1、房颤新型抗凝药物进展,杨新春首都医科大学附属北京朝阳医院心脏中心,阵发性房颤,持续性房颤,年中风率 (%),房颤与中风,房颤增加中风危险4-5倍 中风是非常最常见和灾难性的后果 房颤患者全因中风率5% 房颤是中风的独立危险因素 美国大约15%的中风由房颤引起 中风危险随年龄增长 无症状房颤患者中风危险同样存在 即使是节律控制的患者中风发现同样存在 (AFFIRM, RACE 研究),RACE II = Rate Control Efficacy in Permanent Atrial Fibrillation. Fuster V, et al. J Am Coll Cardiol. 2006;
2、48(4):e149-e246. Kannel WB, et al. Med Clin North Am. 2008;92(1):17-42. Page RL, et al. Circulation. 2003;107(8):1141-1145. Hart RG, et al. J Am Coll Cardiol. 2000; 35(1):183-187. Dulli DA, et al. Neuroepidemiology. 2003;22(2):118-123.,低危,中危,高危,1086420,房颤并发脑卒中的机制,血流缓慢、内皮功能障碍及血液的高凝状态等使血液易发生淤滞,左心耳的栓子可
3、引发栓塞，导致脑卒中或全身动脉栓塞,房颤、高血压与脑卒中,房颤 房颤+高血压,Wolf et al. Stroke 1991; 22: 983-988,1/6的中风归因于房颤,Framingham Study,中国住院房颤病人抗血小板和抗凝治疗现状,阿司匹林,华发林,不用,房颤-中风危险分层,CHADS2,CHA2DS2-VASc,Lip GY, Halperin JL. Am J Med. 2010;123(6):484-488.,0,1,2,3,4,5,6,0,5,10,15,20,中风率 %,0,1.3,2.2,3.2,4.0,6.7,9.8,CHA2DS2-VASc 积分,7,8,9,
4、9.6,15.2,6.7,CHA2DS2-VASc 积分与年中风率,HAS-BLED出血危险积分,ESC AF Guidelines EHJ 2010,华法林抗凝作用: AF 荟萃研究: Meta-analysis,华法林预防房颤缺血性脑卒中不可取代的药物,华法林：优点,INR 评价抗凝强度 多种拮抗药 漏服一、二剂通常不会产生临床问题 多年使用，经历了时间的考验 维持目标INR的能力仍可提高 价格便宜,华法林面临的问题,起效/停药可逆性慢 剂量反应难于预测 治疗剂量范围窄 药物和食物相互反应 监测麻烦 高出血率,过量容易引起出血 不足容易发生中风或肺栓塞 量效曲线棘手、难以处理 剂量调整主要
5、靠反复监测，试试改改,华法林的使用：走钢丝,Fuster et al. J Am Coll Cardiol. 2001;38:1231-1266.,缺血性中风与颅内出血,校正的OR与抗凝强度的关系,房颤应用华法林现状 局限性导致治疗不足,Samsa GP, et al. Arch Intern Med 2000;160:967.,INR 超过目标 6%,未达到治疗剂量INR 13%,INR 在目标范围15%,无华法林65%,房颤患者抗凝治疗一级预防的现状,治疗窗内时间 TTR (Time in Therapeutic Range),口服华法林期间达到目标INR时间的百分比 分析评价口服抗凝剂的
6、疗效差异,SPORTIF III和V 华法林组与对照组患者结果事件差异 TTR 75%,Arch Intern Med. 2007. White HD, Gruber M, Feyzi J, Kaatz S, Tse H, Husted S, Albers G,研究中的新型抗凝剂,TFPI (tifacogin),Idraparinux,Rivaroxaban Apixaban Endoxaban Betrixaban LY517717 YM150 TAK 42,Dabigatran,口服,胃肠外,DX-9065a Otamixaban,Xa,IIa,TF/VIIa,X,IX,IXa,VIII
7、a,Va,II (thrombin),Fibrin,Fibrinogen,AT,APC (drotrecogin alfa) sTM (ART-123),Adapted from Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7.,TTP889,APC 活化蛋白 C AT 抗凝血酶 sTM 可溶性血栓调节素 TF 组织因子 TFPI 组织因子途径抑制物,5 个新开发的药物,Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14 Ericksson BI et al. Clin Pha
