NOACs研发历程 史旭波 北京同仁医院心血管中心.

Presentation on theme: "NOACs研发历程 史旭波 北京同仁医院心血管中心."— Presentation transcript:

1 NOACs研发历程 史旭波 北京同仁医院心血管中心

2 血栓疾病的药物抗栓之路 Death / MI 普通肝素 阿司匹林 低分子肝素 比伐卢定 戊糖 华法林 希美加群 达比加群 利伐沙班 阿哌沙班
替罗非班 氯吡格雷 普拉格雷 替格瑞洛 无抗栓治疗 1988 阿司匹林 1992 阿司匹林 普通肝素 1998 阿司匹林 普通肝素 替罗非班 2003 阿司匹林 氯吡格雷 UFH/LMWH 替罗非班 2006 阿司匹林 氯吡格雷 UFH/LMWH/比伐卢定 替罗非班 2016 阿司匹林 氯吡格雷/普拉格雷/替格瑞洛 UFH/LMWH/比伐卢定 替罗非班 利伐沙班 16-20% The treatment of UA/NSTEMI has evolved considerably over the last decade. In the early 1990s, the “standard” of care was aspirin, unfractionated heparin, a conservative management strategy, and, if done, PCI involved primarily balloon angioplasty. Subsequently a number of management options (upper portion of the slide) as well as major trials (middle portion of the slide) have come forward. The clinical availability of GP IIb/IIIa blockers (green) in 1995, with trials such as PRISM-PLUS and PURSUIT (also in green) showing their efficacy in UA/NSTEMI patients, particularly those undergoing coronary intervention. The LMWH enoxaparin was studied in the mid-1990s in ESSENCE (in dark blue), and was released for use in unstable angina in Clopidogrel (in orange) released in 1998, was a mainstay of therapy for coronary intervention (particularly the rapidly-growing world of stents). It’s utility in UA/NSTEMI was confirmed in the large scale CURE trial. Bivalirudin also was approved (based on the REPLACE 2 trial) for use as procedural anticoagulation for PCI in about Finally, on the basis of trials such as TACTICS, the rapid invasive management strategy began to predominate, particularly in the US, in the late 1990s. Newer data (gray boxes) have come forward (the trial names are color-coded to correspond to the agent and prior trials) that need to be assimilated into modern-day practice. Trials such as SYNERGY ( enoxaparin vs UFH in high-risk ACS patients managed with a rapid invasive management strategy), OASIS 5 (fondaparinux vs enoxaparin in higher-risk ACS), ICTUS (testing a rapid invasive strategy versus a selective invasive strategy in troponin (+) patients). ISAR-REACT 2 (assessing the utility of abciximab in ACS patients already pre-loaded with high doses of clopidogrel), and ACUITY(evaluating bivalirudin in rapidly invasively managed UA/NSTEMI) are going to help define the practice standards for the future. In the bottom of the slide are schematic graphs of the general trends in bleeding and thrombotic (ischemic) events over this same period. The arrival of GP IIb/IIIa antagonists brought with it substantial increases in bleeding. Thienopyridines both reduced this rate (by substituting for IIb/IIIa antagonists in lower-risk patients) and worsened it (by further adding to the antithrombotic milieu. Enoxaparin had some issues in that it did not fit well with anticoagulation management (traditionally done with ACTs and UFH in the cath lab). The emerging early invasive strategy served to further highlight the importance of the transition to the cath lab. The arrival of bivalirudin brought with it an option for reducing the risk of bleeding complications. With time, better technologies, and better adjunctive therapies the clinical events rates have continued to fall, but this is to a large extent somewhat balanced by the emerging use of more sensitive markers for myocardial damage (such as troponin). 12-15% 8-12% 6-10% Death / MI 4-8% 4-6% 3-5% 1

3 未采取预防措施情况下，外科及内科患者中深静脉血栓（DVT）的发生率
患者组别 研究数 患者人数 DVT发生率% 95% CI 卒中 择期髋关节置换术 多发性创伤 全膝关节置换术 髋骨骨折 脊髓损伤 耻骨后前列腺根治术 经尿道前列腺根治术 ICU患者 普外科 神经外科 妇科手术恶性肿瘤 心梗 腹部血管外科 外周血管重建 单发下肢损伤 妇科手术良性疾病 择期脊髓手术 普通内科 烧伤科 老年科 膝关节镜检查 9 17 4 7 15 8 3 54 5 6 2 1 395 851 536 541 805 458 335 150 178 4310 280 297 180 258 102 684 460 151 1026 249 131 832 56 51 43 47 44 35 32 25 22 19 14 12 51% ~ 61% 48% ~ 54% 39% ~ 47% 42% ~ 51% 40% ~ 47% 31% ~ 39% 27% ~ 37% 5% ~ 15% 19% ~ 32% 24% ~ 26% 17% ~ 27% 17% ~ 26% 16% ~ 28% 15% ~ 25% 9% ~ 23% 15% ~ 20% 11% ~ 17% 10% ~ 22% 10% ~ 14% 8.6% ~ 16% 6% ~ 10%

4 普通肝素的发现 2000万人/年 使用肝素 1916年 Mclean
fat-soluble substances, from liver tissues that inhibited blood coagulation. William Henry Howell. The Johns Hopkins University

5 普通肝素抗凝机制 XIIa VIIa XIa IXa Xa IIa 内源性凝血途径 外源性凝血途径 组织因子 肝素 抗凝血酶III
肝素类抗凝药物主要就是通过强化抗凝血酶Ⅲ的作用来达到抗凝效果的，它们与凝血酶Ⅲ结合使其结构改变，从而使抗凝血酶Ⅲ灭活凝血因子的速度明显增加，戊糖的作用也是如此。 IIa 纤维蛋白原 纤维蛋白 Douglas B.Cines.Chest 1986;89;

