CN108236612A - 用于冠脉介入手术中抗凝的组合产品及其用途 - Google Patents
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Abstract
本发明提供一种用于冠脉介入手术中抗凝的组合产品，所述组合产品包含治疗有效量的普通肝素和治疗有效量的低分子量肝素，所述普通肝素和低分子量肝素为各自独立存在的试剂状态，所述普通肝素和低分子量肝素在冠脉介入手术操作中序贯给药予有需要的受试者。本发明所提供的组合产品，为临床择期PCI术提供更好、更安全的术中抗凝组合产品，从而减少患者痛苦和不便，有望改善患者预后，惠及广大冠心病患者，具有重要的社会、科学和经济价值。
Description
技术领域
本发明涉及一种抗凝的组合产品，尤其涉及一种用于冠脉介入手术中抗凝的组合产品。
背景技术
近20年来，冠脉介入（percutaneous coronary intervention, PCI）技术迅猛发展，显著改变着目前冠心病的治疗模式。PCI的成功率、安全性和可靠性，以及远期预后都得到明显改善。这不仅是由于操作技术的进步，还得益于围术期的辅助药物，尤其是抗凝药物，包括普通肝素（unfractioned heparin, UFH）、低分子肝素（low molecular weightheparin, LMWH）、血小板膜糖蛋白（GP）Ⅱb/Ⅲa受体拮抗剂或直接凝血酶抑制剂等的应用。合理应用上述药物，可以显著改善患者预后和 PCI术的安全性。（Cohen M, Diez JE,Levine GN, et al. Pharmaco invasive management of acute coronary syndrome:incorporating the 2007 ACC/AHA guidelines: the CATH (cardiac catheterizationand antithrombotic therapy in the hospital) Clinical Consensus Panel Report--III. J Invasive Cardiol. 2007, 19: 525-538; Casterella PJ, Tcheng JE. Reviewof the 2005 American College of Cardiology, American Heart Association, andSociety for Cardiovascular Interventions guidelines for adjunctivepharmacologic therapy during percutaneous coronary interventions: practicalimplications, new clinical data, and recommended guideline revisions. AmHeart J. 2008, 155:781-790; Moliterno DJ. Advances in antiplatelet therapyfor ACS and PCI. J Interv Cardiol.2008, 21 Suppl 1: S18-S24; Cohen M,Hoekstra J. The use of adjunctive anticoagulants in patients with acute coronary syndrome transitioning to percutaneous coronary intervention. Am JEmerg Med. 2008; 26:932-941.）因此，上述抗凝药物在PCI 技术中占有举足轻重的地位，可以说，没有抗凝就没有PCI的飞速发展。
自PCI技术问世以来，作为传统抗凝药物的UFH一直被用来预防导管内、支架内以及血管内的血栓形成。（Niccoli G, Banning AP. Heparin dose during percutaneouscoronary intervention: how low dare we go Heart. 2002, 88:331-334; Marmur JD,Bullock-Palmer RP, Poludasu S, et al. Avoiding intelligence failur es in thecardiac catheterization laboratory: Strategies for the safe and rational useof dalteparin or enoxaparin during percutaneous coronary intervention. JInvasive Card iol. 2009, 21: 653-664.）但UFH用于PCI术中抗凝存在显而易见的不足，包括：1）生物利用度差，量效关系差，抗凝作用不稳定和不可预测性，因此需要监测活化凝血时间（ACT）；2）肝素诱导的血小板减少症的可能；3）不能抑制结合于血栓的凝血酶；4）停药后缺血事件增加。
