抗栓治疗新进展 河南省人民医院心内科 陈岩.

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1 抗栓治疗新进展 河南省人民医院心内科 陈岩

2 抗凝治疗新进展 达比加群 利伐沙班 阿哌沙班 抗血小板治疗新进展 新型抗血小板药物 阿司匹林用于肿瘤预防 2

3 新型抗凝药物的研发 作用于单靶点的药物（Xa因子）成为研发的热点！ 利伐沙班 阿哌沙班 达比加群 TTP889 TF/VIIa
IX IXa VIIIa Va II 纤维蛋白 纤维蛋白原 Bates Br J Haematol 2006 TTP889 TFPI (tifacogin) NAPc2 口服直接Xa因子抑制剂 利伐沙班 阿哌沙班 DU-176b YM150 注射间接Xa因子抑制剂 磺达肝癸钠 Idraparinux 达比加群 APC sTM (ART-123) Reference Bates S, Weitz J. The status of new anticoagulants. Br J Haematol 2006;134(1):3-19 新型抗凝药物的研发，实际上按照理想抗凝药物为指导标准的， 它们作用于凝血级联反应中的不同靶点。从研发的品种来看， 我们可以看到新产品更加集中在单靶点药物的研发，如IIa和Xa 因子的研发。尤其是口服直接Xa因子抑制剂。当前这些新产品 中，只有达比加群（直接IIa抑制剂）和利伐沙班（直接Xa因子 抑制剂）上市了。而在中国，仅有利伐沙班上市了。但两者均 被批准用于关节置换术后VTE的预防。 关于IIa因子抑制剂和Xa因子谁更优？ 这是一个很有意思的话题。从凝血级联反应图中，我们可看到，Xa因子位于内源性和外源性凝血途径的交汇点，而IIa因子位于血栓形成的前一步。因此，很 多人认为IIa抑制会更好，因为这个靶点位于下游，IIa抑制对血栓形成会有更直接的抑制作用。其实不然。 1.IIa虽然位于下游位置，但是抑制Xa因子会更有效，因为每分子Xa因子会产生约1000分子的凝血酶（IIa),理论上抑制Xa因子比抑制IIa因子具有更强的控制纤维蛋白生成的能力(我下午和您沟通的过程中，这个问题描述有点错误，特此更正。抱歉，说实话，当时有点记不清具体内容了砭妹挥薪彩稣夥矫娴哪谌萘耍海。而且抑制Xa不是灭活凝血酶的催化活性，而是减少凝血酶的生成，因此不会影响已生成的凝血酶对止血系统的正常调节功能，包括细胞增值和血小板激活。相比于IIa因子，Xa因子的作用更单纯。已知Xa因子的功能仅有促凝和促炎，而IIa除了促凝外，还具有抗凝，纤维蛋白溶解以及抗炎茸饔谩Ｒ虼耍啾扔谝种芚a因子，抑制IIa因子会有更多不确定的作用。 2.从关节置换术后VTE预防的III期临床试验的角度看，直接IIa因子抑制剂达比加群同当前的标准方案依诺肝素（克赛）相比，仅是疗效相当，安全性也相当。但直接Xa因子抑制剂的疗效均优于依诺肝素（克赛），两者安全性相当。在VTE预防领域，随着对Xa抑制的增强，疗效会增强。赩TE预防领域，疗效从强到弱排列顺序为：利伐沙班～磺达肝素>低分子肝素＝达比加群>普通肝素。 3.从急性DVT治疗的角度看，达比加群与利伐沙班的疗效和安全性均与标准治疗方案依诺肝素/VKA相当。但是利伐沙班能提高DVT患者的临床净获益。 而且达比加群用于急性DVT的治疗同样是需要使用注射用抗凝药物用于初始治疗，5天后转为达比加群口服150mg，bid。 4.目前新型抗凝药物之间没有头对头直接对比的资料。 作用于单靶点的药物（Xa因子）成为研发的热点！ 3

4 达比加群：RE-LY 研究 华法林 达比加群 R 非瓣膜性房颤 （至少一项卒中危险因素） 主要目标：不劣于华法林 平均随访2年（1-3年）
(INR ) N=6000 达比加群 110 mg b.i.d. 150 mg b.i.d. 44个国家 951个中心 R 主要目标：不劣于华法林 平均随访2年（1-3年） 主要终点：卒中+外周栓塞

5 达比加群：RE-LY 研究 44个国家，951个临床中心。入选的房颤患者必须具备以下至少一条危险因素：既往卒中或TIA史、LVEF＜49%、NYHA＞II极或6个月内有心衰症状、 年龄≥75岁或65至74岁之间并伴有糖尿病、高血压、冠心病。最终入选人群中CHADS2 平均2.1分，≥ 2者约占2/3。主要终点是卒中和体循环栓塞，安全终点是严重的出血. 共入选18113人。平均随访2年。Dabigatran分为110mg每日两次组和150mg每日两次组。 结果卒中和体循环栓塞发生率110mg组和华法林组相同，150mg组低于华法林 严重出血发生率110mg组低于华法林组，150mg组与华法林相同 NEJM. 2009: 1139 5

