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老年房颤抗凝与出血平衡策略

老年房颤抗凝与出血平衡策略. 解放军总医院 王玉堂. 房颤脑卒中风险评价： CHADS 2. CHADS 2 criteria C ongestive heart failure H ypertension A ge ≥75 yrs D iabetes mellitus S troke/transient ischaemic attack. Score 1 1 1 1 2. 0 1 2 3 4 5 6. CHADS 2 score. 0. 5. 10. 15. 20. 25. 30.

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老年房颤抗凝与出血平衡策略

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  1. 老年房颤抗凝与出血平衡策略 解放军总医院 王玉堂

  2. 房颤脑卒中风险评价： CHADS2 CHADS2 criteria Congestive heart failure Hypertension Age ≥75 yrs Diabetes mellitus Stroke/transient ischaemic attack Score 1 1 1 1 2 0 1 2 3 4 5 6 CHADS2score 0 5 10 15 20 25 30 Annual stroke rate (%)* Gage BF et al. JAMA 2001;285:2864–70

  3. 房颤脑卒中风险评价：CHA2DS2-VASc Total score 0 1 2 3 4 5 6 7 8 Patients (n=7329) 1 422 1230 1730 1718 1159 679 294 82 Adjusted stroke rate (%/year)* 0.0 1.3 2.2 3.2 4.0 6.7 9.8 9.6 6.7 CHA2DS2-VASc criteria Congestive heart failure/ left ventricular dysfunction Hypertension Age 75 yrs Diabetes mellitus Stroke/transient ischaemic attack/TE Vascular disease (prior myocardial infarction, peripheral artery disease or aortic plaque) Score 1 1 2 1 2 1 9 14 15.2 *Theoretical rates without therapy; assuming that warfarin provides a 64% reduction in stroke risk, based on Hart RG et al. 2007 Age 65–74 yrs Sex category (i.e. female gender) 1 1 TE = thromboembolism Lip G et al. Chest 2010;137:263-72; Lip G et al. Stroke 2010; 41:2731–8; Camm J et al. Eur Heart J 2010; 31:2369–429; Hart RG et al. Ann Intern Med 2007;146:857–67

  4. 房颤相关出血风险评价： HAS-BLED HAS-BLED total score 0 1 2 3 4 5 6 7 8 9 Number of bleeds 9 13 14 7 4 1 0 – – – Bleeds per 100 patient-yrs* 1.13 1.02 1.88 3.74 8.70 12.5 0.0 – – – HAS-BLED risk criteria Hypertension Abnormal renal or liver function (1 point each) Stroke Bleeding Labile INRs Elderly (e.g. age >65 yrs) Drugs or alcohol (1 point each) Score 1 1 or 2 1 1 1 1 1 or 2 N 798 1286 744 187 46 8 2 0 0 0 *P value for trend = 0.007 INR = international normalized ratio Pisters R et al. Chest. 2010;138:1093–100; ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429

  5. 2012 ESC 房颤管理指南 Use of CHA2DS2-VASc score to identify ‘truly low risk’ patients who do not need antithrombotic therapy NOACs broadly preferable to VKA in the vast majority of patients with nonvalvular AF ASA for stroke prevention should be limited to patients who refuse any form of OAC ASA = acetylsalicylic acid; NOAC = novel oral anticoagulant; OAC = oral anticoagulation; VKA = vitamin K antagonist Camm AJ et al. Eur Heart J 2012;33:2719–47

  6. 2012 ESC 房颤管理指南推荐抗凝治疗 Atrial fibrillation Yes Valvular AF* No (i.e. nonvalvular) Yes <65 years and lone AF (including females) No Assess risk of stroke CHA2DS2-VASc score ≥2 Oral anticoagulant therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences 0 1 No antithrombotic therapy NOAC VKA Antiplatelet therapy with ASA plus clopidogrel or – less effectively – ASA only, should be considered in patients who refuse any OAC or cannot tolerate anticoagulation for reasons unrelated to bleeding. If there are contraindications to OAC or antiplatelet therapy, left atrial appendage occlusion, closure or excision may be considered Colour CHA2DS2-VASc: green = 0, blue = 1, red ≥2; line: solid = best option; dashed = alternative option *Includes rheumatic valvular disease and prosthetic valves; ASA = acetylsalicylic acid; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist Camm AJ et al. Eur Heart J 2012;33:2719–47