鉴于此，需积极探索PCI术中其他抗凝方案，以获得更安全有效的抗凝效果。近年来关于LWMH（主要是依诺肝素）在PCI术中应用的临床证据不断涌现，因而其在PCI术中抗凝的应用从无到有，已引起极大关注。诸多研究对依诺肝素作出有益的探索，通过STEEPLE、SYNERGY和ExTRACT-TIMI 25研究（Montalescot G, White HD, Gallo R, Cohen M, StegPG, Aylward PE, et al. Enoxaparin versus unfractionated heparin in electivepercutaneous coronary intervention. N Engl J Med 2006, 355: 1006-1017; WhiteHD, DSc Kleiman NS, Mahaffey KW, et al. Efficacy and safety of enoxaparincompared with unfractionated heparin in high-risk patients with non–ST-segment elevation acute coronary syndrome undergoing percutaneous coronaryintervention in the Superior Yield of the New Strategy of Enoxaparin,Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. AmHeart J. 2006, 152: 1042-1050；Mehta SR, Granger CB, Eikelboom JW, et al.Efficacy and safety of fondaparinux versus enoxaparin in patients with acutecoronary syndromes undergoing percutaneous coronary intervention: resultsfrom the OASIS-5 trial. J Am Coll Cardiol. 2007; 50:1742-1751.），分别探讨依诺肝素在ACS患者急诊PCI和择期PCI术抗凝中的应用，使依诺肝素获得2007ACC/AHA的UA/NSTEMI指南、STEMI指南和2009中国冠状动脉介入治疗指南推荐，用于UA/NSTEMI和STEMI择期、急诊PCI术中抗凝。但临床对依诺肝素在PCI术中抗凝的导管内血栓问题仍有顾虑，因此其在PCI术中应用的方案有待进一步优化。
而迄今为止，欧美PCI指南明确将依诺肝素和UFH交叉应用列为PCI术中抗凝的Ⅲ类推荐（证据级别B），即PCI术前已接受LMWH抗凝的患者，在PCI术中不建议交叉应用UFH。（Task Force on Myocardial Revascularization of the European Society ofCardiology (ESC) and the European Association for Cardio-Thoracic Surgery(EACTS); European Association for Percutaneous Cardiovascular Interventions(EAPCI). Guidelines on myocardial revascularization. Eur Heart J. 2010, 31:2501-2555.）且尚无任何研究探讨择期PCI术中交叉应用“先UFH-后LMWH”方案的可行性。
发明内容
因此，基于现有技术的缺陷，本发明的目的在于提供一种用于冠脉介入手术中抗凝的组合产品。
为了实现上述目的，本发明提供了一种用于冠脉介入手术中抗凝的组合产品，其中，所述组合产品包含治疗有效量的普通肝素和治疗有效量的低分子量肝素，所述普通肝素和低分子量肝素为各自独立存在的试剂状态，所述普通肝素和低分子量肝素在冠脉介入手术操作中序贯给药予有需要的受试者。
根据本发明提供的组合产品，其中，所述组合产品为试剂盒。
根据本发明提供的组合产品，其中，所述低分子量肝素选自以下一种或多种：依诺肝素（Enoxaparin）、那曲肝素钙和达肝素钠。最优选为依诺肝素。
根据本发明提供的组合产品，其中，所述普通肝素的剂量以受试者体重计算为35~75 U/Kg，优选为40~60 U/Kg，最优选为50U/Kg。
根据本发明提供的组合产品，其中，所述低分子量肝素的剂量以受试者体重计算为0.5~1.0 mg/Kg，优选为0.6~0.8 mg/Kg，最优选为0.75mg/Kg。
根据本发明提供的组合产品，其中，当受试者进行择期冠状动脉介入手术时，所述组合产品中的所述普通肝素在进行冠脉造影前给药予有需要的受试者，所述低分子量肝素在进行冠脉造影后且进行冠状动脉介入手术前给药予有需要的受试者。优选地，冠脉造影前向所述受试者的介入导管内推注所述普通肝素50U/Kg，行冠状动脉介入手术之前向所述介入导管内补充所述依诺肝素0.75mg/Kg。
根据本发明提供的组合产品，其中，所述组合产品中，所述普通肝素和低分子量肝素给药时间间隔为20~40分钟，优选为30~35分钟。
根据本发明提供的组合产品，其中，所述组合产品还包括说明书。
根据本发明提供的组合产品，其中，所述普通肝素和低分子量肝素各自独立地为注射制剂。优选为静脉注射制剂、皮下注射制剂或通过导管动脉推注制剂。
本发明还提供了上述组合产品在制备用于冠脉介入手术中抗凝的药品或医疗产品中的应用。