6 急性深静脉血栓(DVT)患者 29个国家，228个中心，2539例
RECOVER研究 急性深静脉血栓(DVT)患者 29个国家，228个中心，2539例 肝素抗凝9天 随机分组 达比加群 150mg po bid 华法林组 INR 2-3 RECOVER:达比加群（商品名Pradaxa，德国勃林格殷格翰公司生产），已被40个国家批准以Pradaxa(商品名)上市，用于接受全膝关节或全髋关节置换患者VTE的一级预防。达比加群酯在美国未被批准用于临床。 Background The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism. Methods In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (interquartile range, 8 to 11), we compared oral dabigatran, administered at a dose of 150 mg twice daily, with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Safety end points included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests. Results A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI], −0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (P = 0.05). Conclusions For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring. (ClinicalTrials.gov number, NCT ) 主要终点：6个月内VET复发或致死性肺栓塞 安全终点：出血事件、急性冠脉综合征、其他不良事件 RE-COVER Study Group, NEJM 2009 6

7 RECOVER研究 达比加群与华法林疗效及安全性相当
随访六个月 主要终点：复发VTE或致死性肺栓塞，达比加群组中有2.4%的患者，华法林组中有2.1%的患者。每组有一例死亡。 大出血：达比加群组为1.6%，华法林组为1.9%。 所有出血事件：达比加群组为5.6%，华法林组为8.8%。 达比加群组中4例患者发生MI，华法林组2例患者发生MI，没有显著差异（p=0.69）。 唯一被报道的不良反应为消化不良，达比加群组略多于华法林组。 结论：两者预防DVT复发疗效及安全性类似，但Dibigatran不需要实验室监测 RE-COVER Study Group, NEJM 2009 7

8 2010年抗凝治疗领域新进展 利伐沙班 EINSTEIN DVT III期临床研究结果发布 利伐沙班 ROCKET AF研究结果发布
阿哌沙班 Averroes III期临床研究结果发布 阿哌沙班APPRAISE-2 III期临床试验因出血事件的增多提前终止

9 利伐沙班EINSTEIN DVT III期临床研究 ——急性DVT的治疗
15 mg bid DVT(不伴症状性PE) N=3449 利伐沙班 第1天 第 21天 依诺肝素 1.0 mg/kg，一日两次，至少5天, 在48小 时以内加用VKAs，目标INR 2.5 (INR 范围 2–3) 治疗疗程 3，6或12月 20 mg od 30天的观察期 R 试验目的：急性症状性DVT(不伴PE)，利伐沙班单药治疗疗效不劣于当前的标准治疗依诺肝素/VKA 2010 ESC

10 主要疗效终点 利伐沙班与MWH/VKAs疗效相当
（n=1731） 依诺肝素/VKA （n=1718) HR ％CI n (%) (%） VTE的复发率（％） 36 (2.1) 51 (3.0) 0.68 （ ） P<0.0001 1.00 2.00 0.44 1.04 0.68 利伐沙班 优效 利伐沙班 非劣效 利伐沙班 劣效 Hazard Ratio P=0.076，优效 （双边检验） P<0.0001，非劣效（单边检验）

11 主要安全性终点 利伐沙班与LMWH/VKAs出血事件发生率相当
（n=1718） 依诺肝素/VKA （n=1711) HR 95％CI P值 n (%) (%） 大出血和临床相关的非大出血（％） 139 (8.1) 138 0.97 P=0.77 大出血事件（％） 14 (0.8) 20 (1.2) 2010 ESC

12 次要安全性终点 利伐沙班较LMWH/VKAs显著提高临床净获益
(%) 依诺肝素/VKA HR (95％CI) 临床净获益：主要疗效终点＋大出血（％） 2.9 4.2 0.67 （ ) 总死亡率（％） 2.2 ( ) 心血管事件（％） 0.7 0.8 0.79 ( ) 每月监测肝脏功能，无肝脏损伤的迹象 2010 ESC

13 ROCKET-AF研究设计 主要终点：卒中或外周栓塞 房颤（CHADS2高于2分） 每月监测，遵循指南标准 Rivaroxaban
G w_script.ppt 4/6/2017 8:44:32 PM ROCKET-AF研究设计 房颤（CHADS2高于2分） Rivaroxaban 随机/双盲 /双模拟 (n ~ 14,000) 华法林 20 mg/d 15 mg/Cr Cl ml/min INR 目标值2.5 ( ) 每月监测，遵循指南标准 主要终点：卒中或外周栓塞 AHA 2010

14 基线资料 CHADS2 积分 3.48 3.46 利伐沙班 (N=7081) 华法林 (N=7090) 2 (%) 3 (%) 4 (%)
5 (%) 6 (%) 3.48 13 43 29 2 3.46 44 28 12 VKA服用史 (%) 62 63 充血性心衰 (%) 高血压 (%) 90 91 糖尿病 (%) 40 39 卒中/TIA/栓塞史(%) 55 MI史(%) 17 18 AHA 2010