6 UFH saves 7 lives for every 1000 operated patients
Current methods of thromboprophylaxis 70年代中后期普通肝素广泛应用于临床 UFH saves 7 lives for every 1000 operated patients 4121 patients randomized to UFH or no treatment 100 deaths in the control group 80 deaths in the UFH group Death due to PE 16/100 in the control group 2/80 in the UFH group Fatal PE p < 0.005 Number of patients with fatal PE 16/100 2/80 5 10 15 20 25 30 Control UFH This slide shows data from the classic 1975 study of Kakkar et al. This study demonstrated the efficacy of low-dose heparin in preventing fatal postoperative PE in patients undergoing a variety of elective major surgical procedures. In total, 4121 patients undergoing major surgery were randomized to receive UFH (5000 IU 2 hours before surgery and every 8 hours postoperatively for 7 days; UFH group) or no thromboprophylaxis (control group). Patients were followed up until discharge or death in hospital. 180 patients died during the postoperative period: 100 in the control group and 80 in the UFH group. Post-mortem examination was performed in 72% of fatalities in the control group and 66% in the UFH group. The graph shows the number of patients in the control group and the UFH group who died during the study, in whom the cause of death was found to be acute massive PE. PE was considered to have caused death if post-mortem examination revealed massive fresh emboli in the pulmonary trunk, main pulmonary artery, or in at least two lobar arteries, and no other cause of death was found. Treatment with low-dose UFH significantly reduced the rate of fatal PE, saving 7 lives for every 1000 patients treated. Reference Kakkar VV et al. Lancet 1975;2:45–51. 低剂量普通肝素可以显著降低外科大手术患者术后致死性PE发生率 Data from Kakkar VV et al. Lancet. 1975;2:45–51. 5

7 切碎普通肝素 －70年代低分子肝素的发明 UFH LMWH 物理：过滤 化学：解聚 酶学：肝素酶 高亲和力结构

8 低分子量肝素抗凝机制 XIIa VIIa XIa IXa Xa IIa 内源性凝血途径 外源性凝血途径 组织因子 肝素/LMWH
抗凝血酶III Xa 肝素类抗凝药物主要就是通过强化抗凝血酶Ⅲ的作用来达到抗凝效果的，它们与凝血酶Ⅲ结合使其结构改变，从而使抗凝血酶Ⅲ灭活凝血因子的速度明显增加，戊糖的作用也是如此。 IIa 纤维蛋白原 纤维蛋白 Douglas B.Cines.Chest 1986;89;

9 肝素 － 低分子肝素 普通肝素 低分子肝素 蛋白、内皮细胞、巨噬细 高 低 生物利用 15-30% 90% 激活血小板 强 弱
普通肝素 低分子肝素 蛋白、内皮细胞、巨噬细 高 低 生物利用 % % 激活血小板 强 弱 血小板4因子 强 弱 肝素诱导的血小板减少症（HIT) % % 监测抗凝活性 常规 非常规 根据体重调 需要 需要 骨质 高 低 清除方式 网状内皮/肾脏 网状内皮/肾脏 半衰期（SC) h h 鱼精蛋白中和 可以 部分

10 与普通肝素相比LMWH可更有效预防外科大手术患者术后静脉血栓事件
Current methods of thromboprophylaxis LMWH UFH RR DVT, % (n/N) 13.8 (93/672) 21.2 (132/622) 0.68 PE, % (n/N) 1.7 (10/590) 4.1 (24/582) 0.43 Major bleeding, % (n/N) 0.9 (6/672) 1.3 (8/622) 0.75 Nurmohamed et al. conducted a meta-analysis of all studies conducted between 1984 and 1991 comparing LMWH and UFH for the prevention of VTE in patients undergoing general surgery (defined as abdominothoracic or gynaecological surgery) and patients undergoing orthopaedic surgery (defined as elective or traumatic hip surgery). For each report the relative risk and the 95% confidence interval were calculated for the efficacy and safety of LMWH over UFH treatment. Studies of patients undergoing orthopaedic surgery were included where DVT was confirmed by routine venography. Both fatal and non-fatal PE were included if confirmed by at least one of: post-mortem examination, perfusion–ventilation scanning, angiography or clinical diagnosis. In patients undergoing orthopaedic surgery, there was a greater reduction in risk of DVT and PE in those receiving LMWH than in those receiving UFH, without an increase in the risk of major bleeding. The table on this slide is adapted from the Lancet, Nurmohamed MT et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992;340:152–6, with permission from Elsevier. Reference Nurmohamed MT et al. Lancet 1992;340:152–6. Adapted from the Lancet, Nurmohamed MT et al. Lancet 1992;340:152–6, with permission from Elsevier. RR, relative risk in patients receiving LMWH compared with those receiving standard heparin. 9

11 80年代戊糖发现 特殊的戊糖序列是肝素与AT的结合位点

12 人工合成了肝素分子特殊的戊糖序列 个步骤人工合成戊糖

13 2002年上市的戊糖作用机制示意图 普通肝素 平均分子量15000d 有相似的抗Xa与抗IIa活性 低分子肝素
蚯蚓状分子为肝素片段，蓝色多边形为抗凝血酶，红色三角形为10a因子，黄色多边形是2a因子； 肝素对2a 因子灭活有赖于肝素-抗凝血酶和2a 因子三联复合物的形成，此时肝素同时结合于抗凝血酶和因子2a，肝素如要起到模板作用需要至少含有18 个糖单位，其中起桥梁作用需要13个单糖，另需5个单糖作为识别片段。每个单糖平均分子量为300，因此分子量一定要达到5400道尔顿以上才具有抗2a活性。普通肝素平均分子量15000道尔顿，绝大多数分子在5400道尔顿以上，具有相似的抗10a与2a活性；低分子肝素则要以5400以上的分子片段所占比例大小来衡量其抗2a活性，一般情况下其抗10a：抗2a活性约2-4：1；戊糖即磺达肝睽钠的分子量只有1700道尔顿左右，只有抗10a活性没有抗2a活性； 戊糖 分子量1728d 只有抗Xa活性 ACCP7. Chest.2004; 126: ; WALENGA JM, et al. Turk J Haematol 2002;19(2): ; J EFFREY I. WEITZ. The New England Journal of Medicine. 1997;337: ; Alban S. Current Pharmaceutical Design.2008;14:

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15 四个随机双盲对照研究的荟萃分析： 磺达肝癸钠预防骨科大手术后DVT/PE疗效优于依诺肝素
N=7,344 ↓50% DVT+PE P<0.001 RRR:50% 汇总III期研究所做的骨科大手术荟萃分析显示：安卓2.5mg每日一次预防骨科大手术后DVT/PE的发生率比依诺肝素40mg每日一次(欧洲说明书)或30mg每日两次(根据美国说明书)下降50％ N=2,703* N=2,628* *可用于评估的病人数 基于四项比较安卓2.5mg和依诺肝素（根据欧洲说明书自术前开始40mg每日一次，或根据美国说明书自术后开始30mg每日两次） Turpie AGG, et al. Arch Intern Med 2002; 162: (Table 5)

