗时,因剂量不符合标准规定而发生心血管不良事件,例如心源性死亡、心肌梗死甚至需紧急运用血管成形术。MHRA建议,比伐卢定使用过程中     

比伐卢定在经皮冠脉介入治疗术中的应用

目的 探讨比伐卢定在经皮冠脉介入治疗术中的临床应用价值。方法 择期行经皮冠脉介入治疗术的患者40例,将其随机分为对照组和观察组,每组20例。对照组患者在给予普通肝素进行抗凝治疗,观察组患者给予比伐卢定进行抗凝治疗,对两组患者用药前后不同时间点的血小板最大聚集率进行比较,同时对比其手术成功率和术后1个月内心血管不良事件、出血情况的发生率。结果 两组患者在用药后10 min、用药结束后,血小板最大聚集率的比较,差异有统计学意义(P<0.05)。两组患者手术均成功,且术后30 d内均未出现心血管不良事件。观察组和对照组轻度出血的发生率分别为5.0%和15.0%,差异有统计学意义(P<0.05)。结论 在实施经皮冠脉介入治疗术的过程中,使用比伐卢定进行抗凝治疗,不仅能获得良好的临床疗效,还可以在术中抑制血小板活性,降低术后出血事件的发生率,安全有效,值得临床推广应用。     

注射用比伐卢定对健康志愿者纤维蛋白原和凝血酶时间的影响

目的:研究比伐卢定注射液对健康志愿者纤维蛋白原和凝血酶时间的影响。方法:48名健康志愿者随机分为4个试验组,分别为静脉注射比伐卢定0.5,0.75和1.05 mg.kg-1组以及以0.75 mg.kg-1静脉推注后,立即续以1.75 mg.kg-1.h-1的速度匀速静脉滴注4 h组。每组12人,其中9名给予比伐卢定注射剂,3名接受安慰剂。静脉注射组在给药前和给药后20 min,45 min,1 h,2 h,24 h和72 h,静脉推注加静脉滴注组在静脉推注前和静脉滴注开始后2,4,6,8,24和72 h,取血测定纤维蛋白原(fibrinogen,Fib)浓度和凝血酶时间(thrombin time,TT)。结果:比伐卢定剂量依赖性地延长TT,停药后2 h,TT值逐渐恢复正常。比伐卢定剂量依赖性地降低Fib浓度,尤其是静脉推注加静脉滴注组降低明显,但这可能是由于检测方法的影响,产生的假性降低现象。结论:在比伐卢定II期临床试验中,应密切监测受试者的凝血指标,注意观察受试者是否发生出血不良事件。在有直接凝血酶抑制剂存在时,应避免使用冯.克劳斯法检测Fib浓度。     

Bivalirudin in percutaneous coronary intervention.

The chemistry and pharmacology, pharmacokinetics, pharmacodynamics, adverse effects, drug interactions, dosing and administration, and pharmacoeconomics of bivalirudin are reviewed; clinical trials of bivalirudin's application in percutaneous coronary intervention (PCI) are also discussed. Bivalirudin is a direct thrombin inhibitor approved for use in PCI. It reversibly binds to thrombin's catalytic site and substrate recognition site and blocks both circulating and fibrin-bound thrombin. Peak concentrations occur in less than 5 minutes after bolus-dose administration, and its half-life is approximately 25 minutes. It is primarily eliminated renally, and dosage reduction may be required in patients with severe renal dysfunction. Two clinical trials have demonstrated that bivalirudin is at least as effective as unfractionated heparin (UFH) in preventing ischemic complications in PCI. Other trials have shown that bivalirudin has beneficial ischemic and hemorrhagic outcomes in a more modern PCI setting (i.e., intracoronary stent placement, clopidogrel, and glycoprotein IIb/IIIa-receptor inhibitors). Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors was noninferior to UFH with planned glycoprotein IIb/IIIa inhibitors and superior to UFH alone with respect to ischemic and hemorrhagic endopoints in PCI. Major bleeding with bivalirudin has occurred in approximately 3% of patients in clinical trials, and it is not known to have any interactions with the cytochrome P-450 isoenzyme system. The acquisition cost of bivalirudin in one study was less than the combination of UFH and glycoprotein IIb/IIIa inhibitors. Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors appears to be an acceptable alternative to the standard of care and is superior to UFH alone in PCI.     