15 主要疗效终点 卒中和非中枢神经系统栓塞 华法林 事件发生率(%) 利伐沙班 利伐沙班 华法林 事件发生率% 1.71 2.16
HR (95% CI): 0.79 (0.66, 0.96) P（非劣性）: <0.001 天 No. at risk: 利伐沙班 华法林 AHA 2010

16 主要疗效终点 卒中和非中枢神经系统栓塞 利伐沙班好 华法林好 ITT=intention to treat 利伐沙班 华法林
利伐沙班 华法林 Event Rate HR (95% CI) P On Treatment N= 14,143 1.70 2.15 0.79 (0.65,0.95) 0.015 ITT N= 14,171 2.12 2.42 0.88 (0.74,1.03) 0.117 利伐沙班好 华法林好 ITT=intention to treat AHA 2010

17 主要次级疗效终点 基于完成治疗人群分析; 发生率为每100病人年 0.034 卒中类型 出血 缺血 不明原因
利伐沙班 华法林 事件发生率 HR (95% CI) P-value CV死亡，卒中，栓塞 3.11 3.63 0.86 (0.74, 0.99) 0.034 卒中类型 出血 缺血 不明原因 0.59 (0.37, 0.93) 0.94 (0.75, 1.17) 0.65 (0.25, 1.67) 非CNS栓塞 0.04 0.19 0.23 (0.09, 0.61) 0.003 MI 0.91 1.12 0.81 (0.63, 1.06) 0.121 全因死亡率 血管源性 非血管源性 不明原因 0.85 (0.70, 1.02) 0.89 (0.73, 1.10) 0.63 (0.36, 1.08) 0.75 (0.40, 1.41) 基于完成治疗人群分析; 发生率为每100病人年

18 主要次级疗效终点 基于倾向性治疗人群分析; 发生率为每100病人年 利伐沙班 华法林 事件发生率 HR (95% CI) P-value
血管性死亡, 卒中，栓塞 4.51 4.81 0.94 (0.84, 1.05) 0.265 卒中类型 出血 缺血 原因不明 0.26 1.62 0.15 0.44 1.64 0.14 0.58 (0.38, 0.89) 0.99 (0.82, 1.20 1.05 (0.55, 2.01) 0.012 0.916 0.871 非CNS栓塞 0.16 0.21 0.74 (0.42, 1.32 0.308 MI 1.02 1.11 0.91 (0.72, 1.16) 0.464 全因死亡率 血管源性 非血管源性 原因不明 4.52 2.91 1.15 0.46 4.91 3.11 1.22 0.57 0.92 (0.82, 1.03) 0.94 (0.81, 1.08) 0.94 (0.75, 1.18) 0.80 (0.57, 1.12) 0.152 0.350 0.611 0.195 基于倾向性治疗人群分析; 发生率为每100病人年

19 ROCKET-AF 总结 疗效: 利伐沙班预防房颤卒中及非CNS栓塞不劣于华法林 对于完成治疗的AF，利伐沙班疗效优于华法林
基于倾向性治疗分析，利伐沙班不劣于华法林 安全性: 两组出血及不良事件发生率类似 利伐沙班颅内出血及致命性出血发生率低于华法林 结论 对于中高危房颤，利伐沙班已被证实可替代华法林

20 不适合或不愿意服用华法林的卒中高危AF患者
阿哌沙班：AVERROES trial 不适合或不愿意服用华法林的卒中高危AF患者 随机、双盲 阿哌沙班 5mg po bid 阿司匹林 81-324mg qd 研究目的：比较Apixaban与阿司匹林预防房颤患者卒中的疗效与安全性 主要终点：首次出现的缺血性卒中、出血性卒中或全身性栓塞/36月 预计入选：5600例；研究启动：2007年9月；预计完成：2010年8月 由于阿哌沙班明显优于阿司匹林，试验提前终止 初步结果已于2010年8月30日在ESC年会上公布 Bristol-Myers Squibb/Pfizer A Phase III Study of Apixaban in Patients With AF The purpose of this clinical research study is to learn if apixaban is more effective than Acetylsalicylic Acid (ASA) in preventing strokes associated with subjects who have atrial fibrillation. The safety of this treatment will also be studied. 2010 ESC 20

21 阿哌沙班预防卒中和非卒中栓塞优于阿司匹林
AVERROES trial 阿哌沙班预防卒中和非卒中栓塞优于阿司匹林 0.05 0.03 0.01 0.0 3 6 9 12 18 21 ASA Apixaban P ＜ 0.001 月 ASA Apix 累积风险 54% AVERROES是一项随机双盲试验，旨在房颤患者中比较阿匹沙班和阿司匹林的疗效。入选全球522所医院的5600例房颤患者（平均年龄70岁，具有≥1项卒中危险因素），患者因难以控制治疗效果、出血风险增加、拒绝服用华法林等原因不适合维生素K拮抗剂（VKA）治疗。将患者随机分为阿匹沙班组（5 mg BID，部分患者2.5mg BID）和阿司匹林组（ mg)。主要疗效终点是卒中和系统性栓塞，主要安全性终点是严重出血。次要和三级终点是卒中、系统性栓塞、心肌梗死、血管性死亡和全因死亡。 2010 ESC 21

