房颤/房扑的规范化抗凝治疗 董建增 北京安贞医院心内科 13810664099

房颤的发生率 60岁后每10年增加1倍 Go AS, et al. JAMA. 2001;285:2370-2375

“一生”发生房颤的风险(%) Framingham 心脏研究 Background— Atrial fibrillation (AF) is the most common cardiac dysrhythmia and a source of considerable morbidity and mortality, but lifetime risk for AF has not been estimated. Methods and Results— We included all participants in the Framingham Heart Study who were free of AF at index ages of 40 years and older. We estimated lifetime risks for AF (including atrial flutter) to age 95 years, with death free of AF as a competing event. We followed 3999 men and 4726 women from 1968 to 1999 (176 166 person-years); 936 participants had development of AF and 2621 died without prior AF. At age 40 years, lifetime risks for AF were 26.0% (95% CI, 24.0% to 27.0%) for men and 23.0% (21.0% to 24.0%) for women. Lifetime risks did not change substantially with increasing index age despite decreasing remaining years of life because AF incidence rose rapidly with advancing age. At age 80 years, lifetime risks for AF were 22.7% (20.1% to 24.1%) in men and 21.6% (19.3% to 22.7%) in women. In further analyses, counting only those who had development of AF without prior or concurrent congestive heart failure or myocardial infarction, lifetime risks for AF were approximately 16%. Conclusions— Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older. Lifetime risks for AF are high (1 in 6), even in the absence of antecedent congestive heart failure or myocardial infarction. These substantial lifetime risks underscore the major public health burden posed by AF and the need for further investigation into predisposing conditions, preventive strategies, and more effective therapies. Key Words: atrial fibrillation • epidemiology • risk factors Lifetime Risk for Development of Atrial Fibrillation The Framingham Heart Study Donald M. Lloyd-Jones, MD ScM; Thomas J. Wang, MD; Eric P. Leip, MS; Martin G. Larson, ScD; Daniel Levy, MD; Ramachandran S. Vasan, MD; Ralph B. D’Agostino, PhD; Joseph M. Massaro, PhD; Alexa Beiser, PhD; Philip A. Wolf, MD; Emelia J. Benjamin, MD ScM From the Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Ill (D.M.L.-J.); the National Heart, Lung, and Blood Institute’s Framingham Heart Study, National Institutes of Health, Framingham, Mass (all authors); the Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Mass (T.J.W.); the Department of Epidemiology and Preventive Medicine (M.G.L., D.L., R.B.D., R.S.V., E.J.B.), Cardiology Department (R.S.V., E.J.B.), and Department of Neurology (P.A.W.), Boston University School of Medicine, Boston, Mass; and the Department of Epidemiology and Biostatistics, Boston University School of Public Health, Boston, Mass (E.P.L., R.B.D., J.M.M., A.B.). Correspondence to Donald M. Lloyd-Jones, MD, ScM, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N Lake Shore Drive, Suite 1102, Chicago, IL, 60611. E-mail Figure 1. Cumulative risk for AF at selected index ages for men and women, with death free of AF considered a competing event. Lifetime risk for a given index age is cumulative risk through age 94 years. 40岁 50岁 60岁 70岁 80岁 男性 26.0 25.9 25.8 24.3 22.7 女性 23.0 23.2 23.4 23.0 21.6 Circulation. 2004;110:1042-1046

N Engl J Med 1969;281:555). LAA小血栓（5mm） 　　　 　 LA大血栓

房颤危害 临床症状 心功能（心动过速性心肌病） 栓塞（卒中占80％，外周血栓栓塞占20％） Framingham研究 年卒中率平均5% 50-69岁为1.5%, 80-89岁为23.5% 非瓣膜病房颤卒中率 普通人群的2～7倍 瓣膜病房颤卒中率 普通人群的17倍 非瓣膜病房颤的5倍 约2/3外周栓塞在下肢血管，其中上肢占15％，肾动脉加内脏血管占15％

房颤卒中的严重程度

卒中1年死亡率：有房颤者>无房颤者 P<0.001 1年死亡率（%） ---------- change in y axis OK? Kaarisalo et al. Stroke. 1997;28:311-315.