  7. Warfarin 降低房颤脑卒中风险 Warfarin better Placebo better AFASAK SPAF BAATAF CAFA SPINAF EAFT RRR 64%* (95% CI: 49 74%) All trials –50 –100 100 50 0 RRR (%)† Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic), for ischaemic stroke only the RRR was 67% (95% CI: 54–77%) Hart RG et al. Ann Intern Med 2007;146:857–67

  8. SPAF III: 剂量调整的warfarin 与低剂量warfarin和Aspirin Adjusted-dose warfarin better Warfarin (INR 2.0–3.0) Combination therapy better Fixed-dose warfarin (INR 1.2–1.5)* and Aspirin (325 mg/d) Ischaemic stroke or systemic embolism Disabling ischaemic stroke All disabling stroke Ischaemic stroke, systemic embolism, or vascular death Stroke, MI, or vascular death Major haemorrhage 0.0 0.5 1.0 1.5 2.0 Relative risk *Warfarin dose adjusted between 0.5 and 3.0 mg/day to achieve international normalized ratio (INR) 1.2 1.5 when initiating therapy and then fixed for rest of study; Error bars = 95% CI; MI = myocardial infarction SPAF Investigators. Lancet 1996;348:633–8

  9. SPAF III：Stroke Prevention in Atrial Fibrillation III 20 18 16 Cumulative event rate(% per year) 14 12 10 8 6 4 2 0 Combination therapy Adjusted-dose warfarin 0 365 730 Days from randomisation THE LANCET Vol.384, Sept. 7, 1996

  10. VKA 治疗的局限 Numerous food–drug interactions Unpredictable response VKA therapy has Numerous drug–drug interactions several limitations that make it difficult to use in practice Narrow therapeutic window (INR range 2.0–3.0) Slow onset/ offset of action Routine coagulation monitoring INR = international normalized ratio; VKA = vitamin K antagonist Ansell J, et al. Chest 2008;133;160S-198S; Nutescu EA, et al. Cardiol Clin 2008;26:169-187; Umer Ushman MH, et al. J Interv Card Electrophysiol 2008;22:129-137 Warfarin resistance Frequent dose adjustments

  11. VKA 治疗的禁忌症 Pregnancy Coagulation factor abnormalities Thrombocytopenia (<100 000/ L) Haemorrhagic stroke Excessive alcohol intake Dementia Recent or contemplated surgery of the CNS or the eye Frequent falls or seizures Poor drug or clinic compliance Poorly controlled hypertension (>180/110 mmHg) Severe hepatic or renal disease Threatened abortion (eclampsia, pre-eclampsia) Non-steroidal agents Gastrointestinal or urinary bleeding in the previous 6 months CNS = central nervous system; VKA = vitamin K antagonist ACCP Guidelines, 2008: Signer DE et al. Chest 2008;133;546S–92S; Coumadin: SmPC, 2009; Sudlow M et al. Lancet 1998;352:1167–71; Brass LM et al. Stroke 1997;28:2382–9; Kalra L et al. Stroke 1999;30:1218–22; Go AS et al. Ann Intern Med 1999;131:927–34 9

  12. VKAs在房颤患者抗栓治疗的临床应用情况 No anticoagulation VKAs 64% N=23,657 Medicare cohort, USA1 67% N=5,333 EuroHeart survey2 55% N=11,409 ATRIA cohort3 (managed care system, California, USA) VKAs = vitamin K antagonists; ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation 1. Birman-Deych E et al. Stroke 2006;37:1070–4; 2. Nieuwlaat R et al. Eur Heart J 2005;26:2422–34; 3. Go AS et al. JAMA 2003;290:2685–92 11

