老年人房颤治疗进展 中南大学湘雅三医院 袁洪

房颤防治指南内容的更新 新的循证医学证据 治疗的问题

congestive heart failure 一、房颤防治指南内容的更新 S (2分) prior stroke and TIA 既往卒中/TIA C (1分) congestive heart failure 心衰 CHADS２ D (1分) diabetes mellitus 糖尿病 2006AHA指南推荐了新的非瓣膜性房颤患者卒中一级预防风险评估方法-CHADS２评分（CHADS２为congestive heart failure（心衰），hypertension（高血压）, age>75yrs（年龄大于75yrs）,diabetes mellitus（糖尿病）, prior stroke and TIA（既往卒中/TIA）的缩写），前４个危险因素各１分，最后一个危险因素２分，并据此评分对抗栓药物的选择做出了推荐 H (1分) Hypertension 高血压 A (1分) age>75yrs 年龄大于75yrs 2006AHA指南

老年房颤的卒中风险预防 CHADS２评分及抗栓药物选择 CHADS２评分 危险等级 卒中发生率 治疗推荐（依据危险分层） ０ 低 １.0%/y ASA（75-150mg/d） １ 低－中 １.5%/y 华法林INR2-3或ASA（75-150mg/d）＊ ２ 中 2.5%/y 华法林INR2-3＊ ３ 高 5.0%/y 华法林INR2-3 ≥４ 极高 >7%/y         ＊综合患者意愿、出血风险和抗凝检测条件决定。 2006年AHA指南

2010 ESC指南重要更新 血栓风险评分更新—— CHA2DS2-VASc评分 危险因素 评分 充血性心衰/左室功能不全 1 高血压 年龄≥75岁 2 糖尿病 卒中/TIA/血栓栓塞 血管疾病 年龄65－74岁 性别（女性） 总分 9 新增 原CHADS2 评分标准为1分 总分从CHADS2 中6分增加到9分 5 5 5

EHRA房颤相关症状分级 EHRA I级：无任何症状 EHRA II级：症状轻微，日常活动不受影响 EHRA III级：症状严重，日常活动受到影响 EHRA IV级：致残性症状，不能从事日常活动 EHRA：欧洲心律学会

AF的药物治疗策略

2010ESC房颤指南抗栓治疗原则 危险因素 CHADS2-VASc 积分 抗栓建议 1个主要危险因素或≥2个非主要危险因素 ≥2 OAC 1个非主要危险因素 1 OAC 或者阿司匹林75-325mg；首选OAC 无危险因素 阿司匹林75-325mg/d或不需抗栓治疗； 首选后者 OAC: 口服抗凝药 8

房颤指南建议的老年房颤患者抗栓策略 65-74岁房颤患者抗栓治疗建议 临床情况 治疗策略 2006年ACC/AHA/ESC 2010年中国 不合并其它危险因素* 阿司匹林81-325mg 争议 口服抗凝药或阿司匹林 合并1项危险因素 阿司匹林81-325mg或华法林 口服抗凝药 合并1项以上危险因素 华法林 *危险因素在不同指南中定义不同

≥75岁房颤患者抗栓治疗建议 临床情况 治疗策略 2006年ACC/AHA/ESC 2010年中国 2010年ESC 不合并其它危险因素* 阿司匹林81-325mg或华法林 争议 口服抗凝药 合并1项危险因素 华法林 合并1项以上危险因素 *危险因素在不同指南中定义不同

二、新主要循证医学证据 室率、节律控制的主要循证医学证据 试验 例数 年龄 随访 （年） 主要观察 终点 室律控制 （%） 节律控制 P值 PIAF(2000) 252 61 1 症状改善 60.8 55.1 0.317 RACE(2002) 522 68 2.3 综合终点 17.2 22.6 0.11 AFFIRM(2002) 4060 70 3.5 总死亡率 25.9 26.7 0.08 STAF(2003) 200 66 1.6 9 10 NS HOT CAFE(04) 205 1.7 1.0 3.9 >0.71 AF-CHF(08) 1376 3.1 心源性死亡率 25 27 0.59 J-RHYTHM(09) 823 65 22 15.3 0.012

室率还是节律控制的争论持续了很长时间，AFFIRM、RACE、STAF等试验结果未证实节律控制优于室率控制 ESC2010年房颤治疗指南提出根据房颤相关症状积分进行分级治疗策略选择的重要依据（Ⅰb） 大多数老年房颤主要为室率控制，节律控制主要对于初发房颤、症状较重