卒中致残率：有房颤者>非房颤者 卒中患者严重致残率（％） Lin et al. Stroke. 1996;27:1760-1764. This figure was created based on data in a table. No permission is required. Lin et al. Stroke. 1996;27:1760-1764.

无症状脑栓塞(潜在危害?) 无脑栓塞症状房颤患者26％CT检查有梗死灶 年龄>65岁且左房直径>5cm者 >50% 慢性房颤　　　　　　　　　　　 34％ 阵发房颤　　　　　　　　　　　 22% Arch Intern Med 1990;150:2340 Patients With Atrial Fibrillation and Dense Spontaneous Echo Contrast at High Risk A Prospective and Serial Follow-Up Over 12 Months With Transesophageal Echocardiography and Cerebral Magnetic Resonance Imaging Peter Bernhardt, MD*,*, Harald Schmidt, MD , Christoph Hammerstingl, MD*, Berndt Lüderitz, MD, PhD, FACC, FESC, FAHA* and Heyder Omran, MD, PhD * Department of Medicine—Cardiology, University of Bonn, Bonn, Germany St. Marien Hospital Bonn, Bonn, Germany Manuscript received May 16, 2004; revised manuscript received November 3, 2004, accepted November 11, 2004. * Reprint requests and correspondence: Dr. Peter Bernhardt, MRT Center at the Sankt Gertrauden Hospital, Paretzer Str. 12, 10713 Berlin, Germany. (Email: bernhardt@cardiomrt.de ). OBJECTIVES: We sought to assess the prognosis of patients with atrial fibrillation (AF) and dense spontaneous echo contrast (SEC) and to determine the incidence of cerebral embolism under continued oral anticoagulation. BACKGROUND: Patients with AF and dense SEC have an increased risk of cerebral embolism. However, there is little knowledge about the long-term fate and the rate of clinical silent cerebral embolism under continued oral anticoagulation. METHODS: Between 1998 and 2001, all consecutive patients with AF and dense SEC were included in the study. We performed serial and prospective transesophageal echocardiography, cranial magnetic resonance imaging, and clinical examinations during a period of 12 months. RESULTS: A total of 128 patients with dense SEC and AF were included. The control group consisted of 143 patients with faint SEC and AF. During the follow-up period, three patients (2%) had cerebral embolism with neurologic deficits. A total of eight patients (6%) died due to embolic events, and 19 (15%) patients had silent embolism, as documented on cerebral magnetic resonance imaging. Patients with an event had significantly lower left atrial appendage peak emptying velocities and more commonly had a history of previous thromboembolism and denser SEC, as compared with patients without an event. CONCLUSIONS: Patients with AF and dense SEC have a high likelihood of cerebral embolism (22%) and/or death, despite oral anticoagulation. Low peak emptying velocities of the left atrial appendage and dense SEC are independent predictors of an event. Abbreviations and Acronyms   AF = atrial fibrillation   INR = international normalized ratio   LA = left atrium/atrial   LAA = left atrial appendage   LV = left ventricle/ventricular   LVEF = left ventricular ejection fraction   MRI = magnetic resonance imaging   SEC = spontaneous echo contrast   TEE = transesophageal echocardiography