Evolving role of bivalirudin in percutaneous coronary interventions; impact of the REPLACE-2 study

Percutaneous coronary interventions are being used with increasing frequency nowadays for the treatment of patients with coronary heart disease. Acute thrombotic complications remain one of the major limitations of these procedures for which unfractionated heparin has been the standard foundation anticoagulant. It has, however, many limitations and disadvantages that necessitated research and development of alternative anticoagulant therapies. The direct thrombin inhibitor bivalirudin has been approved as a substitute for heparin in patients undergoing angioplasty for unstable angina based on data in higher-risk patients where bivalirudin resulted in lower rates of ischaemic and bleeding complications compared to heparin. This evidence was collected prior to the widespread use of platelet glycoprotein (GP) IIb/IIIa receptor blockers, thienopyridines and intracoronary stents, considered standard practice for such patients today. The REPLACE-2 study was carried out to establish whether, in the current era, bivalirudin used with provisional GP IIb/IIIa blockade if necessary during the procedure could provide equivalent protection from ischaemic events compared with the gold standard of heparin plus routine GP IIb/IIIa blockade. With advantages with regards to bleeding, ease of use and reduced cost, bivalirudin use with provisional GP IIb/IIIa inhibitors in low-to-moderate risk percutaneous coronary interventions allows GP IIb/IIIa receptor antagonists to be used in a selective fashion, rather than in all patients. In this article, background rationale for bivalirudin use in this setting is reviewed as well as past research in this area. Additionally, the implications of the REPLACE-2 study in establishing where bivalirudin fits into our current interventional cardiology practice and future directions are presented.     

Evolving role of bivalirudin in percutaneous coronary interventions; impact of the REPLACE-2 study

Percutaneous coronary interventions are being used with increasing frequency nowadays for the treatment of patients with coronary heart disease. Acute thrombotic complications remain one of the major limitations of these procedures for which unfractionated heparin has been the standard foundation anticoagulant. It has, however, many limitations and disadvantages that necessitated research and development of alternative anticoagulant therapies. The direct thrombin inhibitor bivalirudin has been approved as a substitute for heparin in patients undergoing angioplasty for unstable angina based on data in higher-risk patients where bivalirudin resulted in lower rates of ischaemic and bleeding complications compared to heparin. This evidence was collected prior to the widespread use of platelet glycoprotein (GP) IIb/IIIa receptor blockers, thienopyridines and intracoronary stents, considered standard practice for such patients today. The REPLACE-2 study was carried out to establish whether, in the current era, bivalirudin used with provisional GP IIb/IIIa blockade if necessary during the procedure could provide equivalent protection from ischaemic events compared with the gold standard of heparin plus routine GP IIb/IIIa blockade. With advantages with regards to bleeding, ease of use and reduced cost, bivalirudin use with provisional GP IIb/IIIa inhibitors in low-to-moderate risk percutaneous coronary interventions allows GP IIb/IIIa receptor antagonists to be used in a selective fashion, rather than in all patients. In this article, background rationale for bivalirudin use in this setting is reviewed as well as past research in this area. Additionally, the implications of the REPLACE-2 study in establishing where bivalirudin fits into our current interventional cardiology practice and future directions are presented.     

Bivalirudin: a review of its use in patients undergoing percutaneous coronary intervention

Bivalirudin (Angiox, Angiomax) is a synthetic 20-amino acid peptide analogue of hirudin. It is a direct thrombin inhibitor that binds specifically and reversibly to both fibrin-bound and unbound thrombin. Intravenous bivalirudin is approved in Europe for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI). In the US, bivalirudin is approved in patients with unstable angina pectoris undergoing percutaneous transluminal coronary angioplasty (PTCA) and has recently been approved for use with provisional glycoprotein (GP) IIb/IIIa inhibition in patients undergoing PCI. Bivalirudin plus provisional GP IIb/IIIa inhibition is effective in patients undergoing PCI. The large, well controlled REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events) study showed that bivalirudin plus provisional GP IIb/IIIa inhibition was noninferior to heparin plus planned GP IIb/IIIa inhibition and that bivalirudin was associated with a reduced risk of bleeding complications. In patients with heparin-induced thrombocytopenia (HIT), bivalirudin was effective against ischaemic events and there was a low incidence of bleeding complications. Bivalirudin should be considered as an alternative to heparin plus planned GP IIb/IIIa inhibition in any patient undergoing urgent or elective PCI, especially in any patient with a high risk of bleeding complications.     

比伐芦定对比肝素联合替罗非班用于PCI围手术期抗凝治疗的药物经济学

目的：对比研究比伐芦定及普通肝素联合糖蛋白受体拮抗剂替罗非班（H-T）用于中国急性冠脉综合征（ACS）患者经皮冠状动脉介入（PCI）围手术期抗凝治疗的成本效果,为中国人群PCI围手术期抗凝治疗药物的合理选用提供理论依据。方法：参考我国随机、双盲、多中心Ⅲ期临床实验BRIGHT的研究结果,通过建立决策树模型及Markov长期外推模型,模拟计算使用比伐芦定或H-T治疗患者的调整质量生命年（QLAYs）及治疗成本,对比伐芦定用于中国人群PCI抗凝治疗的成本效益进行分析和研究。结果：比伐芦定和H-T组的治疗总成本分别为46 404.80元和43 552.14元,使用比伐芦定患者可获得的QALYs为10.07,采用H-GPI治疗方案的患者QALYs为9.98。增量成本效果分析显示,采用比伐芦定可提高患者的健康效益（△E>0）,但同时增加了治疗成本（△C>0）,其增量成本效果比（ICER）为28 575.77元/QALYs,小于3倍部分城市人均GDP,提示采用比伐芦定具有成本效果优势。一维敏感度分析显示本研究结果稳定可靠。结论：在我国目前整体经济形势下,与H-T的二联抗凝方案相比,比伐芦定用于PCI抗凝具有成本效果优势,可替代传统抗凝方案用于ACS患者PCI围手术期抗凝治疗。     

