新型口服抗凝药在房颤中的应用

1、新型口服抗凝药在房颤中的应用 主要参考文献：1.50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study.Lancet. 2015;386(9989):154-62.2.Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fi brillation: a Global Burden o

2、f Disease 2010Study. Circulation. 2014; 129: 83747.3.Prevalence and Risk Factors of Atrial Fibrillation in Chinese Elderly: Results from the Chinese Longitudinal Healthy Longevity Survey.Chin Med J (Engl). 2015;128(18):2426-32.4.An epidemiological study on the prevalence of atrial fibrillation in th

3、e Chinese population of mainland China.J Epidemiol 2008;18(5):209-16.5.Cardioembolic stroke in atrial fibrillation-rationale for preventive closure of the left atrial appendage. Korean Circ J. 2009;39(11):443-58.6. Percutaneous left atrial appendage occlusion for patients in atrial fibrillation subo

4、ptimal for warfarin therapy: 5-year results of the PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) Study.JACC Cardiovasc Interv. 2009;2(7):594-600.7.Percutaneous Left Atrial Appendage Transcatheter Occlusion) for prevention of cardioembolic stroke in non-anticoagulation eligible

5、atrial fibrillation patients: results from the European PLAATO study. EuroIntervention. 2010;6(2):220-6.8.Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet. 2009;374(9689

6、):534-42.9.Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation. 2011;123(4):417-24.10. Left atrial appendage clip occlusion:

7、early clinical results. J Thorac Cardiovasc Surg. 2010;139(5): 1269-74.11.Blockage of a Mechanical Aortic Valve Leaflet with BioGlue: A Case Report.Heart Surg Forum. 2012;15(6):E310-2.12.Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial

8、fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol. 2011;57(2):173-80.13.Patients with atrial fibrillation and a CHA2DS2-VASc score of 1: are they at low or hi

9、gh stroke risk? J Am Coll Cardiol. 2015; 65(14):1395-7.14.The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study.Thromb Haemost. 2012;107(6):1172-9. 主要参考文献：15.How to Avoid Adverse Events Duri

10、ng Apixaban Therapy in Patients With Atrial Fibrillation.Circ J. 2015;79(12):2539-40.16.Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial

11、.Circulation 2011;123(21):2363-72 17.Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran.Am Heart J. 2009;157(5):805-10, 810.e1-2. 18.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009;361(12):113

12、9-51. 19.Comparison of dabigatran versus warfarin in diabetic patients with atrial fibrillation: Results from the RE-LY trial.Int J Cardiol. 2015;196:127-31. 20.Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation.Stro

13、ke. 2013;44(7):1891-6. 21.The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study.Circulation. 2013;128(3):237-43. 22.Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin: ROCKET AF Tr

14、ial.J Am Coll Cardiol. 2015;66(21):2271-81. 23.Rivaroxaban in the Prevention of Stroke and Systemic Embolism in Patients with Non-Valvular Atrial Fibrillation: Clinical Implications of the ROCKET AF Trial and Its Subanalyses.Am J Cardiovasc Drugs. 2015;15(6):395-401. 24.Apixaban In Patients With Atr

15、ial Fibrillation: Patient Characteristics Of The Latin America Cohort From A Multinational Clinical Trial.Value Health. 2015 ;18(7):A809.25.Stroke prevention with rivaroxaban in higher-risk populations with atrial fibrillation.Int J Clin Pract. 2015;69(7):743-56. 26.Efficacy and safety of rivaroxaba

16、n in real-life patients with atrial fibrillation.Expert Rev Cardiovasc Ther. 2015;13(4):341-53. 27.Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Ant

17、agonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).Lancet. 2015;385(9985):2363-70. 28.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011;365(10):883-91. 29.REal-LIfe Evidence of stroke prevention in patients with atrial Fibrillation

18、- The RELIEF study.Int J Cardiol. 2015;203:882-884. 主要内容 房颤的流行病学资料房颤的危险因素 房颤抗凝治疗进展NOACs在房颤中的应用AF房颤的危害 主要内容 房颤的流行病学资料房颤的危险因素 房颤抗凝治疗进展NOACs在房颤中的应用AF房颤的危害 房颤的流行病学资料全球房颤患病情况：Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fi brillation: a Global Burden of Disease 2010Study.