22 APPRAISE-2试验 阿哌沙班增加ACS出血风险
计划10800例 阿哌沙班& 单或双联抗血小板 安慰剂& R 主要终点: 死亡, MI, 缺血性卒中；安全终点：大出血 在入选了7500例患者时，由于阿哌沙班组出血风险明显高 于对照组，该试验提前终止 阿哌沙班的其它研究仍在继续进行 Bristol-Myers Squibb and Pfizer

23 阿哌沙班 ARISTOTLE trial 合并卒中高危因素的AF患者 Apixaban 5mg po bid 华法林 目标INR2-3
研究目的：比较预防高危房颤患者卒中的疗效与安全性 主要终点：明确的卒中或全身性栓塞 预计入选：18183例 研究启动：2006年12月；预计完成：2011年4月 A Phase 3, Active (Warfarin) Controlled, Randomized, Double-Blind, Parallel Arm Study to Evaluate Efficacy and Safety of Apixaban in Preventing Stroke and Systemic Embolism in Subjects With Nonvalvular Atrial Fibrillation 23

24 目 录 抗凝治疗新进展 达比加群 利伐沙班 阿哌沙班 抗血小板治疗新进展 新型抗血小板药物 阿司匹林可用于肿瘤预防 24

25 新型抗血小板药物发展迅速 普拉格雷 替卡格雷 坎格雷拉 依利格雷 蛋白酶活化受体1(PAR-1)拮抗剂 SCH-530348 E5555
ADP P2Y12受体拮抗剂 TXA2受体拮抗剂 S18886 普拉格雷 替卡格雷 坎格雷拉 依利格雷 Am Heart J.2010;160:595

26 荟萃分析 新型ADP P2Y12受体拮抗剂优于氯吡格雷
普拉格雷 替卡格雷 坎格雷拉 依利格雷 荟萃分析 新型ADP P2Y12受体拮抗剂优于氯吡格雷 死亡 严重不良事件 P=0.008 P=0.003 支架内血栓 P<0.001 JACC.2010;56;

27 普拉格雷较氯吡格雷显著降低ACS患者PCI术后缺血性事件发生率
TRITON-TIMI 38试验 普拉格雷较氯吡格雷显著降低ACS患者PCI术后缺血性事件发生率 行PCI的ACS的患者13,000例 15个月 主要疗效终点* HR=0.81 P＜0.001 氯吡格雷 12.1% 10 9.9% 事件率 普拉格雷 （%） 5 重要安全终点** HR=1.32 P=0.03 普拉格雷 2.4% 1.8% 氯吡格雷 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 （天） *心源性死亡、非致死性心肌梗死或非致死性脑卒中 **与冠脉桥血管无关的TIMI大出血 N Engl J Med 2007;357: 27 27

28 普拉格雷显著增加出血事件 TRITON-TIMI 38试验 15个月时TIMI出血终点 NNH=167 事件率（%） 0.03 0.01
2.4 1.8 （N=6716） 事件率（%） 1.4 （N=6741） 1.1 0.9 0.9 0.4 0.3 0.3 0.1 TIMI 大出血 生命危险 非致死性 致死性 颅内出血 HR 0.32 1.52 1.25 4.19 1.12 P 0.03 0.01 0.23 0.002 0.74 N Engl J Med 2007;357: 28 28

29 替卡格雷较氯吡格雷显著降低 缺血性事件发生率
PLATO试验 替卡格雷较氯吡格雷显著降低 缺血性事件发生率 复合终点：心血管死亡，心肌梗死，或脑卒中 8 9 10 11 12 13 2 3 4 5 6 7 1 氯吡格雷 11.7 替卡格雷 16% 9.8 累积发生率（%） HR=0.84（95%CL： ）；P<0.001 NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;randomised within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,then 75 mg qd maintenance;(additional 300 mg allowed pre PCI) Ticagrelor180 mg loading dose, then90 mg bid maintenance;(additional 90 mg pre-PCI) 6–12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding 360 300 240 180 120 60 随机后的天数 发生风险的人数 氯吡格雷 9291 8521 8362 8124 6650 5096 4047 替卡格雷 9333 8628 8460 8219 6743 5161 4147 N Engl J Med. 2009;361: 29 29

30 替卡格雷较氯吡格雷安全性无差异 PLATO试验 P值:NS 事件率（%）/年 PLATO 大出血 TIMI 输入红细胞 PLATO 生命
危险/致死性出血 致死性出血 N Engl J Med. 2009;361: 30 30

