房颤合并冠心病的抗栓策略

摘要：房颤合并冠心病在随着年龄的增长，发病率越来越高，需要对两种疾病同时治疗，目前的抗栓药物很多，如何把握和平衡有效抗凝及出血风险，如何个体化制定及调整房颤合并冠心病的抗栓方案，仍有待探索。

关键词：房颤；冠心病；抗栓治疗；急性冠脉综合征；经皮冠脉介入治疗

The Antithrombotic Strategies of Concomitant Atrial Fibrillation and Coronary Artery Disease

LI Xin-ru, QIU Chun-guang

(Department of Cardiology,The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,Henan,China)

Abstract：The coexisting atrial fibrillation(AF) and coronary artery disease(CAD) are prevalent in the elder, there are kinds of antithrombotic agents, how to balance the efficacy and safety, and how to choose the individualized antithrombotic regimen for patient with both AF and CAD, we need more evidence to support.

Key words：Atrial Fibrillation; Coronary Artery Disease; Antithrombotic therapy; Acute Coronary Syndrome ; Percutaneous Coronary Intervention.

房颤是最常见的心律失常之一，常常导致卒中和其他动脉栓塞，抗栓治疗已成为其治疗总策略的首位。临床上经常应用抗凝药如维生素K抑制剂及新型口服抗凝药来预防卒中和栓塞事件[1,2]。对于稳定性冠心病患者，临床上应用阿司匹林或氯吡格雷等抗血小板来预防冠脉事件[3,4]，而对于ACS（Acute Coronary Syndrome，急性冠脉综合征）及PCI（Percutaneous Coronary Intervention，经皮冠脉介入治疗）后的患者则建议应用双联抗血小板来预防冠脉事件[5,6]。目前的抗栓药物包括阿司匹林、ADP(Adenosine Diphosphate，二磷酸腺苷)受体抑制剂（氯吡格雷、普拉格雷、替格瑞洛）和口服抗凝药（华法林以及新型口服抗凝药达比加群、利伐沙班、阿哌沙班）。尤其是在>65岁的人群中，冠心病和房颤的发病率极高，约有1/3的房颤患者同时患有冠心病。目前很多大型随机对照研究都是分开研究冠心病和房颤的抗栓治疗方案，很少有证据是研究冠心病合并房颤的抗栓治疗。

1冠心病的抗栓治疗

1.1抗血小板药和维生素K抑制剂

1.1.1一级预防冠心病一级预防使用小剂量阿司匹林被证明是安全和有效的，但是只对于冠脉事件风险高的人群其获益大于风险[3,4,7,8]。低强度华法林（INR=1.5）也能在冠心病一级预防中也有效果，但是临床很少使用，毕竟阿司匹林使用方便。低强度华法林加阿司匹林两者联用会增加主要出血事件，而阿司匹林联合氯吡格雷并不改善一级预防的结局。

1.1.2二级预防对于已知稳定性冠心病患者，小剂量阿司匹林和氯吡格雷一样有效，两者联用能稍改善预后[4,8]。对于ACS患者，无论是否实施PCI，阿司匹林联合氯吡格雷会降低1年死亡和心梗事件。而目前很多试验是对比研究氯吡格雷、普拉格雷、替格瑞洛三者联合阿司匹林。心梗发生后，高强度华法林、中强度华法林联合阿司匹林及阿司匹林联合ADP受体抑制剂都能降低冠脉事件发生率[8,9]。

1.1.3择期PCI很多随机对照试验已经证实了PCI后阿司匹林联合氯吡格雷的优势，不建议单独应用华法林或者阿司匹林联合华法林。BMS(Bare Mental Stent，金属裸支架)双抗至少1个月，DES(Drug-eluting Stent，药物涂层支架)则要求12个月，新一代DES推荐的双抗时间可以缩短一些[10,11]。