室率控制的目标的更新 室率控制 严格室率控制 症状明显 宽松室率控制 无症状或轻微症 EHRA3-4级 静息<110次/分 中等量运动 静息60－80次/分 中等量运动 90－115次/分 N Engl J Med 2010;362:1363-73

房颤患者抗栓治疗的近期循证医学证据 试验名称 例数 年龄 干预药物 试验结果 ACTIVE-W 6706 70.2 华法林(INR 2～3)和 氯吡格雷(75mg/d)/阿司 匹林(75～100mg/d) 氯吡格雷/阿司匹林组主要终点事件 每年高于华法林组1.7%。严重出血事 件发生率两组相似 Chinese ATAFS 704 63.3 华法林(INR 2.0～3.0) 和阿司匹林(150～ 160mg/d) 与阿司匹林比较，华法林组主要终点 事件相对危险度下降54％。华法林组 轻微出血及严重出血发生率均高于阿 司匹林组（P＜0.05) BAFTA 973 81.5 和阿司匹林(75mg/d) 华法林组一级终点事件的发生率显著 低于阿司匹林组（P＝0.003）。 两组非颅内出血以及所有严重出血事 件的发生率无显著性差异 RE-LY 18113 71 达比加群（150mg/Bid） 和华法林(INR 2.0～3.0 ) /达比加群110mg/Bid） 和华法林(INR 2.0～3.0) 达比加群150mg、每日2次较华法林可 降低房颤患者的脑卒中或栓塞性疾病 发生风险34％；达比加群110mg、每 日2次的疗效与华法林相似；达比加 群的两个剂量出血风险均低于华法林

华法林预防房颤脑卒中临床试验

新型抗凝药物的研发 作用于单靶点的药物（Xa因子）成为研发的热点！ 利伐沙班 阿哌沙班 达比加群 TTP889 TF/VIIa IX IXa VIIIa Va II 纤维蛋白 纤维蛋白原 Bates Br J Haematol 2006 TTP889 TFPI (tifacogin) NAPc2 口服直接Xa因子抑制剂 利伐沙班 阿哌沙班 DU-176b YM150 注射间接Xa因子抑制剂 磺达肝癸钠 Idraparinux 达比加群 APC sTM (ART-123) Reference Bates S, Weitz J. The status of new anticoagulants. Br J Haematol 2006;134(1):3-19 新型抗凝药物的研发，实际上按照理想抗凝药物为指导标准 的，它们作用于凝血级联反应中的不同靶点。从研发的品种 来看，我们可以看到新产品更加集中在单靶点药物的研发， 如IIa和Xa因子的研发。尤其是口服直接Xa因子抑制剂。当前 这些新产品中，只有达比加群（直接IIa抑制剂）和利伐沙班 （直接Xa因子抑制剂）上市了。而在中国，仅有利伐沙班上 市了。但两者均被批准用于关节置换术后VTE的预防。 关于IIa因子抑制剂和Xa因子谁更优？ 这是一个很有意思的话题。从凝血级联反应图中，我们可看到，Xa因子位于内源性和外源性凝血途径的交汇点，而IIa因子位于血栓形成的前一步。因此，很 多人认为IIa抑制会更好，因为这个靶点位于下游，IIa抑制对血栓形成会有更直接的抑制作用。其实不然。 1.IIa虽然位于下游位置，但是抑制Xa因子会更有效，因为每分子Xa因子会产生约1000分子的凝血酶（IIa),理论上抑制Xa因子比抑制IIa因子具有更强的控制纤维蛋白生成的能力(我下午和您沟通的过程中，这个问题描述有点错误，特此更正。抱歉，说实话，当时有点记不清具体内容了砭妹挥薪彩稣夥矫娴哪谌萘耍海。而且抑制Xa不是灭活凝血酶的催化活性，而是减少凝血酶的生成，因此不会影响已生成的凝血酶对止血系统的正常调节功能，包括细胞增值和血小板激活。相比于IIa因子，Xa因子的作用更单纯。已知Xa因子的功能仅有促凝和促炎，而IIa除了促凝外，还具有抗凝，纤维蛋白溶解以及抗炎茸饔谩Ｒ虼耍啾扔谝种芚a因子，抑制IIa因子会有更多不确定的作用。 2.从关节置换术后VTE预防的III期临床试验的角度看，直接IIa因子抑制剂达比加群同当前的标准方案依诺肝素（克赛）相比，仅是疗效相当，安全性也相当。但直接Xa因子抑制剂的疗效均优于依诺肝素（克赛），两者安全性相当。在VTE预防领域，随着对Xa抑制的增强，疗效会增强。赩TE预防领域，疗效从强到弱排列顺序为：利伐沙班～磺达肝素>低分子肝素＝达比加群>普通肝素。 3.从急性DVT治疗的角度看，达比加群与利伐沙班的疗效和安全性均与标准治疗方案依诺肝素/VKA相当。但是利伐沙班能提高DVT患者的临床净获益。 而且达比加群用于急性DVT的治疗同样是需要使用注射用抗凝药物用于初始治疗，5天后转为达比加群口服150mg，bid。 4.目前新型抗凝药物之间没有头对头直接对比的资料。 作用于单靶点的药物（Xa因子）成为研发的热点！ 16