16 口服抗凝药物 华法林 利伐沙班 阿哌沙班 达比加群 TF/VIIa X IX IXa VIIIa Va Xa II IIa
Current methods of thromboprophylaxis 口服抗凝药物 TF/VIIa X IX 华法林 IXa VIIIa Va Xa 利伐沙班 阿哌沙班 There are many targets for novel anticoagulants in the coagulation pathway: Tissue factor pathway inhibitor (TFPI) bound to Factor Xa inactivates the tissue factor (TF)–Factor VIIa complex, preventing initiation of coagulation Activated protein C (APC) degrades Factors Va and VIIIa, and thrombomodulin (soluble; sTM) converts thrombin (Factor IIa) from a procoagulant to a potent activator of protein C Fondaparinux and idraparinux indirectly inhibit Factor Xa, requiring antithrombin (AT) as a cofactor Direct (AT-independent) inhibitors of Factor Xa include rivaroxaban (BAY 59­7939), LY517717, YM150 and DU-176b (all orally available), and DX-9065a (intravenous) Oral, direct thrombin inhibitors include ximelagatran (now withdrawn) and dabigatran Weitz JI & Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853 II IIa 达比加群 Fibrinogen Fibrin 15

17 采用随机对照非劣效设计，与传统标准治疗对照
骨科大手术后VTE预防 患者人群 及目的 新型口服 抗凝药 研究名称 给药方案 对照组 研究结果（与标准治疗相比） 疗效 大出血事件发生率 骨科大手术后VTE预防 达比加群 RE-NOVATE RE-MODEL RE-MOBILIZE 220/150mg qd 依诺肝素 劣于伊诺肝素 RE-MODEL/RE-NOVATE 疗效与依诺肝素相当 相当 利伐沙班 RECORD1 RECORD2 RECORD3 RECORD4 10 mg, QD 一致 优效 阿哌沙班 ADVANCE1 ADVANCE2 ADVANCE3 2.5mg bid ADVANCE1疗效与依诺肝素相当 ADVANCE2-3优于伊诺肝素 采用随机对照非劣效设计，与传统标准治疗对照 Lancet 2007;370:949-56 J Thromb Haemost 2007 Nov;5: J Arthroplasty Jan;24(1):1-9. N Engl J Med 2008;358: Lancet Jul 5;372(9632):31-9. N Engl J Med 2008;358: Lancet 2009; 373: 1673–80 N Engl J Med 2009;361: Lancet 2010; 375: 807–15 N Engl J Med 2010;363:

18 Patients assessed for 3 months
RE-NOVATE 达比加群 Study Design（欧洲方案） New N=3494 Dabi 150 mg once-daily Patient Population Age ≥18 years who are undergoing a primary, unilateral, elective total hip replacement n=1174 Dabi 220 mg once-daily RE-MODEL, 2007, p2179, c1, ¶2-4, c2, ¶2-3; p2180, c2, ¶2,4; p2181, figure 1 n=1157 Enox 40 mg once-daily Primary Efficacy Outcome Composite of total VTE events and all cause mortality during the treatment period Secondary Efficacy Outcome Composite of major VTE (proximal DVT and PE) and VTE-related mortality, proximal DVT, and the individual components of the primary efficacy outcome Safety Outcome The occurrence of bleeding events during treatment n=1162 Patients assessed for 3 months Study Design RE-NOVATE was a phase III clinical trial for dabigatran that randomized 3494 patients who underwent primary elective unilateral total hip replacement. Patients were administered to 1 of 3 once-daily treatments: enoxaparin 40 mg subcutaneously, dabigatran 150 mg, or dabigatran 220 mg The primary efficacy outcome was the composite of total VTE events (symptomatic or venographic DVT and/or symptomatic PE), and all-cause mortality, during treatment The primary safety outcome was the incidence of bleeding events Secondary outcome measures included the composite of major VTE (proximal DVT and PE) and VTE-related mortality, proximal DVT; the incidence of total VTE and all-cause mortality during follow-up; and the individual components of the primary outcome RE-MODEL, 2007, p2179, c1, ¶2-4, c2, ¶2-3; p2180, c2, ¶2,4; p2181, figure 1 115 centers Eriksson BI et al. J Thromb Haemost. 2007;5: Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:

19 Efficacy Outcomes During Treatment Period
RE-NOVATE 达比加群与低分子肝素相当(欧洲方案） Efficacy Outcomes During Treatment Period New Dabigatran Etexilate mg 150 mg Enoxaparin Symptomatic PEc 5/1137 (0.4%) 1/1156 (0.1%) 3/1142 (0.3%) Death 3/1137 (0.3%) 3/1156 (0.3%) 0/1142 (0%) Major VTE and VTE-related 28/ /888 36/917 mortalityd (3.1%, 2.0–4.2%) (4.3%, 2.9–5.6%) (3.9%, 2.7–5.2%) Absolute difference -0.8% (-2.5–0.8%) 0.4 (-1.5–2.2%) .. vs enoxaparin P value for difference vs enoxaparinb RENOVATE 2007, p952, table 2 Efficacy Outcomes During Treatment Period Both doses of dabigatran achieved noninferiority compared with enoxaparin. The primary efficacy outcome occurred in dabigatran 220 mg 6.0% /dabigatran 150 mg 8.6% /enoxaparin6.7% in patients treated with. RENOVATE 2007, p952, table 2 dabigatran 220 mg 6.0% /dabigatran 150 mg 8.6% /enoxaparin6.7% Eriksson BI et al. Lancet. 2007;370: Eriksson BI, Dahl OE, Rosencher N, et al; RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:

20 RE-MOBILIZE 达比加群 Study Design（美国方案） Enox 30 mg SC twice-daily N=2615
New Dabi 150 mg once-daily N=2615 Patient Population Age ≥18 years and who had undergone primary elective unilateral total knee arthroplasty n=877 Dabi 220 mg once-daily RE-MOBILIZE, 2009, p2, c1, ¶3, c2, ¶1-3; p3, c1, ¶1, ¶3-4; p5, figure 1 n=862 Enox 30 mg SC twice-daily Primary Efficacy Outcome Composite of total VTE events (symptomatic or venographic DVT and/or symptomatic PE) and all cause mortality during treatment Secondary Efficacy Outcome Composite of major VTE, defined as proximal DVT, PE, and VTE-related mortality, proximal DVT; incidence of total VTE and all-cause mortality during follow-up; and the individual components of the primary outcome Safety Outcome The incidence of bleeding events during treatment n=876 Treatment for 12 to 15 days Study Design RE-MOBILIZE was a phase III clinical trial for dabigatran that randomized 2615 patients who underwent primary, elective, unilateral total knee arthroplasty to either enoxaparin 30 mg twice-daily, dabigatran 150 mg once-daily, or dabigatran 220 mg once-daily The primary efficacy outcome was the composite of total VTE events and all-cause mortality, during treatment Secondary outcome measures included the composite of major VTE (proximal DVT and PE) and VTE-related mortality, proximal DVT, and the individual components of the primary efficacy outcome The primary safety outcome was the occurrence of bleeding events during treatment RE-MOBILIZE, 2009, p2, c1, ¶3, c2, ¶1-3; p3, c1, ¶1, ¶3-4; p5, figure 1 97 centers 4 countries The RE-MOBILIZE Writing Committee. J Arthroplasty. 2009;24;1-9. The RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9.