Bivalirudin: a review of its potential place in the management of acute coronary syndromes

Bivalirudin, a synthetic analogue of hirudin, is a specific and reversible inhibitor of thrombin which binds directly with both fluid-phase and clot-bound thrombin. In patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA), results from a large well designed study and its reanalysis (n = 4312) indicate that bivalirudin is more effective than heparin in the prevention of ischaemic complications for up to 90 days after the start of treatment. In addition, among patients undergoing PTCA for post myocardial infarction (MI) bivalirudin may be more effective than heparin in preventing ischaemic complications for up to 180 days after treatment was started. Data from dose-finding studies indicate bivalirudin has potential in the treatment of patients with unstable angina not undergoing percutaneous coronary intervention (PCI); however, well designed comparative studies are needed before firm conclusions can be made. Among patients with acute ST elevation MI, randomised trials have demonstrated bivalirudin to be significantly more effective than heparin in improving early patency in patients receiving thrombolytic therapy with streptokinase. Data from the Hirulog and Early Reperfusion/Occlusion (HERO)-1 trial (n = 412) indicate that bivalirudin recipients were significantly more likely to have Thrombin Inhibition in Myocardial Ischaemia (TIMI) grade 3 flow at 90 to 120 minutes than heparin recipients. In addition, data from the HERO-2 trial (n = 17 073) show bivalirudin was significantly more effective than heparin in reducing adjudicated 96-hour reinfarction and 30-day investigator-reported death/reinfarction than heparin. Bivalirudin was as effective as heparin in reducing 30-day mortality. Data from a meta-analysis of four randomised trials among patients undergoing PTCA or treatment for acute coronary syndromes indicate that, at after 30 to 50 days of follow-up, bivalirudin was significantly more effective than heparin in reducing the incidence of nonfatal MI and the combined endpoint of death or nonfatal MI. The most significant adverse events associated with bivalirudin are bleeding complications. In individual trials, bivalirudin was as well tolerated as heparin with, in general, a reduced incidence of bleeding complications. Additionally, bivalirudin provides a more consistent, predictable anticoagulant response. In 4312 patients with unstable angina undergoing PTCA the incidence of retroperitoneal bleeding, blood transfusion and major haemorrhage was significantly lower in bivalirudin than heparin recipients. Data from the HERO-2 trial in patients with acute MI indicate that although bivalirudin recipients had a significantly higher incidence of mild or moderate bleeding than heparin recipients, there was no difference in intracranial haemorrhage, severe bleeding or transfusions. Data from a meta-analysis among 5674 patients with ischaemic heart disease show bivalirudin recipients were at a significantly lower risk of haemorrhagic events than heparin recipients. CONCLUSIONS: Bivalirudin is an effective alternative to heparin in the prevention of ischaemic complications in patients with unstable angina undergoing PTCA. In addition, the drug has shown potential in the treatment of patients with unstable angina not undergoing PCI. For patients with MI, it is clear that bivalirudin can replace heparin in the management of MI where streptokinase is used as the thrombolytic agent. Further data are required on the efficacy of bivalirudin in patients undergoing thrombolysis with newer thrombolytics.     

比伐卢定在高龄经皮冠脉介入治疗急性冠脉综合征患者中的疗效及安全性观察

目的 探讨高龄急性冠状动脉综合征（ACS）患者行经皮冠状动脉介入治疗（PCI）应用比伐卢定抗凝的疗效及安全性.方法 拟行PCI的年龄≥80岁ACS患者155例,随机分为比伐卢定组（78例）及普通肝素组（77例）.比较两组PCI术后24 h、30 d的主要心脑不良事件（MACCE）及出血发生率.结果 两组患者PCI术后24 h、30 d的MACCE发生率差异均无统计学意义（P〉0.05）.比伐卢定组患者术后出血发生率明显低于普通肝素组（P〈0.001）.结论 与普通肝素相比,比伐卢定在老年ACS接受PCI治疗的人群中,明显减少出血事件,且未增加MACCE发生率.     

Direct thrombin inhibitors

This review deals with a newly-developed category of antithrombotic drugs – the direct thrombin inhibitors. These agents interact with thrombin and block its catalytic activity on fibrinogen, platelets and other substrates. Heparin and its derivatives (low molecular weight heparins and the active pentasaccharide) inhibit thrombin and/or other coagulation serine proteases indirectly via antithrombin, and the warfarin-type drugs interfere with the synthesis of the precursors of the coagulation serine proteases. The direct thrombin inhibitors approved for clinical use at present (lepirudin, desirudin, bivalirudin, argatroban) and another in the advanced clinical testing stage (melagatran/ximelagatran), are the subject of this review. The chemical structure; kinetics of thrombin inhibition; pharmacokinetics and clinical use of each of these is discussed.