无症状脑栓塞(潜在危害?) 128例持续性房颤（浓SEC\LAAV↓） 1，3，6，12月MRI 脑栓塞者22例 无症状脑栓塞 19例(15%) 有神经障碍 3例 (2%) 死于栓塞 8例 (6%) Patients With Atrial Fibrillation and Dense Spontaneous Echo Contrast at High Risk A Prospective and Serial Follow-Up Over 12 Months With Transesophageal Echocardiography and Cerebral Magnetic Resonance Imaging Peter Bernhardt, MD*,*, Harald Schmidt, MD , Christoph Hammerstingl, MD*, Berndt Lüderitz, MD, PhD, FACC, FESC, FAHA* and Heyder Omran, MD, PhD * Department of Medicine—Cardiology, University of Bonn, Bonn, Germany St. Marien Hospital Bonn, Bonn, Germany Manuscript received May 16, 2004; revised manuscript received November 3, 2004, accepted November 11, 2004. * Reprint requests and correspondence: Dr. Peter Bernhardt, MRT Center at the Sankt Gertrauden Hospital, Paretzer Str. 12, 10713 Berlin, Germany. (Email: bernhardt@cardiomrt.de ). OBJECTIVES We sought to assess the prognosis of patients with atrial fibrillation (AF) and dense spontaneous echo contrast (SEC) and to determine the incidence of cerebral embolism under continued oral anticoagulation. BACKGROUND Patients with AF and dense SEC have an increased risk of cerebral embolism. However, there is little knowledge about the long-term fate and the rate of clinical silent cerebral embolism under continued oral anticoagulation. METHODS Between 1998 and 2001, all consecutive patients with AF and dense SEC were included in the study. We performed serial and prospective transesophageal echocardiography, cranial magnetic resonance imaging, and clinical examinations during a period of 12 months. RESULTS A total of 128 patients with dense SEC and AF were included. The control group consisted of 143 patients with faint SEC and AF. During the follow-up period, three patients (2%) had cerebral embolism with neurologic deficits. A total of eight patients (6%) died due to embolic events, and 19 (15%) patients had silent embolism, as documented on cerebral magnetic resonance imaging. Patients with an event had significantly lower left atrial appendage peak emptying velocities and more commonly had a history of previous thromboembolism and denser SEC, as compared with patients without an event. CONCLUSIONS Patients with AF and dense SEC have a high likelihood of cerebral embolism (22%) and/or death, despite oral anticoagulation. Low peak emptying velocities of the left atrial appendage and dense SEC are independent predictors of an event. (J Am Coll Cardiol 2005;45: 1807–12) © 2005 by the American College of Cardiology Foundation Figure 2. Cerebral magnetic resonance imaging scan in (A) T2- and (B) diffusion-weighted imaging with (arrow) a cerebral lesion after an embolic event. JACC 2005; 45:1807-1812

危险因素评价

+ 卒中危险分层 CHADS 2 计分(NVAF) CHADS2≥ 1 华发林 AFI : 卒中史、高龄、高血压和 糖尿病 SPAF : 卒中史、高血压、近期心衰、75岁以上女性 年卒中率(%) 危险因素　 记分 近期心衰史 CHF 高血压病史 HP ≥ 75岁 AGE 糖尿病 DM 脑卒中TIA Stroke 1 2 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. CHADS2≥ 1 华发林 CHADS 2 计分 Gage et al. JAMA, 2001, 285: 2864–2870