21 Primary Efficacy Outcome
RE-MOBILIZE 达比加群劣于低分子肝素 Primary Efficacy Outcome New Dabigatran Etexilate mg 150 mg Enoxaparin Treated Treated and operated Include in analysis 604 (100.0) 649 (100.0) 643 (100.0) Total VTE/death during treatmenta Total (%) 188 (31.1) 219 (33.7) 163 (25.3) Distal DVT (%) 167 (27.6) 198 (30.5) 148 (23.0) Proximal DVT (%) 14 (2.3) 20 (3.1) 10 (1.6) Nonfatal PE (%) 6 (1.0) 0 (0.0) 5 (0.8) Death VTE cannot be ruled out (%) 1 (0.2) 0 (0.0) 0 (0.0) Death not associated with VTE (%) 0 (0.0) 1 (0.2) 0 (0.0) Symptomatic DVT, PE, or death during follow upab RE-MOBILIZE, 2009, p6, c2, table 4 Primary Efficacy Outcome The primary efficacy outcome occurred in 31.1% of patients who received dabigatran 220 mg and in 33.7% of patients who received dabigatran 150 mg, compared with 25.3% in those treated with enoxaparin. RE-MOBILIZE, 2009, p6, c2, table 4 Patients were counted only once in the most severe category in the subcategories of DVT, PE and death. a Treatment period: from administration of first dose of study medication and ending 3 days after administration of last dose of study medication. Follow-up is from the end of treatment period to the conclusion of subject participation. b Dabigatran 220 mg; 2 symptomatic DVT, 2 PE, 1 death; dabigatran 150 mg: 4 symptomatic DVT, 0 PE, 2 deaths; enoxaparin: 2 symptomatic DVT, 2 PE, 2 deaths. The RE-MOBILIZE Writing Committee. J Arthroplasty. 2009;24:1-9. The RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9.

22 Apixaban Phase III Trial for VTE Prevention in TKR Surgery（美国方案）
ADVANCE-1 阿哌沙班 Apixaban Phase III Trial for VTE Prevention in TKR Surgery（美国方案） New Apixaban 2.5 mg bid Patient Population Aged 18 years Scheduled for total knee replacement surgery N=3,195 R Lassen, 2009, p595, c1, ¶4, c2, ¶3; p596, c1, ¶3, ¶4, c2, ¶1; p597, Figure 1 n=1,599 Enoxaparin 30 mg bid Primary Efficacy Outcome Composite of adjudicated asymptomatic and symptomatic DVT, nonfatal PE, and all-cause death at end of treatment period Primary Safety Outcome Major bleeding, clinically relevant nonmajor bleeding, minor bleeding, and the composite of major bleeding and clinically relevant nonmajor bleeding n=1,596 Apixaban Phase III Clinical Trial for VTE Prevention in TKR Surgery ADVANCE-1 is completed Phase III clinical trial for apixaban that randomized 3,195 patients scheduled for TKR surgery to 10 to 14 days of double-blind treatment with apixaban 2.5 mg bid or enoxaparin 30 mg bid The treatment period was 10 to 14 days. Follow-up visits were planned 30 days and 60 days following completion of therapy The primary efficacy outcome was a composite of asymptomatic and symptomatic DVT, nonfatal PE, and all-cause death at the end of the treatment period The primary safety outcome was major bleeding Secondary outcomes included a composite of adjudicated asymptomatic and symptomatic proximal DVT, nonfatal PE, and VTE-related death at end of treatment period Continued for days following elective TKR Lassen, 2009, p594, ¶A2-3; p595, c1, ¶3 Lassen, 2009, p595, c1, ¶4, c2, ¶3; p596, c1, ¶3, ¶4, c2, ¶1; p597, Figure 1 Lassen MR et al. N Engl J Med. 2009;361: Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:

23 Results: Primary Efficacy: ITT population
ADVANCE-1 阿哌沙班与低分子肝素相当 Results: Primary Efficacy: ITT population New RR: 1.02 (95% CI: 0.78, 1.32) P=0.06 for noninferiority Absolute difference: 0.11% (95% CI: 2.22, 2.44) P<0.001 for noninferiority Lassen, 2009, p601, Table 2 9.0% (95% CI: 7.5,10.8) N=1,157 8.8% (95% CI: 7.3,10.7) N=1,130 Results: Primary Efficacy: ITT population The primary efficacy outcome occurred in 9.0% of the apixaban-treated patients and 8.8% of the enoxaparin-treated patients Lassen, 2009, p601, Table 2 Apixaban 2.5 mg bid Enoxaparin 30 mg bid Lassen MR et al. N Engl J Med. 2009;361: Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:

24 Study Design – Pooled Analysis （欧洲方案）
ADVANCE 2/3 Pooled Analysis 阿哌沙班 Study Design – Pooled Analysis （欧洲方案） N = 8464 Follow-up evaluation after 60 ± 5 days Continued prophylaxis at discretion of investigator Apixaban (2.5 mg bid, oral) n = 4236 Patient Population Patients ≥18 years, undergoing total hip or knee replacement surgery R Enoxaparin (40 mg qd, subcutaneous) n = 4228 Efficacy Outcomes Composite of asymptomatic or symptomatic proximal DVT, non-fatal pulmonary embolism, and VTE-related death Safety Outcomes Bleeding Major, CRNM and the composite of both MI or stroke Hepatic enzyme elevations Major and non-major bleeding events Randomized, double-blind, double-dummy design Enoxaparin initiated 12 ± 3 hrs preoperatively and resumed 12–24 hrs after wound closure according to the investigator’s standard of care Apixaban initiated 12–24 hrs after wound closure Medication continued 12 ± 2 days after knee and 35 ± 3 days after hip replacement ADVANCE-Pooled analysis A mandatory bilateral venography was performed at the end of the study treatment period Patients with multiple events were counted in the most severe category Identifiers: NCT (ADVANCE-2); NCT (ADVANCE-3) bid, twice daily; CRNM, clinically relevant non-major; DVT, deep-vein thrombosis; MI, myocardial infarction; qd, once daily; VTE, venous thromboembolism. Raskob GE et al. J Bone Joint Surg Br. 2012;94-B:257-64; Lassen MR et al. N Engl J Med. 2010;363:2487–98; Lassen MR et al. Lancet. 2010;375:807–15. National Institutes of Health. Study of an investigational drug for the prevention of thrombosis-related events following hip replacement surgery. Available at: Accessed October 5, 2009.