具体地，本发明提供的用于冠脉介入手术中抗凝的组合产品的使用方法可以为：冠脉造影前给予所述受试者的介入导管内推注UFH50U/Kg，造影后决定行PCI则在PCI术前向所述介入导管内补充依诺肝素0.75mg/Kg。
本发明所提供的用于冠脉介入手术中抗凝的组合产品为临床择期PCI术提供更好、更安全的术中抗凝组合产品，从而减少患者痛苦和不便，有望改善患者预后，惠及广大冠心病患者，具有重要的社会、科学和经济价值。
具体实施方式
下面通过具体的实施例进一步说明本发明，但是，应当理解为，这些实施例仅仅是用于更详细具体地说明之用，而不应理解为用于以任何形式限制本发明。
本部分对本发明试验中所使用到的材料以及试验方法进行一般性的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的，但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚，在上下文中，如果未特别说明，本发明所用材料和操作方法是本领域公知的。
以下实施例中使用的试剂如下：
试剂：
UFH，购自常州千红生物制药厂；依诺肝素购自法国赛诺菲公司。
实施例1
本实施例用于说明本发明提供的用于冠脉介入手术中抗凝的组合产品及其使用方法，以及和传统的UFH抗凝方案的比较。
入选拟行择期 PCI 的冠心病患者 1600 例，随机化分组至UFH组（对照组，n=797）和“小剂量UFH-依诺肝素”序贯抗凝组（试验组，n=803）。所有入选患者行冠脉造影后决定继续予以PCI干预者进入随机化分组。参与本实施例1的冠心病患者基线资料和凝血指标具体如表1和表2。
一、给药方案：
UFH对照组：冠脉造影前于导管内推注UFH3000U，造影之后决定行PCI 术则补充UFH 至总量（含造影时用量）100U/Kg。
“小剂量UFH-依诺肝素”序贯抗凝组：使用本发明提供的用于冠脉介入手术中抗凝的组合产品，即冠脉造影前给予导管内推注UFH50U/Kg，造影后决定行PCI则导管内补充依诺肝素0.75mg/Kg。
二、检测指标
主要终点：30d时主要心脏不良事件（MACE）发生率（死亡、再发心梗、靶血管紧急血运重建或TIMI大出血）。
次要终点：PCI术中导管内血栓、术后48h内TIMI出血、1年时的MACE发生率。
安全性终点：住院期间TIMI大出血。
出血分级（TIMI）的定义为：大出血：颅内出血、出血导致血红蛋白下降≥5g/dl或HCT下降≥15%；小出血：自发性肉眼血尿、呕血、明显出血但血红蛋白下降≥3g/dl，但HCT下降＜15%；不重要出血：出血达不到上述标准。
指标监测：检测指标包括 PCI术前、术中和术后1h、6h、24h的活化部分凝血酶时间（APTT），TIMI出血事件发生率，术中导管内血栓及其相关事件发生率；各个监测时点的MACE发生率；PCI手术的即刻成功率；以及择期PCI患者住院期间和出院随访期间的其他各项常规检查。
三、统计学分析
数据管理使用EPI DATA 3.0录入软件，统计分析使用SPSS15.0统计软件。所有统计分析将在双侧、0.05显著性水平下进行。
尽管本发明已进行了一定程度的描述，明显地，在不脱离本发明的精神和范围的条件下，可进行各个条件的适当变化。可以理解，本发明不限于所述实施方案，而归于权利要求的范围，其包括所述每个因素的等同替换。
Claims (10)
1.一种用于冠脉介入手术中抗凝的组合产品，其特征在于，所述组合产品包含治疗有效量的普通肝素和治疗有效量的低分子量肝素，所述普通肝素和低分子量肝素为各自独立存在的试剂状态，所述普通肝素和低分子量肝素在冠脉介入手术操作中序贯给药予有需要的受试者。
2.根据权利要求1所述的组合产品，其特征在于，所述组合产品为试剂盒。
3.根据权利要求1或2所述的组合产品，其特征在于，所述低分子量肝素选自以下一种或多种：依诺肝素、那曲肝素钙和达肝素钠，最优选为依诺肝素。
4.根据权利要求1至3中任一项所述的组合产品，其特征在于，所述普通肝素的剂量以受试者体重计算为35~75 U/Kg，优选为40~60 U/Kg，最优选为50 U/Kg。
5.根据权利要求1至4中任一项所述的组合产品，其特征在于，所述低分子量肝素的剂量以受试者体重计算为0.5~1.0 mg/Kg，优选为0.6~0.8 mg/Kg，最优选为0.75 mg/Kg。
6.根据权利要求1至5中任一项所述的组合产品，其特征在于，当受试者进行择期冠状动脉介入手术时，所述组合产品中的所述普通肝素在进行冠脉造影前给药予有需要的受试者，所述低分子量肝素在进行冠脉造影后且进行冠状动脉介入手术前给药予有需要的受试者；优选地，冠脉造影前向所述受试者的介入导管内推注所述普通肝素50 U/Kg，行冠状动脉介入手术之前向所述介入导管内补充所述依诺肝素0.75 mg/Kg。
7.根据权利要求1至6中任一项所述的组合产品，其特征在于，所述组合产品中，所述普通肝素和低分子量肝素给药时间间隔为20~40分钟，优选为30~35分钟。
8.根据权利要求1至7中任一项所述的组合产品，其特征在于，所述组合产品还包括说明书。
9.根据权利要求1至8中任一项所述的组合产品，其特征在于，所述普通肝素和低分子量肝素各自独立地为注射制剂，优选为静脉注射制剂、皮下注射制剂或通过导管动脉推注制剂。
10.权利要求1至9中任一项所述的组合产品在制备用于冠脉介入手术中抗凝的药品或医疗产品中的应用。
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