  13. VKAs在老年房颤患者中的应用 The contraindications that make patients unsuitable for VKAs are found most frequently in elderly patients who are often at the greatest risk of stroke 50 for VKAs (%) 40 43% 38% 37% Patients unsuitable 30 20 10 17% 0 >65 yrs1 >65 yrs2 >75 yrs3 All ages4 VKAs = vitamin K antagonists 1. Sudlow M et al. Lancet 1998;352:1167–71; 2. Brass LM et al. Stroke 1997;28:2382–9; 3. Kalra L et al. Stroke 1999;30:1218–22; 4. Go AS et al. Ann Intern Med 1999;131:927–34 13

  14. Warfarin 临床应用不足 Underuse greatest in elderly patients (who are at highest risk of stroke) 100 80 Proportion of eligiible patients usingwarfain(%) Overall use = 55% (n= 11 082) 60 40 61% 58% 57% 44% 35% 20 0 55–64 65–74 75–84 <55 85 Age (yrs) Go A et al. Ann Intern Med 1999;131:927–34

  15. 传统VKA抗凝治疗与血栓风险 OACs are underutilized, with little relationship to stroke risk Risk score Total cohort VKA (%) Aspirin (%) No AT OAC plus n (%) therapy (%) Aspirin (%) CHADS2 0 1 ≥2 855 (8.4) 3674 (36.3) 5599 (55.3) 38.2 46.5 51.2 31.8 27.4 22.2 31.8 27.4 22.2 9.1 11.1 16.8 CHA2DS2-VASc 0 1 ≥2 341 (3.4) 1552 (15.3) 8235 (81.3) 34.6 43.9 49.8 34.9 28.7 23.8 34.9 28.7 23.8 8.5 10.6 15.0 AT = antithrombotic; OAC = oral anticoagulant Global Anticoagulant Registry in the Field (GARFIELD) registry, data from 10 135 patients Lip G et al. ACC 2012; Presentation 1236-167.

  16. VKAs ：窄治疗窗 20 Therapeutic range 15 10 5 1 Stroke Oddsratio Intracranial bleed 0 1 2 3 4 5 6 7 8 International normalized ratio VKAs = vitamin K antagonists ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030 16

  17. 三、挑战：VKA抗凝疗效与出血 Gersh， Rev Esp Cardiol, 2011

  18. INR波动大 ： VKAs often outside the therapeutic range 100 INR 2.0–3.0 INR >3.0 INR <2.0 Time in therapeutic range(%) 80 60 40 20 0 USA (n= 686) Canada (n= 152) France (n= 278) Spain (n= 218) Italy (n= 177) The predominant vitamin K antagonist (VKA) in use was warfarin in the USA, Canada, and Italy; acenocoumarol in Spain; and fluindione in France; INR = international normalized ratio Ansell J et al. J Thromb Thrombolysis 2007;23:83–91

  19. 多数脑卒中发生在抗凝治疗不足：INR Association of stroke events with intensity of anticoagulation for patients with AF treated with warfarin in major randomized trials Target range for study INR at which stroke event occurred ACC/AHA/ESC recommended INR (2.0–3.0) 4.0 3.0 2.0 INR 1.0 AFASAK CAFA SPAF BAATAF SPINAF ACC = American College of Cardiology; AHA = American Heart Association; ESC = European Society of Cardiology; INR = international normalized ratio 18 Levi M et al. Semin Thromb Haemost 2009;35:527–42

  20. 多数脑卒中发生在抗凝治疗不足:INR >70% of ischaemic stroke patients with AF had an INR <2.0 – Only 10% were within the therapeutic range (INR ≥2.0) 15% 25% 3% 39% 29% 29% 29% 10% 2% 18% Therapeutic warfarin (INR ≥2.0) Single antiplatelet therapy Subtherapeutic warfarin (INR <2.0) Dual antiplatelet therapy No antithrombotics Data from a prospective stroke registry of 597 patients with AF INR = international normalized ratio; TIA = transient ischaemic attack Gladstone DJ et al. Stroke 2009;40:235-40

  21. warfarin在房颤中的出血风险 Population-based cohort study involving 125,195 patients with AF who started treatment with warfarin between Apr 1, 1997, and Mar 31, 2008. Major haemorrhage defined as any visit to hospital for hemorrhage. Gomes T et al. CMAJ 2012; Nov 26 [Epub ahead of print]