脑卒中危险分层 A Risk Score for Predicting Stroke or Death in Individuals With New-Onset Atrial Fibrillation in the Community The Framingham Heart Study Thomas J. Wang, MD; Joseph M. Massaro, PhD; Daniel Levy, MD; Ramachandran S. Vasan, MD; Philip A. Wolf, MD; Ralph B. D'Agostino, PhD; Martin G. Larson, ScD; William B. Kannel, MD; Emelia J. Benjamin, MD, ScM JAMA. 2003;290:1049-1056. Context  Prior risk stratification schemes for atrial fibrillation (AF) have been based on randomized trial cohorts or Medicare administrative databases, have included patients with established AF, and have focused on stroke as the principal outcome. Objective  To derive risk scores for stroke alone and stroke or death in community-based individuals with new-onset AF. Design, Setting, and Participants  Prospective, community-based, observational cohort in Framingham, Mass. We identified 868 participants with new-onset AF, 705 of whom were not treated with warfarin at baseline. Risk scores for stroke (ischemic or hemorrhagic) and stroke or death were developed with censoring when warfarin initiation occurred during follow-up. Event rates were examined in low-risk individuals, as defined by the risk score and 4 previously published risk schemes. Main Outcome Measures  Stroke and the combination of stroke or death. Results  During a mean follow-up of 4.0 years free of warfarin use, stroke alone occurred in 83 participants and stroke or death occurred in 382 participants. A risk score for stroke was derived that included the following risk predictors: advancing age, female sex, increasing systolic blood pressure, prior stroke or transient ischemic attack, and diabetes. With the risk score, 14.3% of the cohort had a predicted 5-year stroke rate 7.5% (average annual rate 1.5%), and 30.6% of the cohort had a predicted 5-year stroke rate 10% (average annual rate 2%). Actual stroke rates in these low-risk groups were 1.1 and 1.5 per 100 person-years, respectively. Previous risk schemes classified 6.4% to 17.3% of subjects as low risk, with actual stroke rates of 0.9 to 2.3 per 100 person-years. A risk score for stroke or death is also presented. Conclusion  These risk scores can be used to estimate the absolute risk of an adverse event in individuals with AF, which may be helpful in counseling patients and making treatment decisions. Author Affiliations: Framingham Heart Study, Framingham (Drs Wang, Massaro, Levy, Vasan, Wolf, D'Agostino, Larson, Kannel, and Benjamin); Cardiology Division, Massachusetts General Hospital, Harvard Medical School (Dr Wang); Divisions of Cardiology and Epidemiology, Beth Israel Deaconess Hospital, Harvard Medical School (Dr Levy); Department of Mathematics, Boston University (Drs Massaro and D'Agostino), Boston; National Heart, Lung, and Blood Institute, Bethesda, Md (Dr Levy); and Department of Neurology (Dr Wolf), Division of Cardiology (Drs Levy, Vasan, and Benjamin), and Department of Preventive Medicine (Drs Levy, D'Agostino, Wolf, Kannel, and Benjamin), Boston University School of Medicine, Boston. JAMA 2003; 290:1049-1056 Framingham Heart Study

传统危险因素的局限性 ---“低危定义”的相对性 113例房颤患者的病例资料，年龄<60岁的孤立性房颤59例（52.2％） 孤立性房颤17%检出左房血栓, 29%检出左房血栓或左房自发显影 杜昕，刘晓惠，马长生 中国医刊 2005

房颤卒中预防 抗栓治疗 左心耳堵闭 （ PLAATO，WATCHMAN ） 外科结扎LAA 恢复并维持窦性心律（导管消融根治）

房颤的抗栓治疗 单个抗血小板药物（阿斯匹林） VS.华发林 复合抗血小板药（阿斯匹林＋氯吡格雷） 单个抗血小板药物＋华发林 复合抗血小板药物＋华发林（PCI后） 肝素（暂时替代性措施） 直接凝血酶抑制剂(功败垂成)