1.2新型口服抗凝药有临床随机对照试验研究ACS患者应用新型口服抗凝药联合常规双抗的三联抗栓疗法的疗效和安全性。含有达比加群[12]的三联抗栓与双联抗血小板相比，6个月出血事件发生率增高，150mg bid 优于110mg bid。阿哌沙班的试验[13]中6个月主要出血事件发生率比安慰剂组高，2.5mg bid 与5mg bid相比无统计学差异。利伐沙班试验中[14]，10mg/d比安慰剂组的6月出血事件发生率高很多。这3个试验都是Ⅱ期临床试验，都没有获得理想的风险获益比。阿哌沙班的Ⅲ期临床试验[15]因过高的出血发生率提前终止。达比加群则因Ⅱ期临床结果让人失望根本没有进入Ⅲ期临床试验阶段[16]。只有利伐沙班在Ⅲ期临床试验[17]发现，利伐沙班联合双联抗血小板有良好的结果，无论是2.5mg bid还是5mg bid都能显著减少一级负荷终点（心源性死亡、心梗、卒中），但是也增加了主要出血结局，却未增加致死性出血风险。没有任何指南推荐新型口服抗凝药用于无房颤的ACS患者中。

2房颤的抗栓治疗

2.1华法林在非瓣膜病性房颤中，华法林比阿司匹林更能预防卒中的发生，其心血管获益确切[1,2,18]，但是阿司匹林的主要出血事件更少，因此临床上对低卒中风险的房颤患者使用阿司匹林，而高卒中风险的房颤患者服用华法林[1,18]，目前公认的预测房颤患者的卒中风险用CHADS2评分系统（Congestive heart failure, Hypertension, Age, Diabetes mellitus, Stroke/TIA2），卒中低危者用CHA2DS2-VASc评分(Congestive heart failure, Hypertension, Age≥75, Diabetes mellitus, Stroke/TIA , Vascular disease, Age 65-74,Sex category(female))更准确。如评分≥1则推荐口服抗凝药，年轻的没有任何卒中危险因素的暂不推荐任何抗栓治疗[1]。如今的临床试验显示新型口服抗凝药，如达比加群、利伐沙班、阿哌沙班在预防房颤相关性卒中的疗效不劣于华法林，而且更方便服用[1,10,36],如果有应用口服抗凝药指征时，2012ESC指南推荐选用新型口服抗凝药优于华法林（，A）[19]。

2.2新型口服抗凝药RE-LY研究[20]发现达比加群150mg bid会增加心梗发生率[21,22]，所以很多指南建议房颤合并冠心病者应用华法林优于达比加群[18]。至于达比加群是否能导致心梗、增加心血管风险，可能只是达比加群不能预防高危患者的心梗事件。ROCKET-AF[23]（利伐沙班VS华法林）、ARISTOTLE[24](阿哌沙班VS华法林)都发现Ⅹa因子抑制剂没有明显减少心梗及全因死亡。总之没有一个试验证实房颤患者服用新型口服抗凝药比华法林有额外的冠脉获益[36]。

3房颤与冠心病并存的情况

对于那些同时患有房颤和冠心病的患者，目前还没有随机对照研究明确提出最佳的抗栓方案。

3.1未知或稳定性冠心病一些指南共识提出，冠心病一级预防，对于CHADS2=0且年龄

3.2 ACS对于ACS患者，ACTIVE-W[25]对比研究了华法林VS阿司匹林联合氯吡格雷双联抗血小板，发现后者降低卒中风险欠佳，但是出血风险相当。达比加群的Ⅱ期临床试验就已拒之ACS门外。ATLAS ACS 2 - TIMI 51研究[15,36]发现，在ACS二级预防，利伐沙班是目前惟一在Ⅲ期临床研究获得良好结果的新型口服抗凝药，提示在标准双联抗板治疗基础上联用利伐沙班能进一步获益。2012 ESC STEMI指南[26]首次推荐低剂量利伐沙班2.5 mg bid用于STEMI患者抗凝治疗（Ⅱb，B）。