8、rmacokinet 2009; 48: 1-22 Ruff CR et al. Am Heart J 2010; 160:635-41,CYP = cytochrome P450; NR = not reported,关于新型抗凝剂的试验,ARISTOTLE Apixaban（阿司匹林）RELY Dabigatran（华发林）ROCKET Rivaroxaban（华发林）ENGAGE Edoxaban（华法林）AVERROES Apixaban（华法林）,与warfarin相比，AF III 期临床试验,*Dose adjusted in patients with drug clearan
9、ce. *Max of 10% with CHADS-2 score = 2 and no stroke/TIA/SEE PROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist,为满足临床需要：针对 AF 卒中预防,临床已证实 AF + 卒中危险因素,是否有 Warfarin适应症?,RELY: Dabigatran ROCKET: Rivaroxaban ARISTOTLE: Apixaban ENGAGE: Edoxaban,AVERROES:
10、Apixaban,No,Yes,Apixaban 5 mg BID,ASA (81-324 mg/d),AF 合并 1 危险因素, 不适合服用VKA,主要终点: Stroke or Systemic Embolic Event (SEE),5,600 病人,AVERROES 设计,2.5 mg BID （在选择的病人）,R,36 个国家, 522 个中心,双盲,N Engl J Med 2011;364:806-817.,Cumulative Risk,0.0,0.01,0.03,0.05,0,3,6,9,12,18,21,ASA,Apixaban,No. at Risk,ASA,Apix,2
11、791,2720,2541,2124,1541,626,329,2809,2761,2567,2127,1523,617,353,Months,RR= 0.46 95%CI= 0.33-0.64 p0.001,Stroke or Systemic Embolic Event,54%,Major Bleeding: 与ASA比相似,ACTIVE A, N Engl J Med 2009; 360: 1-13 Hart RG, et al. Ann Intern Med. 2007;146:857-867 AVERROES; ESC Hotline 2010, N Engl J Med 2011;
12、364:806-817,从SPAF 试验我们对使用抗血小板得到什么启发在AF与ASA抗栓治疗相比,Clopidogrel+ASAVKAApixaban,Favors treatment,Favors ASA,50%,0,50%,100%,Relative risk increase (95% CI),Stroke Reduction Increase in Intracranial Bleeding,-28%-38%-54%,+87%+128%-15%,100%,AVERROES 结论,对不适合VKA治疗,相对于 ASA， apixaban 减少卒中 50%, 并不增加大出血与ASA相比，Ap
13、ixaban 可以很好耐受，尚没有肝毒性的证据对不适合VKA的房颤病人, apixaban 有可能降低危险,从SPAF试验我们对使用抗血小板药物 得到什么启发? summary,在预防AF卒中，对不适合华法林时，ASA 仍然是目前仅有的替代药物,但仅是中等有效联合 ASA 和 clopidogrel 比ASA更有效， 但仍不如warfarin有效，且可以引起出血增加在AVERROES 试验，对较广范围的不适合warfarin的AF 病人，Apixaban显示比ASA更有效，安全相似，更好耐受,为满足临床需要：针对 AF 卒中预防,临床已证实 AF + 卒中危险因素,是否有 Warfarin适应
14、症？,RELY: Dabigatran ROCKET: Rivaroxaban ARISTOTLE: Apixaban ENGAGE: Edoxaban,AVERROES: Apixaban,No,Yes,RE-LY: 非劣效性检验设计,Open,房颤伴 1 危险因素 没有禁忌症 患者来自44国家的951 中心,华法林 调整 INR 2.0 3.0 N=6000,Dabigatran etexilate 110 mg BID N=6000,Dabigatran etexilate 150 mg BID N=6000,盲法结果判定,开放,双盲,R,RE-LY: 中风或周围血管栓塞,0.50,0.