达比加群：RE-LY 研究 华法林 达比加群 R 非瓣膜性房颤 （至少一项卒中危险因素） 主要目标：不劣于华法林 平均随访2年（1-3年） (INR 2.0-3.0) N=6000 达比加群 110 mg b.i.d. 150 mg b.i.d. 44个国家 951个中心 R 主要目标：不劣于华法林 平均随访2年（1-3年） 主要终点：卒中+外周栓塞

达比加群：RE-LY 研究 44个国家，951个临床中心。入选的房颤患者必须具备以下至少一条危险因素：既往卒中或TIA史、LVEF＜49%、NYHA＞II极或6个月内有心衰症状、 年龄≥75岁或65至74岁之间并伴有糖尿病、高血压、冠心病。最终入选人群中CHADS2 平均2.1分，≥ 2者约占2/3。主要终点是卒中和体循环栓塞，安全终点是严重的出血. 共入选18113人。平均随访2年。Dabigatran分为110mg每日两次组和150mg每日两次组。 结果卒中和体循环栓塞发生率110mg组和华法林组相同，150mg组低于华法林 严重出血发生率110mg组低于华法林组，150mg组与华法林相同 NEJM. 2009: 1139 18

2010年抗凝治疗领域新进展 利伐沙班 EINSTEIN DVT III期临床研究结果发布 利伐沙班 ROCKET AF研究结果发布 阿哌沙班 Averroes III期临床研究结果发布 阿哌沙班APPRAISE-2 III期临床试验因出血事件的增多提前终止 19

ROCKET-AF研究设计 主要终点：卒中或外周栓塞 房颤（CHADS2高于2分） 每月监测，遵循指南标准 Rivaroxaban G02-536 w_script.ppt 9/10/2017 1:23:57 PM ROCKET-AF研究设计 房颤（CHADS2高于2分） Rivaroxaban 随机/双盲 /双模拟 (n ~ 14,000) 华法林 20 mg/d 15 mg/Cr Cl 30-49 ml/min INR 目标值2.5 (2.0-3.0) 每月监测，遵循指南标准 主要终点：卒中或外周栓塞 AHA 2010 20

基线资料 CHADS2 积分 3.48 3.46 利伐沙班 (N=7081) 华法林 (N=7090) 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) 3.48 13 43 29 2 3.46 44 28 12 VKA服用史 (%) 62 63 充血性心衰 (%) 高血压 (%) 90 91 糖尿病 (%) 40 39 卒中/TIA/栓塞史(%) 55 MI史(%) 17 18 AHA 2010

ROCKET-AF 总结 疗效: 利伐沙班预防房颤卒中及非CNS栓塞不劣于华法林 对于完成治疗的AF，利伐沙班疗效优于华法林 基于倾向性治疗分析，利伐沙班不劣于华法林 安全性: 两组出血及不良事件发生率类似 利伐沙班颅内出血及致命性出血发生率低于华法林 结论 对于中高危房颤，利伐沙班已被证实可替代华法林

三、老年房颤患者治疗的一些困惑 高龄AF患者应用华法林出血风险 时间 研究 年龄 严重出血率/年 时间 研究 年龄 严重出血率/年 1994年 5项临床随机研究 >70 岁 1.3% 1994— 2005年 4项临床随机研究 >70岁 2.7% 2007年 Hglek研究 平均77岁 7.2%。 严重出血——致命性需住院输血2袋以上及致命部位（颅内、腹膜后、脊髓腔内等）的出血。

年龄 研究 AF患者年龄 严重出血发生率 AFI 69岁 1.3% SPORTIF 72岁 3.4% SPAF Ⅱ ＞75岁 4.2% ≤75岁 1.7% Hglek ≥80岁 13.1% ＜80岁 4.7%

