1、心房颤动抗栓治疗进展,北京大学人民医院 心脏中心 孙艺红,The Epidemiology of AF in China and other Countries,5.5%,5.4%,Patients with AF In China 8 million,The Epidemic of Atrial Fibrillation,Increasing prevalence of risk factors for AF: Older age Systemic hypertension Heart failure Valvular heart disease Diabetes mellitus Obes
2、ity,Prevalence of Stroke in Patients with NVAF Stratified by Age,years,0,5,10,15,20,25,Prevalence (%),30,40,4049,6069,50-59,7079,80,HU D, et al. Chin J Intern Med, 2003; 42: 157-161,Efficacy of Warfarin in Atrial Fibrillation,The Covalent Group, Inc.,Combined Endpoint Occurrence (%),Follow-up（m）,0,6
3、,12,18,24,0,20,15,10,5,Aspirin (150-160mg) Warfarin (INR2.0-3.0),RRR 36 %,13.0%,8.4%,Net Clinical Outcome,The Randomized Prospective Trial compared aspirin with adjusted dose warfarin in NVAF Patients,P=0.01,The optimal intensity of anticoagulation,4.0 INR,Embolic Hemorrhage,4 3.5 3.0 2.5 2.0 1.5 1.
4、0 0.5 0,INR 2-3,Anticoagulation of AF in Real-life,100 90 80 70 60 50 40 30 20 10,53.5%,9.8%,37.0%,43.7%,8.9%,47.3%,No antithrombotic Warfarin aspirin,Eligible* (n=3944),Ineligible (n=562),*patients with at least one high-moderate risk factors according to ACC/AHA guideline 2006,The Absolute Inciden
5、ce of Bleeding,Hemorrhage of in-hospital patients with NVAF in China,Hu D, et al. 2004 Chin J Intern Med,P=0.001,WARFARIN ASPIRIN NO,1.4%,6.3,3.3%,MINOR（5.3%） MAJOR（1%）,%,9 8 7 6 5 4 3 2 1,The Dilemma of Anticoagulation Management,Warfarin has a narrow therapeutic window of effectiveness and safety.
6、 Many factors influence a patients stability in that window. Frequent monitoring is required to maintain patients in the therapeutic window. Monitoring is labor intensive and complex. Physicians avoid warfarin use because of its complexity.,Balancing Risk and Benefit,Improve risk stratification Impr
7、ove anticoagulation control Minimize use of concomitant antiplatelet therapy New antithrombotic therapies,Balancing Risk and Benefit,Improve risk stratification,Relative Distribution of Patients by applying different risk stratification schemes,The stratification schemes were applied to a stratified
8、 random sample of 1000 patients was selected from Stroke Prevention in Atrial Fibrillation III participants22,23,Balancing Risk and Benefit,Improve risk stratification Improve anticoagulation control,Variable Dose Response,Drug interference Most potent: Amiodarone (inhibits R- and S-enantiomers) Mos
9、t under-appreciated: Paracetamol (touted interference with enzymes of the vitamin K cycle) Dietary vitamin K,This pathway illustrates genes thought to mediate the eVects of warfarin. It also depicts a simpli- Wed representation of the biotransformation of warfarin and vitamin K,Association of warfar
10、in dose with genes involved in its action and metabolism,VKORC1 Related to Dose of Warfarin,J. Med. Genet. published online 12 Apr 2006;,Patients with homozygous of the dose of warfarin doubled（27mg/w 47mg/w）,GENOTYPE VS STANDARD WARFARIN DOSING Couma-Gen Trial (N=206),Rapid turnaround CYP2C9 and VK