25 Risk difference* (95% CI) Two-sided p for superiority
Efficacy Outcomes ADVANCE 2/3 阿哌沙班优于低分子肝素 Outcome, n/N (%) Apixaban (n = 4236) Enoxaparin (n = 4228) Risk difference* (95% CI) Two-sided p for superiority Evaluable for major VTE 3394 (80) Major VTE† 23/3394 (0.7) 51/3394 (1.5) −0.8 (−1.2, −0.3) 0.001 VTE-related death 2/4236 (<0.1) 0/4228 (0) 0.1 (−0.0, 0.1) Non-fatal symptomatic PE 5/4236 (0.1) 5/4228 (0.1) 0.0 (−0.2, 0.2) Symptomatic proximal DVT −0.1 (−0.2, 0.1) Asymptomatic proximal DVT 14/3386 (0.4) 41/3385 (1.2) −0.6 (−1.0, −0.2) Similar proportions of patients in the two treatment groups were evaluable for the outcome of major VTE. *Apixaban to enoxaparin. †Major VTE = proximal or non-fatal pulmonary embolism or VTE-related death. Patients with multiple events are only counted once for the most severe outcome event category. CI, confidence interval; DVT, deep-vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism. Raskob GE et al. J Bone Joint Surg Br. 2012;94-B:

26 利伐沙班 RECORD 系列VTE预防III期研究
Current methods of thromboprophylaxis Rivaroxaban 10 mg o.d. administered 6–8 hours post surgery compared with enoxaparin Same efficacy and safety outcomes Same independent, blinded adjudication committees Hip replacement Rivaroxaban 10 mg o.d. for 35 ± 4 days vs. Enoxaparin 40 mg o.d. N = 4541 Hip replacement Rivaroxaban 10 mg o.d. for 35 ± 4 days vs. Enoxaparin 40 mg o.d. for 12 ± 2 days followed by placebo N = 2509 Knee replacement Rivaroxaban 10 mg o.d. for 12 ± 2 days vs. Enoxaparin 40 mg o.d. N = 2531 Knee replacement Rivaroxaban 10 mg o.d. for 12 ± 2 days vs. Enoxaparin 30 mg b.i.d. N = 3148 All studies investigated rivaroxaban 10 mg once daily (o.d.), with the same efficacy and safety outcomes. Randomized, active-comparator-controlled, parallel-group, double-blind, double-dummy trials. All studies used the same independent adjudication committees. RECORD1, 2 and 3 compared rivaroxaban 10 mg o.d. administered 6–8 hours after surgery, with enoxaparin 40 mg o.d. initiated 12 hours before surgery and restarted 6–8 hours after surgery. RECORD4 compared rivaroxaban 10 mg o.d. administered 6–8 hours after surgery, with enoxaparin 30 mg b.i.d. given every 12 hours and started 12–24 hours after surgery. RECORD1 compared extended-duration prophylaxis (35 ± 4 days) with rivaroxaban 10 mg o.d., with extended-duration prophylaxis (35 ± 4 days) with enoxaparin 40 mg o.d. in patients undergoing elective hip replacement surgery. This dose of enoxaparin is commonly prescribed for extended prophylaxis after elective hip replacement surgery in Europe.1 Patients underwent mandatory bilateral venography for assessment of efficacy outcomes on the day after the last dose of study drug was received, at 36 days (range, 30–42). RECORD2 compared extended-duration prophylaxis (35 ± 4 days) with rivaroxaban with short-duration prophylaxis with enoxaparin (12 ± 2 days) plus placebo in patients undergoing elective hip replacement surgery.2 This study aimed to answer the question of whether the proposed regimen of rivaroxaban for 35 (± 4) days was superior to the existing regimen of enoxaparin for 12 (± 2) days, with a similar safety profile.2 Patients underwent mandatory bilateral venography for assessment of efficacy outcomes on the day after the last dose of study drug, at 36 days (range, 30–42). RECORD3 compared 12 ± 2 days rivaroxaban 10 mg o.d. with enoxaparin 40 mg o.d. in patients undergoing elective knee replacement surgery.3 Patients underwent mandatory bilateral venography for assessment of efficacy outcomes between days 11 and 15. RECORD4 compared 12 ± 2 days rivaroxaban 10 mg o.d. with the US regimen of enoxaparin, 30 mg b.i.d., in patients undergoing elective knee replacement surgery.4 Patients underwent mandatory bilateral venography for assessment of efficacy outcomes on the day after the last dose of study drug (range, 11–15). References 1. Eriksson BI et al. N Engl J Med 2008;358:2765–75. 2. Kakkar AK et al. Lancet 2008;372:31–9. 3. Lassen MR et al. N Engl J Med 2008; 358:2776–86. 4. Turpie AGG et al. Pathophysiol Haemost Thromb 2007/2008;36:A14. Data from Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; Lassen MR et al. N Engl J Med 2008;358:2776–86; Turpie AGG et al. Pathophysiol Haemost Thromb 2007/2008;36:A14. 25

27 利伐沙班 全髋关节置换术:VTE 事件 欧洲方案 9.3% 2.0% 3.7% 1.1%
Current methods of thromboprophylaxis 利伐沙班 全髋关节置换术:VTE 事件 利伐沙班 10 mg od, 5 周 17/864 2.0% 10 mg od, 5周 18/1595 1.1% 欧洲方案 RRR = 79% p<0.0001 2 4 6 8 10 RRR = 70% p<0.001 Incidence (%) RECORD2 Rivaroxaban regimen resulted in a significantly greater reduction in total VTE (primary efficacy endpoint) than enoxaparin regimen The primary efficacy endpoint occurred in 2.0% of patients receiving rivaroxaban regimen compared with 9.3% of patients receiving enoxaparin regimen The 95% CIs for the point estimate with rivaroxaban regimen did not overlap those with enoxaparin regimen This is equivalent to an absolute risk difference of –7.3% (95% CI –9.4, –5.2) for rivaroxaban regimen compared with enoxaparin regimen. The upper 95% CI was below 0, clearly demonstrating that rivaroxaban regimen had superior efficacy to enoxaparin regimen (p<0.0001) There was an RRR of 78.9% (95% CI –65, –88; p<0.0001) RECORD1 Rivaroxaban significantly reduced the incidence of the primary efficacy endpoint (the composite of DVT, non-fatal PE, and all-cause mortality up to day 36±6) The primary efficacy endpoint occurred in 1.1% of patients receiving rivaroxaban compared with 3.7% of patients receiving enoxaparin This is equivalent to an absolute risk difference (ARD) of –2.6% (95% CI –3.7, –1.5) with rivaroxaban. The upper 95% CI was below 0, clearly demonstrating that rivaroxaban had superior efficacy to enoxaparin (p<0.001) There was a relative risk reduction (RRR) of 70% (95% CI 49, 82; p<0.001) 伊诺肝素 40 mg od, 5 周 58/1558 3.7% 9.3% 伊诺肝素 40 mg od, 2周 81/869 RECORD2, n=1733; RECORD1, n=3153 26 26 26