ASA VS.华发林预防房颤卒中荟萃分析 16个试验中的9874例患者平均随访1.7年 卒中减少: 绝对风险减少: 1.5%每年(一级预防) 22% 绝对风险减少: 1.5%每年(一级预防) 2.5%每年(二级预防) Figure 8. Antithrombotic therapy for prevention of stroke (ischemic and hemorrhagic) in patients with nonvalvular AF: warfarin compared with aspirin and aspirin compared with placebo. Adapted with permission from Hart et al. (170,200) Ann Intern Med 1999;131:492–501. (The American College of Physicians–American Society of Internal Medicine is not responsible for the accuracy of the translation.) Purpose: To characterize the efficacy and safety of anticoagulants and antiplatelet agents for prevention of stroke in patients with atrial fibrillation. Data Sources: Randomized trials identified by using the search strategy developed by the Cochrane Collaboration Stroke Review Group. Study Selection: All published randomized trials testing antithrombotic agents to prevent stroke in patients with atrial fibrillation. Data Extraction: Data on interventions, number of participants, duration of exposure and occurrence of all stroke (ischemic and hemorrhagic), major extracranial bleeding, and death were extracted independently by two investigators. Data Synthesis: Sixteen trials included a total of 9874 participants (mean follow-up, 1.7 years). Adjusted-dose warfarin (six trials, 2900 participants) reduced stroke by 62% (95% CI, 48% to 72%); absolute risk reductions were 2.7% per year for primary prevention and 8.4% per year for secondary prevention. Major extracranial bleeding was increased by warfarin therapy (absolute risk increase, 0.3% per year). Aspirin (six trials, 3119 participants) reduced stroke by 22% (CI, 2% to 38%); absolute risk reductions were 1.5% per year for primary prevention and 2.5% per year for secondary prevention. Adjusted-dose warfarin (five trials, 2837 participants) was more efficacious than aspirin (relative risk reduction, 36% [CI, 14% to 52%]). Other randomized comparisons yielded inconclusive results. Conclusions: Adjusted-dose warfarin and aspirin reduce stroke in patients with atrial fibrillation, and warfarin is substantially more efficacious than aspirin. The benefit of antithrombotic therapy was not offset by the occurrence of major hemorrhage among participants in randomized trials. Judicious use of antithrombotic therapy, tailored according to the inherent risk for stroke, importantly reduces Hart et al. Ann Intern Med 1999;131:492–501

ASA VS.华发林预防房颤卒中荟萃分析 16个试验中的9874例患者平均随访1.7年 卒中减少: 绝对风险减少: 2.7%每年(一级预防) 62% 绝对风险减少: 2.7%每年(一级预防) 8.4%每年(二级预防) 颅外出血风险增加: 0.3%每年 Figure 8. Antithrombotic therapy for prevention of stroke (ischemic and hemorrhagic) in patients with nonvalvular AF: warfarin compared with aspirin and aspirin compared with placebo. Adapted with permission from Hart et al. (170,200) Ann Intern Med 1999;131:492–501. (The American College of Physicians–American Society of Internal Medicine is not responsible for the accuracy of the translation.) Purpose: To characterize the efficacy and safety of anticoagulants and antiplatelet agents for prevention of stroke in patients with atrial fibrillation. Data Sources: Randomized trials identified by using the search strategy developed by the Cochrane Collaboration Stroke Review Group. Study Selection: All published randomized trials testing antithrombotic agents to prevent stroke in patients with atrial fibrillation. Data Extraction: Data on interventions, number of participants, duration of exposure and occurrence of all stroke (ischemic and hemorrhagic), major extracranial bleeding, and death were extracted independently by two investigators. Data Synthesis: Sixteen trials included a total of 9874 participants (mean follow-up, 1.7 years). Adjusted-dose warfarin (six trials, 2900 participants) reduced stroke by 62% (95% CI, 48% to 72%); absolute risk reductions were 2.7% per year for primary prevention and 8.4% per year for secondary prevention. Major extracranial bleeding was increased by warfarin therapy (absolute risk increase, 0.3% per year). Aspirin (six trials, 3119 participants) reduced stroke by 22% (CI, 2% to 38%); absolute risk reductions were 1.5% per year for primary prevention and 2.5% per year for secondary prevention. Adjusted-dose warfarin (five trials, 2837 participants) was more efficacious than aspirin (relative risk reduction, 36% [CI, 14% to 52%]). Other randomized comparisons yielded inconclusive results. Conclusions: Adjusted-dose warfarin and aspirin reduce stroke in patients with atrial fibrillation, and warfarin is substantially more efficacious than aspirin. The benefit of antithrombotic therapy was not offset by the occurrence of major hemorrhage among participants in randomized trials. Judicious use of antithrombotic therapy, tailored according to the inherent risk for stroke, importantly reduces Hart et al. Ann Intern Med 1999;131:492–501