19、Circulation 2014; 129: 83747. 房颤的流行病学资料我国房颤患病情况：总体发病率3.5%Prevalence and Risk Factors of Atrial Fibrillation in Chinese Elderly: Results from the Chinese Longitudinal Healthy Longevity Survey.Chin Med J (Engl) 2015;128(18):2426-32. 主要内容 房颤的流行病学资料房颤的危险因素 房颤抗凝治疗进展NOACs在房颤中的应用AF房颤的危害 房颤的危险因素 Title in he

20、re先天性心脏病Title in here种族Title in here年龄1.房颤的发生与年龄明显相关，年龄增长是房颤发生的主要原因；2.男性房颤患者多于女性房颤患者，二者比例为1.1:0.8；3.房颤患者中白种人多于黑种人，二者比例为2.2:1.5；4.基础心脏疾病或相关疾病：瓣膜病导致的房颤明显减少，高血压成为了房颤最常见的危险因素 独立危险因素Title in here性别Title in here高血压性心脏病Title in here心功能不全Title in here急性心梗Title in here瓣膜病50 year trends in atrial fibrillation

21、 prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study.Lancet 2015;386(9989):154-62. 主要内容 房颤的流行病学资料房颤的危险因素 房颤抗凝治疗进展NOACs在房颤中的应用AF房颤的危害 房颤的危害 、 病人生活质量下降治疗困难，医疗费用高血栓栓塞 心房扩大、心力衰竭增加死亡率 心动过速性心肌病Left atrial appendage clip occlusion: early clinical results. J Thor

22、ac Cardiovasc Surg. 2010;139(5): 1269-74. 阵发性房颤持续性房颤卒中的年发生率(%)卒中是房颤最常见的并发症：非瓣膜性房颤卒中危险约增加5倍瓣膜病房颤卒中风险约增加17倍卒中是房颤最严重的并发症，致残率高，房颤患者的主要死因；卒中亦可在无症状的房颤患者中发生；即便是接受节律控制，房颤患者仍然存在较高的卒中风险RACE II = Rate Control Efficacy in Permanent Atrial Fibrillation.Fuster V, et al. J Am Coll Cardiol. 2006;48(4):e149-e246. Ka

23、nnel 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.LowRiskModerateRiskHighRisk1086420.Blockage of a Mechanical Aortic Valve Leaflet wit

24、h BioGlue: A Case Report.Heart Surg Forum. 2012;15(6):E310-2.房颤的危害房颤与卒中房颤抗凝治疗核心策略 主要内容 房颤的流行病学资料房颤的危险因素 房颤抗凝治疗进展NOACs在房颤中的应用AF房颤的危害 房颤抗凝治疗进展 推荐CHA2DS2-VASc评分系统 发现卒中“真正低危”患者 在抗凝策略中的重要性降低卒中风险关注重点转变 抗血小板治疗新型口服抗凝药强力推荐 非瓣膜病房颤患者卒中风险评估 非瓣膜病房颤患者卒中风险评估 危险因素评分充血性心衰/左室功能不全（C） 1高血压（H） 1年龄75岁（A） 1糖尿病（D） 1卒中/TIA/

25、血栓栓塞（S） 2 总 分 6危险因素评分充血性心衰/左室功能不全（C） 1高血压（H） 1年龄75岁（A） 2糖尿病（D） 1卒中/TIA/血栓栓塞（S） 2血管疾病（V） 1年龄6574岁（A） 1 性别（女性）（Sc） 1 总 分 9CHADS2评分CHA2DS2-VASc评分The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort

26、study.Thromb Haemost. 2012;107(6):1172-9. 2分者：除外存在禁忌证者推荐OAC治疗 主要内容 房颤的流行病学资料房颤的危险因素 房颤抗凝治疗进展NOACs在房颤中的应用AF房颤的危害新型口服抗凝药的优点 达比加群酯依度沙班阿派沙班利伐沙班NOACs优点：作用迅速，失效快口服剂量相对固定与食物、药物相互作用小可预计抗凝效果肾脏清除率正常时勿需监测凝血功能 NOACs在房颤中的应用新型口服抗凝药的药理学性质比较性质达比加群利伐沙班阿哌沙班依度沙班靶点凝血酶Xa 因子Xa 因子Xa 因子前体药物是否否否生物利用度6%80%60%50%给药剂量b.i.d. q.