15、75,1.00,1.25,1.50,Dabigatran 110 vs. 华法林,Dabigatran 150 vs. 华法林,非劣效性,p-值,0.001,0.001,优效性,p-值,0.34,0.001,Margin = 1.46,HR (95% CI),华法林更好,Dabigatran 更好,Connolly et al., NEJM, 2009,RR 0.40 (95% CI: 0.270.60) p0.001 (sup),RE-LY: 颅内出血,RR 0.31 (95% CI: 0.200.47) p0.001 (sup),Number of events,0,23 %,0,74 %
16、,0,30 %,RRR 69%,RRR 60%,Connolly et al., NEJM, 2009,Camm J.: Oral presentation at ESC on Aug 30th 2009.,缺血性中风与周围血管栓塞荟萃分析,W vs placebo W vs W low dose W vs ASA W vs ASA + clopidogrel W vs dabigatran 150,0,0.3,0.6,0.9,1.2,1.5,1.8,2.0,倾向华法林,倾向其他治疗,150mg BID,MODERN ERA: RE-LYStuart Connolly MD, Michael
17、D. Ezekowitz MD, Salim YusufMD, Wallentin . Dabigatran versus Wafarin in Patients withAtrial Fibrillation. NEJM 2009, 361.c & NEJM 2010, 363,RE-LY 结 论,与传统的华法林相比，达比加群两种剂量均显示出优势达比加群 150mg更有效而达比加群 110 mg有更好的安全性两种有效剂量各有其优缺点，在临床上对不同特点的患者可做不同的治疗选择,Warfarin (target INR 2-3),Apixaban 5 mg oral twice daily (
18、2.5 mg BID in selected patients),Primary outcome: stroke or systemic embolism,Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death,Randomize double blind, double dummy (n = 18,201),Inclusion risk factors Age 75 years Prior stroke, TIA or S
19、E HF or LVEF 40% Diabetes mellitus Hypertension,Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device,Exclusion Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine,Atrial Fibrillation with at Least One Additional Ri
20、sk Factor for Stroke,ARISTOTLE Main Trial Results,21% RRR,31% RRR,ISTH major bleeding,Stroke or systemic embolism,Median TTR 66%,Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.660.95); P=0.011,Apixaban 327 patients, 2.13% per year Warfarin 462 patients
21、, 3.09% per year HR 0.69 (95% CI, 0.600.80); P0.001,Warfarin (target INR 2-3),Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients),Primary outcome: stroke or systemic embolism,Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, deat
22、h,Randomize double blind, double dummy (n = 18,201),Inclusion risk factors Age 75 years Prior stroke, TIA, or SE HF or LVEF 40% Diabetes mellitus Hypertension,Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device,Major exclusion criteria Mechanical prosth
23、etic valve Severe renal insufficiency Need for aspirin plus thienopyridine,Atrial Fibrillation with at Least One Additional Risk Factor for Stroke,Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism,Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79
24、 (95% CI, 0.660.95); P (superiority)=0.011,No. at Risk Apixaban 9120 8726 8440 6051 3464 1754 Warfarin 9081 8620 8301 5972 3405 1768,P (non-inferiority)0.001,21% RRR,Major Bleeding ISTH definition,Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.600.80);
25、 P0.001,No. at Risk Apixaban 9088 8103 7564 5365 3048 1515 Warfarin 9052 7910 7335 5196 2956 1491,31% RRR,MODERN ERA: ARISTOTLE,Granger, Alexander, MacMurray . Wallentin .,NEJM 2011,Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011,New antithrombotic therapies compared t
26、o warfarin Stroke or systemic embolismDabigatran 150 mg b.i.d.Dabigatran 110 mg b.i.d.Rivaroxaban 20 mg o.d.Abixaban 5 mg b.i.d.,0.5,1,2,New antithrombotic therapies compared to warfarin Hemorrhagic strokeDabigatran 150 mg b.i.d.Dabigatran 110 mg b.i.d.Rivaroxaban 20 mg o.d.Abixaban 5 mg b.i.d.,0.1C