ASA VS.华发林预防房颤卒中荟萃分析 16个试验中的9874例患者平均随访1.7年 卒中减少: 36% Figure 8. Antithrombotic therapy for prevention of stroke (ischemic and hemorrhagic) in patients with nonvalvular AF: warfarin compared with aspirin and aspirin compared with placebo. Adapted with permission from Hart et al. (170,200) Ann Intern Med 1999;131:492–501. (The American College of Physicians–American Society of Internal Medicine is not responsible for the accuracy of the translation.) Purpose: To characterize the efficacy and safety of anticoagulants and antiplatelet agents for prevention of stroke in patients with atrial fibrillation. Data Sources: Randomized trials identified by using the search strategy developed by the Cochrane Collaboration Stroke Review Group. Study Selection: All published randomized trials testing antithrombotic agents to prevent stroke in patients with atrial fibrillation. Data Extraction: Data on interventions, number of participants, duration of exposure and occurrence of all stroke (ischemic and hemorrhagic), major extracranial bleeding, and death were extracted independently by two investigators. Data Synthesis: Sixteen trials included a total of 9874 participants (mean follow-up, 1.7 years). Adjusted-dose warfarin (six trials, 2900 participants) reduced stroke by 62% (95% CI, 48% to 72%); absolute risk reductions were 2.7% per year for primary prevention and 8.4% per year for secondary prevention. Major extracranial bleeding was increased by warfarin therapy (absolute risk increase, 0.3% per year). Aspirin (six trials, 3119 participants) reduced stroke by 22% (CI, 2% to 38%); absolute risk reductions were 1.5% per year for primary prevention and 2.5% per year for secondary prevention. Adjusted-dose warfarin (five trials, 2837 participants) was more efficacious than aspirin (relative risk reduction, 36% [CI, 14% to 52%]). Other randomized comparisons yielded inconclusive results. Conclusions: Adjusted-dose warfarin and aspirin reduce stroke in patients with atrial fibrillation, and warfarin is substantially more efficacious than aspirin. The benefit of antithrombotic therapy was not offset by the occurrence of major hemorrhage among participants in randomized trials. Judicious use of antithrombotic therapy, tailored according to the inherent risk for stroke, importantly reduces Hart et al. Ann Intern Med 1999;131:492–501

ASA VS.华发林预防房颤卒中荟萃分析 16个试验中的9874例患者平均随访1.7年 结论 监测调整剂量的华发林和阿斯匹林可减少房颤卒中 华发林较阿斯匹林更有效 抗栓治疗的益处不会因增加出血而减小 Figure 8. Antithrombotic therapy for prevention of stroke (ischemic and hemorrhagic) in patients with nonvalvular AF: warfarin compared with aspirin and aspirin compared with placebo. Adapted with permission from Hart et al. (170,200) Ann Intern Med 1999;131:492–501. (The American College of Physicians–American Society of Internal Medicine is not responsible for the accuracy of the translation.) Purpose: To characterize the efficacy and safety of anticoagulants and antiplatelet agents for prevention of stroke in patients with atrial fibrillation. Data Sources: Randomized trials identified by using the search strategy developed by the Cochrane Collaboration Stroke Review Group. Study Selection: All published randomized trials testing antithrombotic agents to prevent stroke in patients with atrial fibrillation. Data Extraction: Data on interventions, number of participants, duration of exposure and occurrence of all stroke (ischemic and hemorrhagic), major extracranial bleeding, and death were extracted independently by two investigators. Data Synthesis: Sixteen trials included a total of 9874 participants (mean follow-up, 1.7 years). Adjusted-dose warfarin (six trials, 2900 participants) reduced stroke by 62% (95% CI, 48% to 72%); absolute risk reductions were 2.7% per year for primary prevention and 8.4% per year for secondary prevention. Major extracranial bleeding was increased by warfarin therapy (absolute risk increase, 0.3% per year). Aspirin (six trials, 3119 participants) reduced stroke by 22% (CI, 2% to 38%); absolute risk reductions were 1.5% per year for primary prevention and 2.5% per year for secondary prevention. Adjusted-dose warfarin (five trials, 2837 participants) was more efficacious than aspirin (relative risk reduction, 36% [CI, 14% to 52%]). Other randomized comparisons yielded inconclusive results. Conclusions: Adjusted-dose warfarin and aspirin reduce stroke in patients with atrial fibrillation, and warfarin is substantially more efficacious than aspirin. The benefit of antithrombotic therapy was not offset by the occurrence of major hemorrhage among participants in randomized trials. Judicious use of antithrombotic therapy, tailored according to the inherent risk for stroke, importantly reduces Hart et al. Ann Intern Med 1999;131:492–501