11、ORC1 testing vs. “empiric” Primary endpoint: TTR Smaller and fewer dosing changes with genetic testing No difference in TTR,Circulation 2007; 116: 2563-2570,Pie chart showing the known sources of variability in warfarin dose needed for a stable INR. Each estimate is based on a summary analysis of pa
12、rtial r2 values from multivariate regression analysis reported in six studies that included genotyping on both CYP2C9 and VKORC1,Factors Contribute to Stable Dose Warfarin,OBJECTIONS TO GENETIC TESTING: Warfarin,1. Considered costly, inconvenient. (Coverage by CMS just shifts costs.) 2. Slows down p
13、rescribing warfarin. 3. Not proven to be as good or superior to the current standard of care (“educated guess” approach)which is getting better. 4. Will genetic profiling improve maintenance dosing? If so, how? 5. Can Anticoag Clinics/ POC testing improve warfarin anticoagulation more than rapid tur
14、naround genetic testing? 6. Novel anticoagulantsfixed dose, no coagulation monitoring,Models of AC Management, Routine medical care or usual care (UC)1 Anticoagulation clinic care (ACC)1 Point-of-care (POC) testing2 Provider testing and dosing Patient self-testing (PST), but Dosing by provider Patie
15、nt self-management (PSM), with Dosing by patient,Balancing Risk and Benefit,Improve risk stratification Improve anticoagulation control Minimize use of concomitant antiplatelet therapy,Recommendation of patients with indications of long-term oral anticoagulation after PCI,Balancing Risk and Benefit,
16、Improve risk stratification Improve anticoagulation control Minimize use of concomitant antiplatelet therapy New antithrombotic therapies,左心耳堵闭术取代药物抗凝？,PLAATO,Watchman,New anticoagulants,新型抗凝药物,Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism-Kaplan-Meier,first
17、confirmed symptomatic recurrent stroke or non-CNS systemic embolism,First clinically relevant bleeding during the randomised treatment period,Lancet 2008; 371: 31521,stop after randomisation of 4576 patients, mean follow-up period of 107,新型抗凝药物-利伐沙班,ACC/AHA心房颤动指南2006,结 论,心房颤动是卒中的重要危险因素。 中高危房颤患者，监测下调
18、整剂量华法林（INR 2.0-3.0），中国人同样适用；但多数AF患者没有进行抗凝治疗。 房颤抗栓策略选择：血栓/出血的平衡。 新型抗凝药物可能是未来抗凝的方向，简便、无需监测。 长期抗凝治疗管理，建立抗凝门诊。,谢谢,抗凝治疗的管理,抗凝门诊 1 患者手提式自我监测仪 2,3 计算机辅助 4,5,1 Arch Intern Med 1998;158:1641-7 2 Thromb Haemost 2000;839:661-5 3 Lancet 2000;356:97-102 4 Lancet 1998;352:1505-9 5 Thromb Haemost 2000;83:849-52,严重
19、出血的发生率,13559名房颤病人 颅内出血的发生率,J Am Geriatr Soc 2006;54:1231-1236,年龄 服华法林事件数（n） 率（95%CI）未服华法林事件数（n） 率（95%CI）,服华法林 未服华法林,年事件发生率（%）,血栓栓塞和出血事件与INR,4.0 INR,血栓栓塞 出血,4 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0,接受华法林治疗的房颤病人发生严重出血的危险因素：HEMORR2HAGES,Am Heart J 2006;151:713-719,肝、肾疾病 1 酒精滥用 1 恶性肿瘤 1 老年 1 血小板计数减少 1 再次出血危险 2 高