27、d. b.i.d.q.d.半衰期12-14 h7-11 h12 h9-11 h肾排泄80%33% (66%)25%35%监测否否否否相互作用P-gp3A4/P-gp3A43A4/P-gp起效时间0.5-2h2-4h1-4h1-4h NOACs在房颤中的应用 新型口服抗凝药的作用机制XaIIaTF/VIIaXIXIXaVIIIaVaII 纤维蛋白纤维蛋白原TTP889TFPI(tifacogin)NAPc2口服直接Xa因子抑制剂利伐沙班阿哌沙班依度沙班DU-176bYM150注射间接Xa因子抑制剂磺达肝癸钠Idraparinux直接凝血酶抑制剂达比加群APCsTM (ART-123) NOACs

28、在房颤中的应用新型口服抗凝药的相关期临床试验药物作用途径期临床试验对照组研究设计研究例数达比加群Dabigatran凝血酶抑制剂RELY华法林WarfarinNon-inferiority18113利伐沙班RivaroxabanXa因子拮抗剂ROCKE-AF华法林WarfarinNon-inferiority14264阿哌沙班ApixabanXa因子拮抗剂ARISTOTLE华法林WarfarinNon-inferiority18000依度沙班EdoxabanXa因子拮抗剂ENGAGE华法林WarfarinNon-inferiority16500 NOACs在房颤中的应用 直接凝血酶抑制剂达比加

29、群酯（Dabigatran）商品名：泰毕全剂型：110mg、150mg口服前体药物强效、可逆性、直接凝血酶抑制剂起效迅速可预测抗凝效果较少发生药物相互作用，无药物食物相互作用无需进行常规凝血监测 达比加群酯在房颤中的应用 Dabigatran Compared to Warfarin in 18113 Patients with Atrial Fibrillation at Risk of Stroke达比加群150mg bid、110mg bid与经INR调整的华法林进行非劣效比较其他6%拉美5%亚洲15%北美36%欧洲38%44个国家,951个中心,18113例 达比加群酯的RE-LY研究

30、 达比加群酯在房颤中的应用RE-LY研究设计 Atrial fibrillation 1 Risk FactorAbsence of contra-indications951 centers in 44 countriesWarfarinadjusted (INR 2.0-3.0)N=6000Dabigatran Etexilate 110 mg BIDN=6000Dabigatran Etexilate 150 mg BIDN=6000Blinded Event Adjudication.OpenBlinded 达比加群酯在房颤中的应用RDabigatran versus warfarin

31、 in patients with atrial fibrillation.N Engl J Med. 2009;361(12):1139-51. 达比加群酯150mg显著降低卒中或全身性栓塞风险年0.00.51.01.52.02.50.010.020.030.050.04累积危险比0.00华法林达比加群酯110mgBID达比加群酯150mgBIDRR 0.90(95% CI: 0.741.10)P0.001 (NI)P=0.29 (Sup)RR 0.65(95% CI: 0.520.81)P0.001 (NI)P0.001 (Sup)RRR 35% 达比加群酯在房颤中的应用Dabigatra

32、n versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009;361(12):1139-51. 达比加群酯150mg显著降低缺血性卒中风险缺血性卒中或未明确卒中(100患者-年)n:159/6015111/6076143/6022达比加群酯110 mg BID达比加群酯150 mg BID华法林00.51.01.52.01.34%0.92%1.21%RR 1.11 (95% CI: 0.88-1.39)P=0.35 (Sup)RR 0.76 (95% CI: 0.590.97)24%P=0.03 (Sup)

33、达比加群酯在房颤中的应用Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009;361(12):1139-51. 达比加群酯150mg显著降低血管性死亡风险血管性死亡(100患者-年)n:289/6015274/6076317/6022达比加群酯110 mg BID达比加群酯150 mg BID华法林00.51.01.52.02.43%2.28%2.69%RR 0.90 (95% CI: 0.771.06)P=0.21 (Sup)RR 0.85 (95% CI: 0.720.99)P=

34、0.04 (Sup)15%2.53.0 达比加群酯在房颤中的应用Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009;361(12):1139-51. 亚洲人群卒中或全身性栓塞结果达比加群酯150mg bid达比加群酯110mg bid华法林933923926Subjects at riskDE 150mg bidDE 110mg bid华法林906888886875866858697683664420401382237216198061218243000.020.040.060.0

35、80.10月累积危险比 达比加群酯150mg bid HR 0.45 (95% CI: 0.280.72)RRR 55% 达比加群酯在房颤中的应用Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation.Stroke. 2013;44(7):1891-6. 04.0HR 0.57 (p= 0.0079)(95% CI: 0.380.84)2.0% / 年HR 0.57( p= 0.07

36、05)(95% CI: 0.380.85)3.0达比加群酯150mg bid(39/933)达比加群酯110mg bid(39/923)华法林(66/926)21.0亚洲人群中两种剂量达比加群酯均显著降低大出血风险43% 达比加群酯在房颤中的应用Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation.Stroke. 2013;44(7):1891-6. 达比加群酯的RELY-ABLE研究The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study.Circulation. 2013 ;128(3):237-43. 达比加群酯在房颤中的应用 Discovery