31 阿司匹林是抗血小板治疗的基础

32 2010ESC血运重建指南 推荐普拉格雷、替卡格雷用于治疗ACS
非ST段抬高心肌梗死 阿司匹林I,C 氯吡格雷I,C 普拉格雷IIa，B 替卡格雷I,B ST段抬高心肌梗死 阿司匹林I,B 普拉格雷I,B

33 目 录 抗凝治疗新进展 达比加群 利伐沙班 阿哌沙班 抗血小板治疗新进展 新型抗血小板药物 阿司匹林可用于肿瘤预防 33

34 阿司匹林降低所有癌症患者死亡风险21% 阿司匹林 vs.安慰剂对全部受试者癌症死亡风险的作用 因癌症死亡 风险比 阿司匹林组 对照组
8项随机研究，共25570例患者，674例癌症死亡 Lancet.Published Online December 7, 2010 34

35 阿司匹林降低所有实体癌20年死亡风险20% HR 0.80, 95%CL 0.72-0.88, p<0.001
3项研究，阿司匹林vs.安慰剂对任意实体瘤20年死亡风险的作用 25 20 降低 20% HR 0.80, 95%CL , p<0.001 15 10 5 5 10 15 20 至死亡年数 7595 5064 6967 4681 6185 4167 5217 3503 2981 1692 风险数目 阿司匹林 对照组 Lancet.Published Online December 7, 2010 35

36 阿司匹林降低 结肠癌发病率及死亡率 长期服用阿司匹林（75-1200 mg）vs对照组 降低的风险（%） 发病率 死亡率
N=278 N=174 P=0.02 P=0.005 24% 35% 该项研究共纳入BDAT、TPT、SALT 、UK-TIA四项阿司匹林随机对照实验，总计14 033例患者，平均治疗时间为6年，平均随访时间18.3年。结果显示：长期服用阿司匹林可显著降低患者结肠癌风险率，结肠癌发病率降低24%，死亡率降低35%。 纳入BDAT、TPT、SALT 、UK-TIA四项研究14 033例患者，平均治疗6年，平均随访18.3年 Lancet.2010; 376(9754):1741 36

37 患者获益随治疗时间延长而增加 低剂量阿司匹林（75-300 mg）vs对照组
发病率 死亡率 n/N HR P 所有患者 196/8073 0.75 0.02 130/8073 0.61 0.005 治疗时间≥2.5年 185/7383 0.69 0.003 119/7383 0.54 0.001 治疗时间≥5年 135/5077 0.62 91/5077 0.48 该研究纳入TPT、SALT 、UK-TIA(阿司匹林300mg组)三项低剂量阿司匹林（75-300mg）随机对照试验中预定治疗时间≥2.5年和≥5年的患者。 与对照组相比，低剂量阿司匹林（ mg）治疗时间延长，患者获益进一步增加，治疗时间≥2.5年与≥5年患者发病率风险分别为0.69、0.62；死亡率风险分别为0.54、0.48. 纳入TPT, SALT , UK-TIA(阿司匹林300mg组)三项试验中预定治疗时间≥2.5年和≥5年的患者 Lancet.2010; 376(9754):1741

38 Professor Peter Rothwell, John Radcliffe Hospital, Oxford, and University of Oxford, UK, noted that “previous guidelines have rightly cautioned that in healthy middle aged people the small risk of bleeding on aspirin partly offsets the benefit from prevention of strokes and heart attacks, but the reductions in deaths due to several common cancers will now alter this balance for many people.” 英国牛津大学教授Peter Rothwell解释道：既往的指南已经正确的提示，健康的中年人使用阿司匹林时，微小出血风险仅会部分抵消预防卒中和心脏病发作带来的获益，但是对许多人而言由于阿司匹林降低几个常见癌症的死亡，将进一步增加受益，降低风险。 Lancet.Published Online December 7, 2010

39 华法林的应用历史 二十世纪三十年代，美国Wisconsin大学的Karl Link从腐败的甜三叶草（马草）中分离出了双香豆素，家畜吃了这种物质会诱发出血性疾病 华法林开始注册为老鼠药-杀鼠灵，使鼠体内出血而致死 三周内灭鼠率可达90% NEJM 2003;349:1762 39

40 华法林预防房颤脑卒中临床试验

41 阿司匹林预防房颤脑卒中临床试验

42 基因测试指导华法林剂量选择 基因测定结合年龄、性别、体重决定初始华法林剂量 ACCP8th不推荐使用药物基因测定指导华法林剂量
两组监测INR的频率相同 Background—Pharmacogenetic-guided dosing of warfarin is a promising application of “personalized medicine” but has not been adequately tested in randomized trials. Methods and Results—Consenting patients (n206) being initiated on warfarin were randomized to pharmacogeneticguided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1 C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses (P0.001), resulting in smaller (P0.002) and fewer (P0.03) dosing changes and INRs (P0.06). However, percent out-of-range INRs (pharmacogenetic30.7%, standard33.1%), the primary end point, did not differ significantly between arms. Despite this, when restricted to wild-type patients (who required larger doses; P0.001) and multiple variant carriers (who required smaller doses; P0.001) in exploratory analyses, results (pharmacogenetic29%, standard39%) achieved nominal significance (P0.03). Multiple variant allele carriers were at increased risk of an INR of 4 (P0.03). Conclusions—An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes. (Circulation. 2007;116: ) 基因测定结合年龄、性别、体重决定初始华法林剂量 ACCP8th不推荐使用药物基因测定指导华法林剂量 Anderson, Circulation.2007:2563 42