3.3 PCI在冠心病PCI合并房颤的患者，一定要选择双抗时，置入BMS比DES有优势，尤其是支架内血栓形成风险较高的患者。DES一般用于那些血管较细、长病变或分叉病变或糖尿病，但现实中总体DES置入的比例比BMS高[11]。WOEST试验[27]将口服抗凝药并实施PCI的随机分组，一部分应用三联抗栓，一部分用口服抗凝药联合氯吡格雷的双联抗栓，随访1年期间，发现两种方法的血栓事件无差异，但三联抗栓比双联抗栓累计出血风险要高，主要体现在消化道出血，但主要出血事件的差异无统计学意义。但是这个试验不是双盲的，且随访时间短。华法林联合阿司匹林的双联抗栓不能减少支架内血栓和其他临床时间，因此不推荐使用。PCI前口服抗凝药的桥接治疗安全性和有效性尚待论证，因此暂不推荐PCI围手术期中断口服抗凝药。

房颤抗凝常用的出血风险分层工具是HAS-BLED评分系统[31]（Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INRs, Elderly, Drugs or alcohol），比ATRIA评分[32]有更好的预测价值。

欧洲专家共识[33]建议：见表1。

而北美专家共识[34]则建议：见表2。

都建议含有阿司匹林的联合抗栓期间应用PPI(尤其是那些对CYP2C19活性影响最小的，如泮托拉唑)，避免联用非甾体类抗炎药，双联抗板时氯吡格雷优于普拉格雷或替格瑞洛[34,35]，不中断口服抗凝药，桡动脉入路优于股动脉入路，华法林优于新型口服抗凝药。暂时缺少更多支持性数据，只能认为欧洲或北美的共识是合理的。

对于近期ACS（无论是否PCI）、实施过PCI（无论是择期还是急诊），抗栓方案是根据卒中风险来选择，对于卒中风险相对较低者（CHADS2≤1），那么双联抗血小板即可，而卒中风险较高者（CHADS2≥2），则选择口服抗凝药加阿司匹林加氯吡格雷三联抗栓，数据表明纯获益，但问题是出血风险增加，其消化道出血风险是双联抗板的5倍，也有人建议即使出血风险高也应该坚持三联抗栓，如果出血风险特别高和或冠脉事件发生率确实低，那么推荐缩短三联抗栓的时限，并给与胃黏膜保护剂等减少消化道出血[28,29]。新一代DES甚至生物可降解支架让缩短三联抗栓时间变得可能[11,30]。目前没有公开发表的试验评价含有普拉格雷或替格瑞洛来三联抗栓的，但可以预测出血风险也都高。我们需要更多关于房颤合并冠心病患者的抗栓策略的随机试验数据。

参考文献：

[1]Hart RG, Pearce LA, Aguilar MA. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation[J].Ann Intern Med,2007,146(12):857-867.

[2]Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardi ology ( ESC),[J].Eur Heart J, 2010, 31 (19) : 2369- 2429.

[3]Caprie Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee[J].Lancet, 1996,348(9038): 1329-1339.

[4]Baigent C,Blackwell L, Antithrombotic Trialists Collaboration et al.Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials[J].Lancet, 2009,373 (9678): 1849-1860.

[5]Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study[J].Lancet, 2001,358 (9281) : 527-533.

[6]Kolh P. Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS), European Association for Percutaneous Cardiovascular Interventions (EAPCI), Guidelines on myocardial revascularization[J].Eur J Cardiothorac Surg,2010, 38 (suppl) : S1-52.

[7]Sanmuganathan PS, Ghahramani P, Jackson PR, et al.Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials[J].Heart, 2001,85 (3): 265-271.

[8]Vandvik PO, Lincoff AM, Gore JM,et al.Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines[J].Chest,2012, 141 (2 suppl) :e637S-e668S.

[9]Levine GN, Bates ER, Blankenship JC,et al. 2011ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report ofthe American College of Cardiology Foundation/American Heart Association task force on practice guidelines and the society forcardiovascular angiography and interventions[J].Circulation, 2011, 124(23):e574-651.

[10]Valgimigli M,Campo G, Monti M,et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial[J].Circulation,2012, 125 (16) : 2015-2026.

[11]Stefanini GG, Holmes DR Jr. Drug-eluting coronary-artery stents[J].N Engl J Med, 2013,368 (3) : 254-265.