  22. 新型药物 vs. 模拟的安慰剂=70-80% RRR 卒中风险的降低： 近期随机对照临床试验中与华法林的对比的相对疗效 Granger CB et al. Circulation. 2012;125:159-164. 22% 28% 43% 12% 21% 36% 氯吡格雷+阿司匹林 氯吡格雷+阿司匹林 阿司匹林 阿司匹林 安慰剂 华法林 华法林 阿哌沙班 利伐沙班 华法林 华法林 达比加群 阿司匹林 氯吡格雷 华法林 利伐沙班 阿哌沙班 达比加群 150 综述 ACTIVE-A ACTIVE-W 综述 RELY ROCKET ARISTOTLE

  23. 抗栓治疗相关大出血事件* Odds Ratios 4 3,5 3 2,5 2 1,5 1 0,5 0 * non-fatal and fatal VKA ASA Clopi ASA+Clopi VKA+ASA VKA+Clopi Triple Hansen et al. Arch Intern Med 2010;170:1433-1441 VKA

  24. 抗凝出血相关事件死亡率比较 Warfarin 0.2 Dabigatran 0.1 0.3 0 Mortality rate (%) 5 10 15 20 25 30 35 Time (days) The Kaplan–Meier analysis suggest a reduced risk for death with dabigatran* vs warfarin during 30 days after the bleeding (P=0.052) *Data combined from dabigatran 150 mg and 110 mg BID treatment groups. Only first major bleed included. Analysis not adjusted for covariates

  25. 不同种族房颤患者颅内出血风险差异 Shen et al J Am Coll Cardiol 2007;50:309–15 无ICH事件的比例 种族 白人 黑人 西班牙人 亚洲人 年 颅内出血 相对风险: 白人 vs 亚洲人 4.06 (95% CI 2.47 – 6.65) 白人 vs 西班牙人 2.06 (95% CI 1.31 – 3.24) 白人 vs 非裔人 2.04 (95% CI 1.25 – 3.35) 非白种人房颤患者华法林相关的颅内出血风险更高

  26. 近期新型抗凝药与华法林在房颤患者中的比较研究：RELY, ROCKET-AF, ARISTOTLE Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011

  27. 近期房颤患者中NOAC与华法林的比较研究 大出血 HR (95% CI) 达比加群 150mg BID 0.93(0.81-1.07) 0.80(0.69-0.93) 达比加群 110mg BID 1.04(0.90-1.20) 利伐沙班 20mg od Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011 阿哌沙班 5mg BID 0.69(0.60-0.80) 0.5 1 2 HR (95% CI) 颅内出血 达比加群 150mg BID 0.40(0.27-0.60) 达比加群 110mg BID 0.31(0.20-0.47) 利伐沙班 20mg od 0.67(0.47-0.93) 0.42(0.30-0.58) 阿哌沙班 5mg BID 2 0.1 1

  28. 近期房颤患者中NOAC与华法林的比较研究 心肌梗死 HR(95% 可信区间) 达比加群 150mg BID 1.27 0.94-1.71 Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011 达比加群 110mg BID 1.29 0.96-1.75 利伐沙班 20mg od 0.81 0.63-1.06 阿哌沙班 5mg BID 0.88 0.66-1.17 0.0 0.5 1.0 1.5 2.0 胃肠道出血 HR(95% 可信区间) 达比加群 150mg BID 1.48 1.18-1.85 达比加群 110mg BID 1.08 0.85-1.38 利伐沙班 20mg od (x) 阿哌沙班 5mg BID 0.89 0.70-1.15 0.0 0.5 1.0 1.5 2.0

  29. 抗凝相关出血管理策略 Camm et al. Eur Heart J 2012

  30. 一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤中风危险因子一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤中风危险因子 1234 房颤患者纳入2007年10月至2010年7月 以前诊断阵发性，持续性及永久性房颤患者以及住院期间新发生房颤患者 排除：200例不完整随访患者 最终纳入分析患者： 1034例 平均随访1.9年，随访主要不良临床事件：中风，血栓，大出血，死亡 未抗凝治疗： 885例 中国老年房颤调查，王玉堂等，2012