43 卒中危险分层 ——CHADS 2 计分 危险因素 记分 近期心衰史 CHF 1 高血压病史 HP ≥ 75岁 AGE 糖尿病 DM
危险因素 记分 近期心衰史 CHF 高血压病史 HP ≥ 75岁 AGE 糖尿病 DM 脑卒中TIA Stroke 1 2 卒中危险分层 ——CHADS 2 计分 New method of predicting stroke in heart patients St. Louis, June 13, 2001 — Researchers at Washington University School of Medicine in St. Louis have developed a formula to predict the risk of stroke in patients with an irregular heart rhythm called atrial fibrillation. “Our hope is that this new classification scheme will help physicians select the appropriate course of treatment for patients with atrial fibrillation,” says Brian F. Gage, M.D., who led the study. Gage is assistant professor of medicine at the School of Medicine and medical director of Barnes-Jewish Hospital’s blood thinner clinic. The results are published in the June 13 issue of the Journal of the American Medical Association. Patients with atrial fibrillation, an irregular, uncoordinated contraction of heart muscles, are estimated to have a fivefold increased risk of stroke. A blood thinner called warfarin sodium (sold as Coumadin® and others) often is used to reduce this risk, but the drug itself can cause hemorrhage and other side effects. It also is more expensive and more difficult to administer and monitor than the alternative treatment, aspirin. To help predict when the benefits of warfarin outweigh the risks, two earlier studies completed by two other research groups determined independent factors that significantly increase the risk of stroke. However, the studies reached somewhat different conclusions: The Atrial Fibrillation Investigators (AFI) found that stroke risk correlated with prior stroke, advanced age, hypertension and diabetes; the Stroke Prevention and Atrial Fibrillation (SPAF) team found that prior stroke, blood pressure, recent heart failure and the combination of being over 75 years old and female increased the risk of stroke. “The two predictor models were helpful, but discrepancies between them sometimes led to confusion,” says Gage. “We needed a simple, uniform system to help select warfarin for patients at moderate or high risk of stroke, while avoiding this potentially dangerous blood thinner in low-risk patients.” So Gage and colleagues combined the factors from both models and developed a points system called CHADS2, an acronym for the five factors: Congestive heart failure, Hypertension, Age, Diabetes and Stroke. Since both the AFI and SPAF found that a history of stroke is the best predictive factor, it was given a value of two points, delineated by the “2” at the end of the mnemonic. The other factors each are allocated one point. Patients therefore are assigned a score ranging from 0 to 6. In general, the researchers suggest prescribing warfarin to patients with a CHADS2 rating of one or greater, depending on the patient’s preferences and risk of hemorrhage. In collaboration with Peer Review Organizations representing seven states, the team obtained data from 1,733 Medicare beneficiaries aged 65 to 95 years. They followed each patient for an average of 1.2 years and assembled a National Registry of Atrial Fibrillation (NRAF). They then compared the predictive value of each of the three models — CHADS2, AFI and SPAF. The AFI and SPAF schemes both predicted stroke better than chance, but CHADS2 yielded significantly more accurate results than either of these models. In addition, the risk of stroke as estimated using CHADS2 ranges from less than two percent to roughly 18 percent. Both AFI and SPAF include only three categories — low, moderate and high risk — with stroke risk ranging from roughly one percent to ten percent. “Having a wider range of scores provides a more quantitative approach to predicting stroke, which is very helpful,” explains Gage. “For example, even for high-risk patients, it’s important to know how high their score is so that you can take extra precautions if necessary during future surgeries and other medical treatments.” Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke. Journal of the American Medical Association, 285(22), , June 13, 2001. Funding from the Agency for Healthcare Research and Quality supported this research. The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Healthcare Validation of Clinical Classification Schemes for Predicting Stroke Results From the National Registry of Atrial Fibrillation Brian F. Gage, MD,MSc; Amy D. Waterman, PhD; William Shannon, PhD; Michael Boechler, PhD; Michael W. Rich, MD; Martha J. Radford, MD JAMA. 2001;285: Context  Patients who have atrial fibrillation (AF) have an increased risk of stroke, but their absolute rate of stroke depends on age and comorbid conditions. Objective  To assess the predictive value of classification schemes that estimate stroke risk in patients with AF. Design, Setting, and Patients  Two existing classification schemes were combined into a new stroke-risk scheme, the CHADS2 index, and all 3 classification schemes were validated. The CHADS2 was formed by assigning 1 point each for the presence of congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and by assigning 2 points for history of stroke or transient ischemic attack. Data from peer review organizations representing 7 states were used to assemble a National Registry of AF (NRAF) consisting of 1733 Medicare beneficiaries aged 65 to 95 years who had nonrheumatic AF and were not prescribed warfarin at hospital discharge. Main Outcome Measure  Hospitalization for ischemic stroke, determined by Medicare claims data. Results  During 2121 patient-years of follow-up, 94 patients were readmitted to the hospital for ischemic stroke (stroke rate, 4.4 per 100 patient-years). As indicated by a c statistic greater than 0.5, the 2 existing classification schemes predicted stroke better than chance: c of 0.68 (95% confidence interval [CI], ) for the scheme developed by the Atrial Fibrillation Investigators (AFI) and c of 0.74 (95% CI, ) for the Stroke Prevention in Atrial Fibrillation (SPAF) III scheme. However, with a c statistic of 0.82 (95% CI, ), the CHADS2 index was the most accurate predictor of stroke. The stroke rate per 100 patient-years without antithrombotic therapy increased by a factor of 1.5 (95% CI, ) for each 1-point increase in the CHADS2 score: 1.9 (95% CI, ) for a score of 0; 2.8 (95% CI, ) for 1; 4.0 (95% CI, ) for 2; 5.9 (95% CI, ) for 3; 8.5 (95% CI, ) for 4; 12.5 (95% CI, ) for 5; and 18.2 (95% CI, ) for 6. Conclusion  The 2 existing classification schemes and especially a new stroke risk index, CHADS2, can quantify risk of stroke for patients who have AF and may aid in selection of antithrombotic therapy. JAMA. 2001: 2864 Gage et al. JAMA, 2001, 285: 2864–2870