20、血压 1 贫血 1 遗传因素 - 额外的跌倒危险 1 中风 1,ACC/AHA心房颤动指南2006,类推荐 除孤立性房颤和有禁忌证外，所有房颤患者均建议服用抗栓药物以预防血栓栓塞。（A） 抗栓药物的选择根据卒中和出血的绝对危险，对患者的相对危险和获益。（A） 监测INR频率：初始用药时至少每周一次，稳定后每月一次。（A） 因手术需要中断抗凝治疗超过1周以上的高危患者，给与普通肝素或低分子肝素替代，尽管这些替代治疗的疗效还不确定。（b C）,芬兰6家医院2003-2004调查,European Heart Journal (2007) 28, 726732,房颤患者进行PCI的抗栓治疗,Greg
21、ory Y. H. Lip and Manas Karpha Chest 2006;130;1823-1827,INR异常升高的处理建议,治疗与研究方向,Moderate-risk factors High-risk factors age 75 previous stroke hypertension mitral valve stenosis Heart failure prosthetic heart valve diabetes,Preventing Thromboembolism Risk category recommended therapy No risk factors AS
22、A 81-325mg QDOne moderate risk factor ASA 81-325 QDor warfarinAny high-risk factor Or 1 moderate-risk factor Warfarin,ACTIVE研究设计,Documented AF + 1 risk factor: Age 75, Hypertension, Prior stroke/TIA, LVEF45, PAD, Age 55-74 + CAD or diabetes,ACTIVE W Clopidogrel+ASA vs. OAC,Contra-indications to OAC
23、or Unwilling,ACTIVE A Clopidogrel+ASA vs. ASA,No Exclusion criteria for ACTIVE I,ACTIVE I Irbesartan vs placebo,6500 patients,7500 patients,9000 patients,Clopidogrel 75mg +ASA 75-100 mg,OAC (INR 2.0 3.0),ACTIVE W - 主要终点 Stroke, Non-CNS Systemic Embolism, MI & Vascular Death,Cumulative Hazard Rates,年
24、,# at Risk C+A 3335 3149 2387 916 OAC 3371 3220 2453 911,3.93 %/year,5.64 %/year,RR = 1.45 P = 0.0002,ACTIVE W结果- 严重出血,Cumulative Hazard Rates,# at Risk C+A 3335 3172 2403 914 OAC 3371 3212 2423 901,2.4 %/year,2.2 %/year,RR = 1.06 P = 0.67,ACTIVE W主要终点,高危房颤患者，三氟醋柳酸联合华法林优于单独抗凝或抗血小板，尤其是极高危AF患者（血栓栓塞事件）
25、，出血无显著差异。 联合抗凝治疗中，为减少出血可适当降低抗凝治疗强度，但INR1.8-1.9无效。 三氟醋柳酸（triflusal）600mg相当于阿司匹林300mg，但出血明显减少。,NASPEAF 研究结论,新型抗凝药物,TFPI (tifacogin),Fondaparinux Idraparinux,Rivaroxaban LY517717 YM150 DU-176b,Ximelagatran Dabigatran,ORAL,PARENTERAL,DX-9065a,Xa,IIa,TF/VIIa,X,IX,IXa,VIIIa,Va,II,Fibrin,Fibrinogen,AT,APC
26、(drotrecogin alfa) sTM (ART-123),Adapted from Weitz & Bates. J Thromb Haemost 2005,TTP889,直接凝血酶抑制剂ximelagtran,-AMADEUS研究 -idraparinux,达比加群RELY,新型抗凝药物存在的问题,Amadeus研究是近期第3个替代华法林失败的研究。第一个研究是SPORTIF，该研究显示直接凝血酶抑制剂ximelagatran与华法林同样有效且出血并发症降低，但是其肝脏毒性大。ACTIVE-W研究显示华法林优于双重抗血小板治疗，同时证实即使强化的抗血小板治疗也不能有效预防心房的血栓栓
27、塞。在Amadeus研究中idraparinux组出血发生率较高，提示正确药物的正确剂量十分重要。,2% 华法林,60% 无抗凝,阿司匹林38%,中国心房颤动抗栓治疗现状,胡大一等。中华内科杂志，2004； 孙艺红等。中华内科杂志，2004；43：258-260,9.64%华法林,90.36% 非抗凝,人群流调 住院病人,VKORC1基因多态性与华法林的初始剂量相关,J. Med. Genet. published online 12 Apr 2006;,1542 G/G 、 2255C/C 及1173C/C纯合子患者的华法林周剂量倍增27mg to 47mg,华法林的个体差异基因多态性,ht
28、tp:/,围手术期抗凝,高危 肝素 15000U bid 低分子肝素100U/kg术前24小时停用静脉滴注（1300U/h）至术前5小时停用,术前 术后*,术后12小时同时给予肝素与华法林 持续45天直至INR达标,*术后出血高危，肝素和低分子肝素推迟24小时或更长的时间。 对牙科操作，可以用氨甲环酸、氨基乙酸漱口，不需要停用抗凝药物。,中危,术前45天停用华法林使INR1.31.5,低危,维持剂量华法林 低剂量肝素（5000U）/低分子肝素皮下,肝素 5000U 低分子肝素3000U皮下注射每日两次,NASPEAF 研究设计,NVAF+embolism,NVAF+危险因素,平均INR 2.4
29、7 1.93 2.5 2.17,NASPEAF结果,中危组无事件生存率,高危组无事件生存率,口服直接凝血酶抑制剂预防房颤卒中,SPORTIF III 23 nations Open label n=3,407 SPORTIF V U.S., Canada Double blind n=3,913,Fixed-dose ximelagatran (36 mg bid),Adjusted-dose warfarin (INR 2-3),Patients with nonvalvular AF and risk factors for stroke n=7,320,不良事件肝酶升高,CP110859