  31. 一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤中风危险因子一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤中风危险因子 CAD: Coronary artery disease HF: Heart failure, TIA: Transient ischaemic attack PVD: Peripheral vascular disease Co-morbidities in Chinese patients with AF 中国老年房颤调查，王玉堂等，2012

  32. Cox regression analysis for TE event in AF Chinese patients without warfarin 一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤中风危险因子 • TE event: Ischemic stroke, pulmonary embolism, or peripheral embolism • Vascular disease: Coronary artery disease, peripheral vascular disease, or a previous thromboembolism other than stroke/TIA. 中国老年房颤调查，王玉堂等，2012

  33. 一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤中风危险因子一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤中风危险因子 老年未抗凝房颤患者中风风险评价（885例） Net Reclassification Improvement (NRI) ： 16.6% (95%CI 4%-29%, p=0.009) Integrated Discrimination Improvement (IDI) ： 1.1% (95% CI 0.3%-1.7%, p=0.002). 中国老年房颤调查，王玉堂等，2012

  34. 一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群老年房颤中风风险与北美、欧洲、日本人群比较一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群老年房颤中风风险与北美、欧洲、日本人群比较 中国老年房颤人群中风及血栓发生率高于欧洲心脏病调查及日本人群 中国老年房颤调查，王玉堂等，2012

  35. 一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤出血风险一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤出血风险 HAS-BLED score ： c-statistic 0.61, 95% CI: 0.51-0.71, p=0.042 中国老年房颤调查，王玉堂等，2012

  36. 一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤生存分析一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤生存分析 使用CHADS2将老年房颤患者分为低，中及高危患者，三组间患者的累计生存率没有差异(Log rank: p=0.060) 中国老年房颤调查，王玉堂等，2012

  37. 一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤生存分析一、正确评估中风及出血风险是选择合适抗凝策略的关键：中国人群高龄老年房颤生存分析 CHA2DS2-VASC高危中风老年房颤患者累计生存率明显低于低及中危组患者 (Log rank: p<0.001) 中国老年房颤调查，王玉堂等，2012

  38. 中国房颤患者的卒中风险和未满足的血栓预防：新型口服抗凝药是否可以起到作用？中国房颤患者的卒中风险和未满足的血栓预防：新型口服抗凝药是否可以起到作用？ Guo … Lip. Int J Cardiol 2012 40 CHA2DS2-VASc≥1 CHA2DS2-VASc ≥ 2 35 30 25 额外卒中预防/TE 20 15 10 5 0 阿哌沙班 达比加群 110mg 达比加群 150mg “抗血小板药物与口服抗凝血药物预防卒中效果并无差异，表明可能选取了不适当的 INR范围。”模型分析表明, 中国房颤患者应用新型口服抗凝血药物较抗血小板药物(或华法林)有更好的卒中预防效果，具有积极的临床获益 INR：国际标准化比值

  39. 北美专家共识：房颤及支架置入患者抗栓治疗 (CHADS2 ≥2) Low stent thrombosis risk and low bleeding risk BMS VKA DES 1 mo 6 mo 12 mo VKA + Clopidogrel (or ASA) VKA + ASA + Clopidogrel High stent thrombosis risk and low bleeding risk BMS DES 1 mo 6 mo 12 mo Any stent thrombosis risk and high bleeding risk BMS DES NOT RECOMMENDED 1 mo 6 mo 12 mo Adapted from Faxon DP. Circ Cardiovasc Interv 2011;4:522-534

  40. 欧洲房颤指南：房颤及支架置入患者抗栓治疗 Low bleeding risk VKA (INR 2.0-3.0) VKA (INR 2.0-2.5) + Elective BMS* Elective DES (-olimus) Elective DES (paclitaxel) Clopidogrel (or ASA) ACS + BMS/DES 1 mo 6 mo 12 mo VKA (INR 2.0-2.5) + ASA + Clopidogrel High bleeding risk** Elective BMS ACS + BMS 1 mo 6 mo 12 mo Adapted from Camm J et al. Eur Heart J 2010;31:2369-2429

  41. 谢 谢 Apr 2012

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