44 CHADS 2 计分的两面性 CHADS 2 计分 不抗凝---1年卒中率（％） 抗凝---1年大出血率（％）
New method of predicting stroke in heart patients St. Louis, June 13, 2001 — Researchers at Washington University School of Medicine in St. Louis have developed a formula to predict the risk of stroke in patients with an irregular heart rhythm called atrial fibrillation. “Our hope is that this new classification scheme will help physicians select the appropriate course of treatment for patients with atrial fibrillation,” says Brian F. Gage, M.D., who led the study. Gage is assistant professor of medicine at the School of Medicine and medical director of Barnes-Jewish Hospital’s blood thinner clinic. The results are published in the June 13 issue of the Journal of the American Medical Association. Patients with atrial fibrillation, an irregular, uncoordinated contraction of heart muscles, are estimated to have a fivefold increased risk of stroke. A blood thinner called warfarin sodium (sold as Coumadin® and others) often is used to reduce this risk, but the drug itself can cause hemorrhage and other side effects. It also is more expensive and more difficult to administer and monitor than the alternative treatment, aspirin. To help predict when the benefits of warfarin outweigh the risks, two earlier studies completed by two other research groups determined independent factors that significantly increase the risk of stroke. However, the studies reached somewhat different conclusions: The Atrial Fibrillation Investigators (AFI) found that stroke risk correlated with prior stroke, advanced age, hypertension and diabetes; the Stroke Prevention and Atrial Fibrillation (SPAF) team found that prior stroke, blood pressure, recent heart failure and the combination of being over 75 years old and female increased the risk of stroke. “The two predictor models were helpful, but discrepancies between them sometimes led to confusion,” says Gage. “We needed a simple, uniform system to help select warfarin for patients at moderate or high risk of stroke, while avoiding this potentially dangerous blood thinner in low-risk patients.” So Gage and colleagues combined the factors from both models and developed a points system called CHADS2, an acronym for the five factors: Congestive heart failure, Hypertension, Age, Diabetes and Stroke. Since both the AFI and SPAF found that a history of stroke is the best predictive factor, it was given a value of two points, delineated by the “2” at the end of the mnemonic. The other factors each are allocated one point. Patients therefore are assigned a score ranging from 0 to 6. In general, the researchers suggest prescribing warfarin to patients with a CHADS2 rating of one or greater, depending on the patient’s preferences and risk of hemorrhage. In collaboration with Peer Review Organizations representing seven states, the team obtained data from 1,733 Medicare beneficiaries aged 65 to 95 years. They followed each patient for an average of 1.2 years and assembled a National Registry of Atrial Fibrillation (NRAF). They then compared the predictive value of each of the three models — CHADS2, AFI and SPAF. The AFI and SPAF schemes both predicted stroke better than chance, but CHADS2 yielded significantly more accurate results than either of these models. In addition, the risk of stroke as estimated using CHADS2 ranges from less than two percent to roughly 18 percent. Both AFI and SPAF include only three categories — low, moderate and high risk — with stroke risk ranging from roughly one percent to ten percent. “Having a wider range of scores provides a more quantitative approach to predicting stroke, which is very helpful,” explains Gage. “For example, even for high-risk patients, it’s important to know how high their score is so that you can take extra precautions if necessary during future surgeries and other medical treatments.” Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke. Journal of the American Medical Association, 285(22), , June 13, 2001. Funding from the Agency for Healthcare Research and Quality supported this research. The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Healthcare Validation of Clinical Classification Schemes for Predicting Stroke Results From the National Registry of Atrial Fibrillation Brian F. Gage, MD,MSc; Amy D. Waterman, PhD; William Shannon, PhD; Michael Boechler, PhD; Michael W. Rich, MD; Martha J. Radford, MD JAMA. 2001;285: Context  Patients who have atrial fibrillation (AF) have an increased risk of stroke, but their absolute rate of stroke depends on age and comorbid conditions. Objective  To assess the predictive value of classification schemes that estimate stroke risk in patients with AF. Design, Setting, and Patients  Two existing classification schemes were combined into a new stroke-risk scheme, the CHADS2 index, and all 3 classification schemes were validated. The CHADS2 was formed by assigning 1 point each for the presence of congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and by assigning 2 points for history of stroke or transient ischemic attack. Data from peer review organizations representing 7 states were used to assemble a National Registry of AF (NRAF) consisting of 1733 Medicare beneficiaries aged 65 to 95 years who had nonrheumatic AF and were not prescribed warfarin at hospital discharge. Main Outcome Measure  Hospitalization for ischemic stroke, determined by Medicare claims data. Results  During 2121 patient-years of follow-up, 94 patients were readmitted to the hospital for ischemic stroke (stroke rate, 4.4 per 100 patient-years). As indicated by a c statistic greater than 0.5, the 2 existing classification schemes predicted stroke better than chance: c of 0.68 (95% confidence interval [CI], ) for the scheme developed by the Atrial Fibrillation Investigators (AFI) and c of 0.74 (95% CI, ) for the Stroke Prevention in Atrial Fibrillation (SPAF) III scheme. However, with a c statistic of 0.82 (95% CI, ), the CHADS2 index was the most accurate predictor of stroke. The stroke rate per 100 patient-years without antithrombotic therapy increased by a factor of 1.5 (95% CI, ) for each 1-point increase in the CHADS2 score: 1.9 (95% CI, ) for a score of 0; 2.8 (95% CI, ) for 1; 4.0 (95% CI, ) for 2; 5.9 (95% CI, ) for 3; 8.5 (95% CI, ) for 4; 12.5 (95% CI, ) for 5; and 18.2 (95% CI, ) for 6. Conclusion  The 2 existing classification schemes and especially a new stroke risk index, CHADS2, can quantify risk of stroke for patients who have AF and may aid in selection of antithrombotic therapy. CHADS 2 计分 Gage. JAMA 2001: 2864 Hylek. Circulation 2007:2689 44