30、6-20,Incidence (no.),Treatment duration (mo),Event rate (%),ALT 3 x ULN,6.5,0.7,P0.001,主要终点：卒中和栓塞(Intention-to-Treat),有效抗凝,出血并发症,INR （2.0-3.0）,积极治疗高血压和糖尿病,Adverse Events Hemorrhage,Event rate (%/yr),0.2,0.5,1.8,1.3,29.5,25.5,P=NS,P=NS,P=0.007,Combined Major Adverse Events On-Treatment Analysis,Event
31、 rate (%/yr),4.6,6.1,RRR = 25% P=0.022,Primary events + major bleeding + death,心房颤动复律,华法林3周（B）,UFH 或LMWH华法林(INR2-3),不抗凝(C),UFH IV或LMWH,UFH IV: 目标PTT60s范围5070s；VKA：如华法林（目标INR2.5；范围2.03.0）,无,有,（a B）,肝脏,保泰松、磺吡酮、甲硝唑、甲氧苯啶磺胺二甲氧基嘧啶 胺碘酮,西咪替丁 奥美拉唑 胺碘酮,巴比土酸盐利福平 卡马西平,饮酒,+,-,-,基因,P450 CYP2C9,叶绿醌,-,中草药,NVAF患者卒中危
32、险因素,年龄 75 岁,高血压,糖尿病,LA血栓,收缩压,1.76 (1.08-2.89),1.52 (1.28-1.80),1.39 (1.11-1.76),1.71 (1.21-2.28),1,2,3,4,5,2.77 (1.25-6.13),HU D, et al. Chin J Intern Med, 2003; 42: 157-161,低分子量肝素,半寿期较长 可预测性良好的生物利用度（皮下注射高于90%）和清除率（可以每日使用一次或两次） 根据体重调整的抗血栓反应 采用固定剂量而不必进行实验室监测，除非发生了以下特殊情况，如：肥胖、肾功能不全或者妊娠。 低分子量肝素引起血小板减少症
33、的危险性低于肝素。 院外自行注射低分子量肝素是一个很有前途的方法，与择期心律转复联合使用可以减少患者费用。,Pre-Randomization Anti-thrombotic Medications,入选情况 6706 pts from 522 centers in 31 countries,急性房颤导致卒中的溶拴治疗,理论上，房颤时脱落的陈旧血栓栓塞对溶拴药物的效果不好。由于房颤时缺血性卒中的面积大，合并出血的发生率高NINDS研究亚组分析 t-PA治疗房颤患者的急性卒中 115例急性卒中（ct 证实）3小时内溶栓 t-PA 0.9mg/kg 最大剂量为100mg 安慰剂双盲对照 评价6个月
34、后的功能状态 所有患者均较优，没有关于房颤的亚组分析,心源性栓塞卒中的特点,心源性卒中的可能性发生在不同血管床的多发梗塞 既往有体循环栓塞病史 不明原因的脑梗塞,血栓栓塞性卒中,患病率高 多发性梗死、面积大 易发生出血性卒中 神经功能缺失症状重 死亡率高,缺血性卒中的急性期治疗,房颤患者卒中急性期抗凝,房颤患者最初2周内缺血性卒中的复发率约为5。 临床研究（IST和CAST）中未发现房颤患者和窦性心律患者对抗栓治疗反映有明显区别。 肝素在卒中急性期抗凝减少缺血性卒中再发的作用还不确定。IST亚组分析和HAEST研究的结果不一致，但总体卒中的再发率和功能恢复没有改善。 抗凝治疗在减少缺血事件复发
35、的获益被同时增加出血抵消。,缺血性卒中的急性期抗凝,Circulation 2007;115;478-534,急性期华法林应用的时机,在EAFT研究中，大约100例在缺血性卒中和TIA后的2周内开始口服华法林，并且没有继发出血。（未包括大面积致残，易出血的卒中） 因通常继发出血出现在卒中发生后的12小时到4天，当患者临床和神经系统稳定后尽早开始应用，通常23天，710天可达到稳定的INR。,ACCP指南建议：应用任何抗凝药物前，均应该经CT或MRI扫描证实确定没有颅内出血并评价缺血的范围。 对梗塞面积大，临床症状恶化，不明原因头痛，常规复查头部CT。 没有颅内出血并且梗塞范围较小的房颤患者，只
36、要患者血压正常，可以应用华法林，并使INR维持在2-3。 颅内出血患者长期应用华法林？,急性期华法林应用的时机,心室附壁血栓,通常STEMI伴LV附壁血栓，华法林抗凝3个月（INR 2-3）； 3个月时随访超声心动图，附壁血栓仍然存在（新形成、血栓扩大、活动），需延长抗凝治疗。 联合抗血小板?,感染性心内膜炎,赘生物、感染组织、心腔内的血栓。 急性IE，发生率22-43%。 高危人群， 细菌病源学 超声发现大赘生物（10mm），形态，原位二尖瓣，活动，密度低 二尖瓣多于主动脉瓣 预防 病因治疗：迅速和有效的抗生素治疗 抗血小板药物能减少赘生物体积 没有抗凝治疗的适应证 正在应用口服抗凝治疗者，
37、改用肝素,其他心源性卒中的预防,主动脉弓动脉粥样硬化病变相关的卒中患者，抗血小板治疗。（1C+） 原因不明缺血性卒中患者，如果合并卵圆孔未闭，推荐抗血小板治疗；（1C+）有TIA或卒中病史的二尖瓣脱垂患者，建议抗血小板治疗。（1C+） 人工瓣膜置换术后，华法林抗凝（INR2.5-3.5），根据瓣膜的位置和种类。,ACCP 2004抗栓和溶栓指南,Risk factors for AF patients on warfarin：HEMORR2HAGES,Am Heart J 2006;151:713-719,肝、肾疾病 1 酒精滥用 1 恶性肿瘤 1 老年 1 血小板计数减少 1 再次出血危险
38、2 高血压 1 贫血 1 遗传因素 - 额外的跌倒危险 1 中风 1,NHLBI Randomized Controlled Trial: 2008-2011,Primary Endpoint: Percent of Time in Therapeutic Range (PTTR) Hypothesis: 60% PTTR in standard arm versus 72% PTTR in Genetics Plus Clinical Nomogram arm,RISK FACTORS FOR AN ELEVATED INR (Its not all Genetics),Advanced A