28 利伐沙班 全膝关节置换术:VTE事件 RECORD3, n=1702; RECORD4, n=1924 18.9% 9.6%
Current methods of thromboprophylaxis 利伐沙班 全膝关节置换术:VTE事件 18.9% Incidence (%) 5 10 15 20 25 伊诺肝素 40 mg od 166/878 利伐沙班 10 mg od 79/824 9.6% RRR = 49% p<0.001 欧洲方案 美国方案 伊诺肝素 30 mg bid 97/959 利伐沙班 mg od /965 10.1% 6.9% RRR = 31.4% p<0.012 RECORD3 Rivaroxaban resulted in a significantly greater reduction in the composite of DVT, PE, and all-cause mortality (primary efficacy endpoint; total VTE) than enoxaparin The primary efficacy endpoint occurred in 9.6% of patients receiving rivaroxaban compared with 18.9% of patients receiving enoxaparin The 95% CIs for the point estimate with rivaroxaban did not overlap those with enoxaparin This is equivalent to an absolute risk difference of –9.15% (95% CI –12.4, –5.89) with rivaroxaban. The upper 95% CI was below 0, clearly demonstrating that rivaroxaban had superior efficacy to enoxaparin (p<0.001) There was a RRR of 49% (p<0.001) RECORD4 959 patients in the enoxaparin group and 965 patients in the rivaroxaban group were evaluable for the primary efficacy endpoint The p-value is based on the absolute (weighted) risk difference and not relative risk differences. The primary analysis method is based on absolute risk differences RECORD3, n=1702; RECORD4, n=1924 27 27 27

29 采用随机对照非劣效设计，与传统标准治疗对照
骨科大手术后VTE预防 患者人群 及目的 新型口服 抗凝药 研究名称 给药方案 对照组 研究结果（与标准治疗相比） 疗效 大出血事件发生率 骨科大手术后VTE预防 达比加群 RE-NOVATE RE-MODEL RE-MOBILIZE 220/150mg qd 依诺肝素 劣于伊诺肝素 RE-MODEL/RE-NOVATE 疗效与依诺肝素相当 相当 利伐沙班 RECORD1 RECORD2 RECORD3 RECORD4 10 mg, QD 一致 优效 阿哌沙班 ADVANCE1 ADVANCE2 ADVANCE3 2.5mg bid ADVANCE1疗效与依诺肝素相当 ADVANCE2-3优于伊诺肝素 采用随机对照非劣效设计，与传统标准治疗对照 Lancet 2007;370:949-56 J Thromb Haemost 2007 Nov;5: J Arthroplasty Jan;24(1):1-9. N Engl J Med 2008;358: Lancet Jul 5;372(9632):31-9. N Engl J Med 2008;358: Lancet 2009; 373: 1673–80 N Engl J Med 2009;361: Lancet 2010; 375: 807–15 N Engl J Med 2010;363:

30 普通肝素/LMWH8~11d后，达比加群 150 mg, bid 采用随机对照非劣效设计，与传统标准治疗对照
急性VTE(DVT/PE)的治疗 患者人群 及目的 新型口服 抗凝药 研究名称 给药方案 研究结果（与标准治疗相比） 疗效 大出血事件发生率 急性VTE(DVT/PE)患者 达比加群 RE-COVER 桥接治疗 普通肝素/LMWH8~11d后，达比加群 150 mg, bid 相当 利伐沙班 Einstein DVT/PE 单药治疗 15 mg, bid 3周后，20 mg, QD 降低 阿哌沙班 AMPLIFY 10mg bid 7天，后5mg bid 采用随机对照非劣效设计，与传统标准治疗对照 N Engl J Med 2009;361 N Engl J Med 2010;363:

31 采用随机对照非劣效设计，与传统标准治疗对照
VTE(DVT/PE)二级预防 患者人群 及目的 新型口服 抗凝药 研究名称 给药方案 对照组 研究结果（与标准治疗相比） 疗效 大出血事件发生率 VTE(DVT/PE)二级预防 达比加群 RE-MEDY 150mg bid 华法林 相当 RE-SONATE 安慰剂 优效 增加 利伐沙班 Einstein EXT 20 mg, QD 阿哌沙班 AMPLIFY EXT 5或2.5mg bid 优效 相当 采用随机对照非劣效设计，与传统标准治疗对照 N Engl J Med 2010;363:

32 采用随机对照非劣效设计，与传统标准治疗对照
房颤卒中预防研究 患者人群 及目的 新型口服 抗凝药 研究名称 给药方案 研究结果（与标准治疗相比） 疗效 大出血事件发生率 房颤卒中预防研究 达比加群 RELY 开放 110mg bid 相当 降低 150mg bid 优效 利伐沙班 ROCKET AF 双盲 20 mg, QD 阿哌沙班 ARISTOTLE 5 mg, bid 采用随机对照非劣效设计，与传统标准治疗对照 N Engl J Med 2009; 361(12): N Engl J Med 2011; 365; N Engl J Med 2011; 365(11):

33 ACS二级预防 患者人群 及目的 新型口服 抗凝药 研究名称 给药方案 研究结果（与标准治疗相比） 疗效 大出血事件发生率 ACS 二级预防
达比加群 REDEEM 50/75/110/150mg bid 疗效差，未进行三期 利伐沙班 ATLAS ACS TIMI46 5/10/15/20mg 2.5/5mg bid 进行三期 ATLAS ACS TIMI51 2.5/5mg bid+标准治疗 显著降低 CV风险16% 相当 阿哌沙班 APPRAISE-1 10mg qd 或2.5mg bid 5mg bid APPRAISE-2 失败，提前终止