45 2006年ACC/AHA/ESC房颤指南 无危险因素： ASA 81- 325mg 1个中危因素：ASA 81- 325mg 或 华法林
1个高危或>1个中危因素: 华法林 高危因素 ： 卒中史、TIA、栓塞，二尖瓣狭窄，人工瓣 中危因素： ≥75岁、高血压、心衰、LVEF≤35%、糖尿病 低危因素： 女性、65~74岁、冠心病

46 2010年ESC房颤指南 CHA2DS2VASC积分 非瓣膜性AF卒中与血栓栓塞的危险因素 主要危险因素（2分） 非主要危险因素（1分）
卒中/TIA/全身栓塞史 年龄≥75岁 HF /中重度LV功能障碍（EF≤0.4） 高血压 糖尿病 女性 年龄 65-74岁 血管疾病 在卒中和血栓栓塞的危险分层方面，既往常用的CHADS2积分[心衰、高血压、年龄、糖尿病、卒中（2分）]相对简单，便于易记，但其并未包括所有的卒中危险因素。新指南提出了新的评分系统——CHA2D2VASC积分(表)，其在CHADS2积分基础上将年龄≥75岁由1分改为了2分，增加了血管疾病、年龄65-74岁、性别（女性）三个危险因素，最高积分为9分。根据CHA2D2VASC积分，指南提出了选择抗栓治疗策略的方案（下图）。 46

47 CHA2DS2VASC积分 危险因素 积分 CHF/LV功能障碍(C) 1 高血压（H） 年龄≥75岁（A） 2 糖尿病（D）
卒中/TIA/栓塞史（S） 血管疾病（V） 年龄65-74（A） 性别（女性）（Sc） 总积分 9

48 2010ESC房颤指南抗栓治疗原则 危险因素 CHADS2-VASc 积分 抗栓建议 1个主要危险因素或≥2个非主要危险因素 ≥2 OAC
1个非主要危险因素 1 OAC 或者阿司匹林75-325mg；首选OAC 无危险因素 阿司匹林75-325mg/d或不需抗栓治疗； 首选后者 OAC: 口服抗凝药 48

49 谢谢！