27、onnolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011,1,2,Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011,New antithrombotic therapies compared to warfarin Stroke of ischemic or unknown originDabigatran 150 mg b.i.d.Dabigatran 110 mg b.i.d.Rivar
28、oxaban 20 mg o.d.Abixaban 5 mg b.i.d.,0.5,1,2,Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011,New antithrombotic therapies compared to warfarin All-cause mortalityDabigatran 150 mg b.i.d.Dabigatran 110 mg b.i.d.Rivaroxaban 20 mg o.d.Abixaban 5 mg b.i.d.,0.5,1,2,Connoll
29、y S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011,New antithrombotic therapies compared to warfarin Major bleedingDabigatran 150 mg b.i.d.Dabigatran 110 mg b.i.d.Rivaroxaban 20 mg o.d.Abixaban 5 mg b.i.d.,0.5,1,2,Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et
30、 al NEJM 2011,New antithrombotic therapies compared to warfarin Major + clinically relevant bleedingDabigatran 150 mg b.i.d.Dabigatran 110 mg b.i.d.Rivaroxaban 20 mg o.d.Abixaban 5 mg b.i.d.,0.5,1,2,Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011,New antithrombotic the
31、rapies compared to warfarin Gastrointestinal bleedingDabigatran 150 mg b.i.d.Dabigatran 110 mg b.i.d.Rivaroxaban 20 mg o.d.Abixaban 5 mg b.i.d.,0.5,1,2,New antithrombotic therapies compared to warfarin Intracranial hemorrhageDabigatran 150 mg b.i.d.Dabigatran 110 mg b.i.d.Rivaroxaban 20 mg o.d.Abixa
32、ban 5 mg b.i.d.,0.1Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011,1,2,Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011,New antithrombotic therapies compared to warfarin Myocardial infarctionDabigatran 150 mg b.i.d.Dabigatran 110 mg b.i.d.
33、Rivaroxaban 20 mg o.d.Abixaban 5 mg b.i.d.,0.5,1,2,New anticoagulants compared to warfarin in AF 2011,Effet on outcome event,D150 D110 Riva,Apix,Noninferiority strokeReduction hemorrhagic stroke,Reduction ischemic stroke,Reduction mortalityReduction major bleedingIncrease gastrointestinal bleeding,(
34、),(),(),Increase myocardial infarctionFewer treatment discontinuationsValidation in a second randomized trial,Connolly S et al NEJM 2009 Granger C et al NEJM 2011,从SPAF试验我们对使用抗凝药物 得到什么启发? -summary,Dabigatran, rivaroxaban, apixaban 都提供比warfarin重要的优势，包括方便，至少有相似预防卒中的效果，少的颅内出血ARISTOTLE 发现在预防卒中和系统性栓塞，使用单
35、剂量的apixaban比 warfarin有效，且发生出血减少，死亡率降低，期望新的药物对房颤病人提供改善机会，包括有适应症,但目前又未服用任何口服抗凝药物的病人,WarfarinRisk for stroke and Intracranial bleeding,ApixabanDabigatran Rivaroxaban,side effects e.g. other bleedingsSurvivalPatient preferencesHealth economy,Three new anticoagulants superior to Warfarin for prevention o
36、f stroke and intracranial bleeding in AFavailable 2011,在2011年，与 warfarin相比，,Effet on outcome event,D150 D110 Riva,Apix,Stroke or systemic embolism( Noninferiority),Reduction ischemic stroke,Reduction mortalityReduction major bleedingIncrease gastrointestinal bleeding,(),(),(),Increase myocardial inf
37、arctionFewer treatment discontinuationsValidation in a second randomized trial,Connolly S et al NEJM 2009 Granger C et al NEJM 2011,新抗凝剂Apixaban 对房颤病人提供全面保护作用,Reduction hemorrhagic stroke,Stroke or systemic embolism( superiority),谢谢！,C. Michael Gibson, M.S., M.D.,Patel MR et al, NEJM 2011; Connolly