34 NOAC在获批适应症比较 产品 全球获批适应症 中国获批适应症 剂量和用法 利伐沙班 关节置换术后VTE预防 房颤卒中预防
深静脉血栓的治疗和二级预防 肺栓塞的治疗 急性冠脉综合症（ACS） 10mg QD 20mg 或15mg QD* 15mg BID +20mg QD 阿哌沙班 2.5mg bid 达比加群 110mg bid 150mg bid 利伐沙班获批适应症最多，目前还在探索冠心病、心衰、外周动脉疾病、内科急症等多种适应症。 我们也可以注意到不同的NOAC剂量和用法是不一样的。 *低体重和高龄（>75岁）的患者、中度（Crcl mL/min）或重度肾功能损害（1Crcl5–29 mL/min）为15mg Qd。

35 ESUS：隐源性卒中; HF: 心衰; CAD: 冠状动脉粥样硬化性心脏病; ACS: 急性冠脉综合征; PAD: 外周动脉疾病
利伐沙班抗凝治疗探索之路 PE患者 AF患者 DVT患者 ESUS患者 NAVIGATE ESUS 具有继发性VTE风险的患者 HF和CAD患者 VTE儿童患者 ACS患者 GEMINI-ACS 行骨科大手术的患者 慢性CAD或PAD患者 VOYAGER-PAD 内科疾病患者 PAD患者 ESUS：隐源性卒中; HF: 心衰; CAD: 冠状动脉粥样硬化性心脏病; ACS: 急性冠脉综合征; PAD: 外周动脉疾病

36 EINSTEIN-CHOICE:VTE长期抗凝患者

37 TRACE研究：TIA或小卒中患者

38 隐源性卒中抗血小板？抗凝？

39 Eur J Heart Fail. 2015 Jul;17(7):735-42
COMMANDER研究:心力衰竭患者 Eur J Heart Fail Jul;17(7):735-42

40 MARINER研究:住院患者血栓预防

41 经导管主动脉瓣植入术（TAVI)

42 ACS合并AF患者如何选择抗凝抗栓治疗？
冠状动脉粥样硬化斑块 破裂，继发完全或不完 全闭塞性血栓形成 急性期以抗血小板为主 ACS事件发生后期，凝血 酶水平持续升高1 左心房附壁血栓脱落为 AF相关性卒中的主要发 病机制2 合理的抗凝治疗是预防 AF患者脑卒中的有效措 施3 抗血小板 + 抗凝 房颤为什么要抗凝呢？是因为左心房附壁血栓脱落可以导致房颤相关的卒中，抗凝可以预防卒中的发生。对于ACS患者来说，主要病理是冠脉粥样硬化斑块破裂，从而继发完全或不完全的血栓形成，它的急性期需要以抗血小板为主。随着时间推移，血小板活性逐渐减弱，ACS事件发生后期，凝血酶水平持续升高。那么ACS合并AF患者如何选择抗栓治疗？是选择抗血小板还是抗凝还是两者都需要呢? C. Michael Gibson ACC 苏克江, 等. 国外医学(脑血管疾病分册). 2002;10(2): 张澍, 等. 中华心律失常学杂志. 2015; 19(3):

43 02 血运重建或ACS出院后的抗栓治疗 出院 1个月 3个月 6个月 1年 三联疗法 OAC+A+C 双联疗法 OAC+A或C NOAC
单一疗法 择期PCI术使用新一代DES 或BMS 替代：仅，DAPT，若CHA2DS2-VASc=1(男)或2(女)(仅CAD)&高出血风险 三联疗法 OAC+A+C ACS 双联疗法 OAC+A或C NOAC 单一疗法 对于出院后至ACS发病一年内的AF 患者，应按如下建议处理 抗血小板联合抗凝治疗(NOACs以及VKAs)显著增加出血风险；需评估动脉血栓、卒中和出血风险，并尽量缩短合用时间 ACS指南推荐：在急性事件发生后一年内起始双重抗血小板治疗，减少NOACs剂量可能更安全 缩短联合疗法的因素 延长联合疗法的因素 (无法纠正的)高出血风险 低血栓风险(若择期REACH或SYNTAX评分？；若ACS则GRACE≥118？) 第一代DES 高血栓风险(评分同上；左主干、左前降支、近端分叉植入支架；复发性心梗等)和低出血风险 A：阿司匹林75-100mg 一日一次；C：氯匹格雷75mg一日一次 H. Heidbuchel et al.Europace 2015

44 PIONEER AF-PCI 利伐沙班用于接受PCI的房颤患者
12 月后结束治疗 利伐沙班 15 mg qd* 氯吡格雷 75 mg qd† 随机 2100例NVAF患者 无既往卒中/TIA 行PCI 1,6, or 12 月 利伐沙班2.5mg bid 氯吡格雷75mg qd† 阿司匹林75-100mg qd‡ 利伐沙班 15mg qd 阿司匹林 mg qd 1,6, or 12 月 VKA (INR控制在 ) 氯吡格雷75mg qd† 阿司匹林75-100mg qd‡ VKA (INR控制在 ) 阿司匹林 mg qd 主要终点: TIMI大出血,小出血和需要治疗的出血 次要终点: 心血管死亡, MI, 卒中和支架内血栓 *CrCl 30 to <50 mL/min的患者推荐利伐沙班剂量为10 mg一日一次. † P2Y12 抑制剂二选其一: 普拉格雷10 mg 一日一次或替格瑞洛90 mg 一日两次 ‡低剂量华法林(75-100mg qd) CV=心血管; NVAF=非瓣膜性房颤; qd=一日一次; bid=一日两次; TIA=短暂性脑缺血发作. ClinicalTrials.gov Identifier: NCT