CHADS 2 计分的两面性 CHADS 2 计分 不抗凝---1年卒中率（％） 抗凝---1年大出血率（％） New method of predicting stroke in heart patients St. Louis, June 13, 2001 — Researchers at Washington University School of Medicine in St. Louis have developed a formula to predict the risk of stroke in patients with an irregular heart rhythm called atrial fibrillation. “Our hope is that this new classification scheme will help physicians select the appropriate course of treatment for patients with atrial fibrillation,” says Brian F. Gage, M.D., who led the study. Gage is assistant professor of medicine at the School of Medicine and medical director of Barnes-Jewish Hospital’s blood thinner clinic. The results are published in the June 13 issue of the Journal of the American Medical Association. Patients with atrial fibrillation, an irregular, uncoordinated contraction of heart muscles, are estimated to have a fivefold increased risk of stroke. A blood thinner called warfarin sodium (sold as Coumadin® and others) often is used to reduce this risk, but the drug itself can cause hemorrhage and other side effects. It also is more expensive and more difficult to administer and monitor than the alternative treatment, aspirin. To help predict when the benefits of warfarin outweigh the risks, two earlier studies completed by two other research groups determined independent factors that significantly increase the risk of stroke. However, the studies reached somewhat different conclusions: The Atrial Fibrillation Investigators (AFI) found that stroke risk correlated with prior stroke, advanced age, hypertension and diabetes; the Stroke Prevention and Atrial Fibrillation (SPAF) team found that prior stroke, blood pressure, recent heart failure and the combination of being over 75 years old and female increased the risk of stroke. “The two predictor models were helpful, but discrepancies between them sometimes led to confusion,” says Gage. “We needed a simple, uniform system to help select warfarin for patients at moderate or high risk of stroke, while avoiding this potentially dangerous blood thinner in low-risk patients.” So Gage and colleagues combined the factors from both models and developed a points system called CHADS2, an acronym for the five factors: Congestive heart failure, Hypertension, Age, Diabetes and Stroke. Since both the AFI and SPAF found that a history of stroke is the best predictive factor, it was given a value of two points, delineated by the “2” at the end of the mnemonic. The other factors each are allocated one point. Patients therefore are assigned a score ranging from 0 to 6. In general, the researchers suggest prescribing warfarin to patients with a CHADS2 rating of one or greater, depending on the patient’s preferences and risk of hemorrhage. In collaboration with Peer Review Organizations representing seven states, the team obtained data from 1,733 Medicare beneficiaries aged 65 to 95 years. They followed each patient for an average of 1.2 years and assembled a National Registry of Atrial Fibrillation (NRAF). They then compared the predictive value of each of the three models — CHADS2, AFI and SPAF. The AFI and SPAF schemes both predicted stroke better than chance, but CHADS2 yielded significantly more accurate results than either of these models. In addition, the risk of stroke as estimated using CHADS2 ranges from less than two percent to roughly 18 percent. Both AFI and SPAF include only three categories — low, moderate and high risk — with stroke risk ranging from roughly one percent to ten percent. “Having a wider range of scores provides a more quantitative approach to predicting stroke, which is very helpful,” explains Gage. “For example, even for high-risk patients, it’s important to know how high their score is so that you can take extra precautions if necessary during future surgeries and other medical treatments.” Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke. Journal of the American Medical Association, 285(22), 2864-2870, June 13, 2001. Funding from the Agency for Healthcare Research and Quality supported this research. The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Healthcare Validation of Clinical Classification Schemes for Predicting Stroke Results From the National Registry of Atrial Fibrillation Brian F. Gage, MD,MSc; Amy D. Waterman, PhD; William Shannon, PhD; Michael Boechler, PhD; Michael W. Rich, MD; Martha J. Radford, MD JAMA. 2001;285:2864-2870. Context  Patients who have atrial fibrillation (AF) have an increased risk of stroke, but their absolute rate of stroke depends on age and comorbid conditions. Objective  To assess the predictive value of classification schemes that estimate stroke risk in patients with AF. Design, Setting, and Patients  Two existing classification schemes were combined into a new stroke-risk scheme, the CHADS2 index, and all 3 classification schemes were validated. The CHADS2 was formed by assigning 1 point each for the presence of congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and by assigning 2 points for history of stroke or transient ischemic attack. Data from peer review organizations representing 7 states were used to assemble a National Registry of AF (NRAF) consisting of 1733 Medicare beneficiaries aged 65 to 95 years who had nonrheumatic AF and were not prescribed warfarin at hospital discharge. Main Outcome Measure  Hospitalization for ischemic stroke, determined by Medicare claims data. Results  During 2121 patient-years of follow-up, 94 patients were readmitted to the hospital for ischemic stroke (stroke rate, 4.4 per 100 patient-years). As indicated by a c statistic greater than 0.5, the 2 existing classification schemes predicted stroke better than chance: c of 0.68 (95% confidence interval [CI], 0.65-0.71) for the scheme developed by the Atrial Fibrillation Investigators (AFI) and c of 0.74 (95% CI, 0.71-0.76) for the Stroke Prevention in Atrial Fibrillation (SPAF) III scheme. However, with a c statistic of 0.82 (95% CI, 0.80-0.84), the CHADS2 index was the most accurate predictor of stroke. The stroke rate per 100 patient-years without antithrombotic therapy increased by a factor of 1.5 (95% CI, 1.3-1.7) for each 1-point increase in the CHADS2 score: 1.9 (95% CI, 1.2-3.0) for a score of 0; 2.8 (95% CI, 2.0-3.8) for 1; 4.0 (95% CI, 3.1-5.1) for 2; 5.9 (95% CI, 4.6-7.3) for 3; 8.5 (95% CI, 6.3-11.1) for 4; 12.5 (95% CI, 8.2-17.5) for 5; and 18.2 (95% CI, 10.5-27.4) for 6. Conclusion  The 2 existing classification schemes and especially a new stroke risk index, CHADS2, can quantify risk of stroke for patients who have AF and may aid in selection of antithrombotic therapy. CHADS 2 计分 Gage. JAMA 2001: 2864 Hylek. Circulation 2007:2689 25