39、ge (one-third dose) Abnormal Liver Function Decreased Vitamin K Intake (NPO, diarrhea, antibiotics) Alcohol in Binges Change in Warfarin Preparation Drug-drug and drug-food interactions,BRIDGING TRIAL (N=1,293),Prospective cohort; all receiving long-term warfarin; average age: 72 years; mostly AF pa
40、tients 80% had warfarin held 5 days 0.7% had thromboembolism; none had been bridged; 0.4% rate when warfarin was held 5 days Of those bridged, 3.7% had major bleed. (Garcia DA, et al. Arch Intern Med2008; 168: 63-69),RISK FACTORS FOR AF,Older age Systemic hypertension Heart failure Valvular heart di
41、sease Diabetes mellitus Obesity,Comparison of 12 Risk Stratification Schemes to Predict Stroke in Patients With Nonvalvular Atrial Fibrillation,(Stroke. 2008;39:000-000.),Is There a Critical Value of Daily Atrial Tachyarrhythmia Burden from Device Diagnostics that Raises Stroke Risk? The TRENDS Stud
42、y,Taya V. Glotzer, Emile G. Daoud, D. George Wyse, Daniel E. Singer, Michael Ezekowitz, Christopher Hilker, Clayton Miller, Dongfeng Qi, Paul D. Ziegler. Taya V. Glotzer MD Clinical Assistant Professor of Medicine Hackensack University Medical Center,Results,The median value for maximum daily burden
43、 in all 30-day windows with non-zero AT/AF was 5.5h, 5.5h, 5.5h,Results Annualized TE Event Rates,华法林的个体差异基因多态性,http:/,华法林维持剂量与体重的关系,77例瓣膜置换术后患者,中华心血管病杂志2005年2月第33卷第2期,Dayi Hu, MD, FACC, FHRS Department of Cardiology Peking University Peoples Hospital,Management of AF: A Worldwide Perspective The Ch
44、inese Approach,Balancing Risk and Benefit,? Lower target intensity,VKORC1 gene in Chinese population,唐和年，等，中国优生与遗传杂志2007年第15卷第3期,Per-patient % out-of range INRs,Anderson JL et al. Circulation 2007; 116: 2563-2570,Benefits vs Barriers of POCT,Benefits of POC Simplifies anticoagulation management1 Imm
45、ediate and accurate INR results2 Provider communicates results and dosage adjustments directly to patient2 May improve patient outcomes Face-to-face instruction may improve quality of care Improves business and office efficiency by avoiding2,3 Venous draw Proper handling of sample Sending to central
46、 laboratory for testing Allows more frequent testing Longer TTR may improve patient outcomes Ability to detect INR changes may allow detection prior to clinically significant event Enhances patient involvement in own care Provides consistency of instrumentation and reagents,Barriers to PST/PSMLack o
47、f physician awareness or acceptance1,2 Fear it will lead to unintended self-management3 Implementation of PST/PSM3 Reimbursement3,Hospitalized Patients with AF in China: Causes and Associated Condition,Idiopathic AF,RVD,CHF,CAD,Advanced age,58.1%,40.3%,Hypertension,caidiomyopathy,34.8%,33.1%,23.9%,7.4%,5.4%,4.1%,Diabetes,CAD: coronary artery disease; CHF: congestive heart failure; RVD: rheumatic valve disease,Chinese J Cardiol, 2003；31：913-916,Prevalence of Stroke in Chinese Patients with AF,%,12.95%,24.81%,17.5%,Hu D, 2004,Qi W, 2003,