45 利伐沙班+DAPT vs. VKA华法林+DAPT
严重心血管不良事件 Kaplan-Meier 评估 风险比（95% CI） 总体 Riva+P2Y12 （N=694） Riva+DAPT（N=704） VKA+DAPT（N=695） 利伐沙班+P2Y12 vs. 华法林+DAPT 利伐沙班+DAPT vs. VKA华法林+DAPT CV不良事件 41（6.5%） 36（5.6%） 36（6.0%） 1.08( ) p=0.750 0.93（ ） p=0.765 CV死亡 15（2.4%） 14（2.2%） 11（1.9%） 1.29( ) p=0.523 1.19( ) P=0.064 心梗 19（3.0%） 17（2.7%） 21（3.5%） 0.86( ) p=0.625 0.75( ) p=0.374 卒中 8（1.3%） 10（1.5%） 7（1.2%） 1.07( ) p=0.891 1.36 ( ) p=0.530 支架血栓 5（0.8%） 6（0.9%） 4（0.7%） 1.20( ) p=0.790 1.44( ) p=0.574 CV不良事件+支架血栓 0.93( ) 治疗突发期：随机后从第一次研究药物给药开始至停止给予研究药物2天后之间的这段时间。 一个受试者可以出现多个不良事件。n=出现不良事件的受试者数量。N=处在危险的受试者数量。% =研究末期的KM估计值。 与VKA组对照的风险比，基于（分层，与VKA相比，仅用于整体，2.5mg BID/ 15 mg QD ）Cox比例风险模型。 与VKA组对照的对数秩P值基于（分层，与VKA相比，仅用于总体2.5mg BID/15 mg QD）两侧对数秩检验。 CI=置信区间，DAPT=双联抗血小板疗法，HR=风险比，VKA=维生素K拮抗剂 6名受试者因为违反了GCP指南被排除出全部疗效分析。

46 TIMI大出血、小出血和需要临床关注的出血（%）
结果： 两组利伐沙班均显著减少出血事件 利伐沙班 15 mg OD + 单抗血小板 vs VKA + DAPT: HR=0.59; (95% CI 0.47–0.76); p<0.001 利伐沙班2.5 mg BID + DAPT vs VKA +DAPT: HR=0.63 (95% CI 0.50–0.80); p<0.001 30 TIMI大出血、小出血和需要临床关注的出血（%） 26.7% 25 ARR 9.9% ARR 8.7% 20 18.0% 16.8% NNT= 12 NNT= 11 15 10 组 2 (利伐沙班 2.5 mg BID + DAPT) 组 1 (利伐沙班 15 mg +单抗血小板) 组 3 (VKA + DAPT) 5 30 60 90 180 270 360 时间 (天)

47 GEMINI-ACS-1:ACS患者 Am Heart J 2016;174:120-8

48 GEMINI-ACS-1试验疗效结果 两组患者的缺血性复合终点事件（心血管死亡、心梗、卒中或明确支架血栓）发生率无差异（HR = 1.06; 95% CI, ），具体的缺血事件风险无明显区别。

49 GEMINI-ACS-1试验安全性结果 两组的TIMI大出血、TIMI轻微出血、GUSTO致命性或严重出血，GUSTO致命性、严重或中度出血和BARC 3a及更高级出血发生率无差异。

50 COMPASS研究： 利伐沙班疗效上取得“压倒性”的优势
A Randomized Controlled Trial of Rivaroxaban for the Prevention of Major Cardiovascular Events in Patients With Coronary or Peripheral Artery Disease (COMPASS - Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) 目的: 评估利伐沙班，低剂量利伐沙班联合阿司匹林与单用阿司匹林比较，在降低冠心病/外周动脉疾病患者心肌梗死、卒中、心血管死亡风险的疗效和安全性 利伐沙班 2.5 mg bid + 阿司匹林 100 mg od ± 泮托拉唑 40 mg od 30天洗脱期* N=27,402 冠心病或外周动脉疾病患者 利伐沙班 5 mg bid ± 泮托拉唑 40 mg od R 1:1:1 阿司匹林100 mg od ± 泮托拉唑 40 mg od 30天导入期 阿司匹林100mg Final follow-up visit# Final washout period visit 随机，双盲，对照临床研究 适应症：CAD/PAD尚未获批

51 2016年荟萃分析 长期服用NOACs患者心肌梗死风险
Tornyos A, Kehl D, D'Ascenzo F, Komócsi A.Risk of Myocardial Infarction in Patients with Long-Term Non-Vitamin K Antagonist Oral Anticoagulant Treatment. Prog Cardiovasc Dis Mar-Apr;58(5):

52 ACCP10专家建议针对不同特征患者选择合适的NOAC
考虑 建议服用的 NOAC 高卒中风险，低出血风险 降低缺血性卒中效果最好的药物/剂量 达比加群 150 mg 既往卒中史 （二级预防） 使用经最佳验证的药物或最大限度减少再次卒中的药物 利伐沙班 阿哌沙班 合并肾脏损害 依赖肾脏清除少的药物 CAD，既往MI病史，或高危ACS/MI 风险 对 ACS 效果较好的药物 合并冠状动脉疾病 唯一降低ACS死亡率的NOAC GI 不适/失调 无报告 GI 并发症的药物/剂量 既往有GI 出血，或目前存在高危GI出血风险 GI 报告出血发生率最低的药剂 拟行电复律 唯一与华法林对比有前瞻性研究的NOAC 患者意愿 每日一次 艾多沙班 基于既往研究的发表，专家建议针对不同特征患者选择最合适的NOAC，以利伐沙班为例： 对于既往卒中病史的病人，优先考虑，因为它证据最充分（ROCKET AF研究纳入了52%的既往卒中/TIA的病人）； 对于合并肾脏损害的病人，优先考虑，因为它肾脏清除率最低（只有35%经过肾脏排泄，而达比加群高达80%）； 对于合并CAD，既往MI的病人，或合并冠脉疾病的，优先考虑，因为它对ACS效果好（利伐沙班2.5mg bid被欧盟获批用于ACS二级预防，是目前唯一的NOACs）； 对于GI不适的病人，优先考虑，因为它辅料中只含有淀粉，不像达比加群胶囊中含有酒石酸易导致消化道不良反应和出血（发生率15-20%） 对于逆行电复律的病人，优先考虑，因为它是目前唯一拥有前瞻性研究证据的NOAC，研究名为X-VERT； 对于患者依从性，优先考虑，因为它是小药片，OD给药。 下面我们来看一些NOAC的临床研究数据。 ACS：急性冠脉综合征；CAD：冠状动脉疾病； GI：肠胃；MI：心肌梗塞 1. Savelieva I & Camm AJ. Clin Cardiol 2014;37:32–47.；2. Verheugt FW, et al. Lancet Jul 18;386(9990):

53 总 结 与UFH/LMWH及华法林比较，新型抗凝药物NOACs具有卓越的疗效和良好的安全性 VTE预防 DVT/PE治疗 AF患者 ACS
总 结 与UFH/LMWH及华法林比较，新型抗凝药物NOACs具有卓越的疗效和良好的安全性 VTE预防 DVT/PE治疗 AF患者 ACS 现有临床随机对照研究荟萃分析显示口服IIa因子抑制剂有增加冠脉心肌梗死事件趋势，需要进一步临床及基础研究证实。

54 谢谢！