出血与因素分层关系 Hglek研究 0分 3.12% 15.59% 1分 4.28% 17.12% 2分 2.04% 12.92% CHADS2评分 严重出血的年发生率 停药年发生率 0分 3.12% 15.59% 1分 4.28% 17.12% 2分 2.04% 12.92% 3分 19.54% 32.56% ≥4分 23.42% 35.12% Circulation 2007;115:2689-2696

老年人房颤患者适合的INR范围 在各个临床试验中所用的INR各不相同 AFASK：2.8~4.2 SPAF：2.0~4.5 BAATF：1.5~2.7 CAFA：1.0~3.0 SPINAF：1.4~2.8

国际标准化比值（INR） Hglek研究 ,严重出血发生率与INR关系： ＜2.0组 4.11% 2.0—3.0组 3.78% ＜2.0组 4.11% 2.0—3.0组 3.78% 3.1—3.9组 15.78% ≥4.0组 99.26% Circulation 2007;115:2689-2696

Effect of CYP2C9 Genotype WARFARIN MAINTENANCE DOSE mg warfarin/day N 127 28 4 18 3 5 2007年FDA批准了第一个遗传分子检测，CYP2C9和VKORC1基因多态性预测华法林的安全性 - Higashi et al., JAMA 2002 -

基因测试指导华法林剂量选择 基因测定结合年龄、性别、体重决定初始华法林剂量 ACCP8th不推荐使用药物基因测定指导华法林剂量 两组监测INR的频率相同 Background—Pharmacogenetic-guided dosing of warfarin is a promising application of “personalized medicine” but has not been adequately tested in randomized trials. Methods and Results—Consenting patients (n206) being initiated on warfarin were randomized to pharmacogeneticguided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1 C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses (P0.001), resulting in smaller (P0.002) and fewer (P0.03) dosing changes and INRs (P0.06). However, percent out-of-range INRs (pharmacogenetic30.7%, standard33.1%), the primary end point, did not differ significantly between arms. Despite this, when restricted to wild-type patients (who required larger doses; P0.001) and multiple variant carriers (who required smaller doses; P0.001) in exploratory analyses, results (pharmacogenetic29%, standard39%) achieved nominal significance (P0.03). Multiple variant allele carriers were at increased risk of an INR of 4 (P0.03). Conclusions—An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes. (Circulation. 2007;116:2563-2570.) 基因测定结合年龄、性别、体重决定初始华法林剂量 ACCP8th不推荐使用药物基因测定指导华法林剂量 Anderson, Circulation.2007:2563 30

抗凝药物的选择 ROCKET AF试验显示利伐沙班对重症患者有较好疗效，肝病患者在应用该药时可能需要对剂量进行校正， 80%的达比加群酯通过肾脏代谢，对伴有肾脏疾病可能存在隐患 价格因素 几个新药循证结果均为药物三期临床试验非劣效比较，断言其一定优于华法林还为时尚早

展 望 更多的中国老年房颤流行病学调查 更大样本的中国老年房颤抗凝研究 更有针对性的中国房颤指南 房颤的抗凝门诊

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