38、SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011,3+ 86%,ARISTOTLE COVER ACROSS CHADS2 SCORE,临床试验中TTR的情况,C. Michael Gibson, M.S., M.D.,Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011,The international n
39、ormalized ratio (INR) test is the laboratory test used to determine the degree to which the patients coagulation has been successfully suppressed by the vitamin K antagonist (VKA). For most patients, the goal is to keep the INR between 2 and 3, which roughly corresponds to the blood taking 2 to 3 ti
40、mes as long to clot as would a normal persons blood. This level of anticoagulation has been shown to maximize benefit (i.e., protect patients from blood clots) while minimizing risk (i.e., risk of hemorrhage attributable to excessive anticoagulation). Therapeutic INR range (TTR) is a way of summariz
41、ing INR control over time,RE-LY Dabigatran 110 mg 1.53% /yr Dabigatran 150 mg 1.11% /yr Warfarin 1.69% /yrROCKET AF Rivaroxaban 20mg 2.1% /yr Warfarin 2.4% /yrARISTOTLE Apixaban 5 mg 1.27%/yr Warfarin 1.60%/yr,主要终点 Stroke or Systemic Embolism: 非劣效性分析,p0.001,p0.001,p0.001,Non Inferiorirty p vs warfar
42、in,ITT Analysis,Modified ITT,No ITT analysis is available for non-inferiority in Rocket AF. An on treatment or per-protocol analysis is generally performed in the assessment of non-inferiority. If numerous patients come off of study drug, this biases the trial towards a non-inferior result in an ITT
43、 analysis. This is the basis for performing a per-protocol analysis in a non-inferiority assessment.,C. Michael Gibson, M.S., M.D.,p0.001,ITT Analysis,Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011,HR = 0.88,HR = 0.79,HR = 0.91,HR
44、= 0.66,superiority,p=0.12,p0.001,p=0.34,ITT Analysis,Modified ITT,P=0.01,ITT Analysis,出血性卒中,Dabigatran 110 mg 0.12% / yr 0.31 0.001 Dabigatran 150 mg 0.10% / yr 0.26 0.001 Warfarin 0.38% / yr,HR,ITT P-value,Rivaroxaban 20 mg 0.26% / yr 0.59 0.024* Warfarin 0.44% / yr,ROCKET,RELY,C. Michael Gibson, M
45、.S., M.D.,*In an on treatment analysis in Rocket AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr for warfarin, p=0.024. No on treatment analysis is available from RE-LY.,Apixaban 5 mg 0.24% / yr 0.51 0.001 Warfarin 0.47% / yr,ARISTOTLE,Patel MR et al, NEJM 2011; Connolly SJ
46、, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011,缺血性卒中,Dabigatran 110 mg 1.34% / yr 1.11 0.35 Dabigatran 150 mg 0.92% / yr 0.76 0.03 Warfarin 1.20% / yr,HR,ITT P-value,Rivaroxaban 20 mg 1.62% / yr 0.99 0.92*Warfarin 1.64% / yr,ROCKET,RELY,C. Michael Gibson, M.S., M.D.,*I
47、n an on treatment analysis in Rocket AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and 1.42% / yr for warfarin, p=0.58. No on treatment analysis is available from RE-LY and Aristotle.,Aoixaban 5 mg 0.97% / yr 0.92 0.42Warfarin 1.05% / yr,ARISTOTLE,Patel MR et al, NEJM 2011; Connolly SJ, et
48、 al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011,Dabigatran 110 mg 2.71% / yr 0.8 0.003 Dabigatran 150 mg 3.11% / yr 0.93 0.31Warfarin 3.36,150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.001.34) p = 0.052,大出血Major Bleeding,HR,ITT P-value,RE-LY,Rivaroxaban 20 mg 3.60% / yr 1.04 0.58*Warfarin 3.4% / yr,ROCKET,C. Michael Gibson, M.S., M.D.,*There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.,On Treatment P-value,P-value,Apixaban 5 mg 2.13% / yr 0.69 0.001Warfarin 3.09% / yr,