[12]Oldgren J, Budaj A, Granger CB, Khder Y, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial[J].Eur Heart J,2011, 32 (22) : 2781-2789.

[13]Alexander JH, Lopes RD, James S, et al.Apixaban with antiplatelet therapy after acute coronary syndrome[J].N Engl J Med,2011, 365 (8): 699-708.

[14]Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial[J].Lancet,2009, 374 (0683): 29-38.

[15]Appraise Steering Committee Investigators, Alexander JH, Becker RC, Bhatt DL, et al.Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial[J].Circulation, 2009,119 (22): 2877-2885.

[16]Oldgren J, Budaj A, Granger CB, et al, for the RE-DEEM Investigators. Dabigatran vs. Placebo in patients with acute coronary syndromes on dual antiplatelet therapy:a randomized, double-blind, phase-II trial[J].Eur Heart J,2011,32(22):2781-2789.

[17]Gibson CM, Mega JL, Burton P, et al. Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome thrombolysis in myocardial infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome[J].Am Heart J,2011,161(5):815-821.e6.

[18]Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association[J].Eur Heart J, 2012,33 (10): 2719-2747.

[19]Ruff CT, Giugliano RP, Braunwald E,et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials[J].Lancet,2013 (13)s0140-6736, 62343-0.

[20]Hart RG, Diener HC, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial[J].Circulation, 2012,125 (5) : 669-676.

[21]Eikelboom JW, Weitz JI. Anticoagulation therapy. Dabigatran and risk of myocardial infarction[J].Nat Rev Cardiol,2012, 9 (5) : 260-262.

[22]Mak KH. Coronary and mortality risk of novel oral antithrombotic agents: a meta-analysis of large randomised trials[J].BMJ Open, 2012,2 (5): e001592.

[23]Patel MR, Mahaffey KW, Garg J,et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[J].N Engl J Med,2011, 365 (24) : 883-891.

[24]Christopher B. Granger, John H. Alexander, et al.Apixaban versus warfarin in patients with atrial fibrillation[J].N Engl J Med ,2011,365(11):981-992.

[25]Connolly S, Pogue J, Hart R, et al.ACTIVE Writing Group of the ACTIVE Investigators ACTIVE Writing Group of the ACTIVE Investigators Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE-W): a randomised controlled trial[J].Lancet. 2006;367(9526):1903-1912.

[26]Steg G, James S, Atar D, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC)[J].Eur Heart J,2012, 33(20):2569-619.

[27]Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoiagulant therapy and undegoing percutaneous cornary intervention: an open-label, randomised, controlled trial[J].Lancet, 2013,381 (9872) : 1107-1115.

[28]Fosbol EL, Wang TY, Li S, al.Safety and effectiveness of antithrombotic strategies in olderpatients with atrial fibrillation and non-ST elevation myocardial infarction[J].Am Heart J,2012, 163 (4) : 720-728.

[29]Lamberts M, Olesen JB, Ruwald MH,et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study[J].Circulation, 2012,126 (10) : 1185-1193.

[30]Kim BK, Hong MK, Shin DH,et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation)[J].J Am Coll Cardiol, 2012;60 (15) : 1340-1348.

[31]Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey[J].Chest 2010,138(5): 1093-1100.

[32]Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study[J].Am Coll Cardiol,2011;58(4):395-401.

[33]Lip GY, Huber K, Andreotti F, et al.European Society of Cardiology Working Group on Thrombosis European Society of Cardiology Working Group on Thrombosis Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting[J].Thromb Haemost. 2010,1031(1):13-28.

[34]Faxon DP, Eikelboom JW, Berger PB, et al.Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective[J].Thromb Haemost, 2011, 106 (4) : 572-584.

[35]Huber K, Airaksinen KJ, Cuisset T,et al. Antithrombotic therapy in patients with atrial fibrillation undergoing cornary stenting: similarities and dissimilarities between North America and Europe[J].Thromb Haemost, 2011,106 (4) : 569-571.

[36]袁祖贻,胡大一. 新型口服抗凝药物在心血管领域的研究进展[J.中华心血管病杂志, 2013, 41(11):988-991.编辑/哈涛