非瓣膜病房颤(NVAF) ASA VS.华发林随机对比研究 Age 40-80 平均随访19个月 Randomize (n =704 ) ASA 150-160mg N=369 华发林 INR 2.0-3.0 N=335 主要终点: 死亡和缺血性卒中 次要终点: 腔隙性脑梗塞, 外周栓塞, TIA, 无症状卒中, AMI, 严重出血

华发林 VS.阿斯匹林 华发林组 阿斯匹林组 △ p值 INR2~3(74.48%) 160mg 主要终点 2.7% 6.0% 44% 0.03 缺血卒中 1.8% 4.6% 62% 0.04 总栓塞　　　5.4% 10.6% 52% 0.01 次要终点 5.67% 7.05% 0.457 ICH 0.89% 0 <0.05 major 1.49% 0 <0.05 Major+minor 6.86% 2.44% <0.05 主要终点: 死亡和缺血性卒中 次要终点: 腔隙性脑梗塞, 外周栓塞, TIA, 无症状卒中, AMI, 严重出血

全因死亡 Total 8 4 P=NS Ischemic Stroke 2 1 Hemorrhage 0 2 Neoplasia 2 1 Aspirin N=369 Warfarin N=335 Ischemic Stroke 2 1 Hemorrhage 0 2 Neoplasia 2 1 AMI 1 0 HF 1 0 SD 2 0 Total 8 4 P=NS 缺血性脑卒中1例、肿瘤1例、严重出血2例。阿司匹林组8例死亡中包括缺血性脑卒中2例、肿瘤2例、急性心肌梗死1例、严重心力衰竭1例、心脏骤停2例。

结论 中国 NVAF 多数 (63.5% )至少有1个危险因素 华发林有增加出血之风险 华发林 (INR 2.0-3.0) 较ASA (150-160mg) 主要终点减少 44% 血栓栓塞事件减少 52% 联合终点减少 36%

房颤的抗栓治疗 单个抗血小板药物（阿斯匹林） 复合抗血小板药（阿斯匹林＋氯吡格雷） 单个抗血小板药物＋华发林 复合抗血小板药物＋华发林（PCI后） 肝素（暂时替代性措施） 直接凝血酶抑制剂(功败垂成) 华发林

阿斯匹林＋氯吡格雷 房颤氯吡格雷试验 (ACTIVE－W ) 入选 6500 例至少伴有一项卒中危险因素的房颤患者 阿司匹林＋氯吡格雷 VS. 华法林 主要终点事件（卒中、心肌梗死、栓塞和血管性死亡） 双重抗血小板组：5.6%/年 华法林组： 3.9%/年 两组大出血发生率相同 2005年9月提前中止 ???? AHA 2005，Dallas

房颤的抗栓治疗 单个抗血小板药物（阿斯匹林） 复合抗血小板药（阿斯匹林＋氯吡格雷） 单个抗血小板药物＋华发林 复合抗血小板药物＋华发林（PCI后） 肝素（暂时替代性措施） 直接凝血酶抑制剂(功败垂成) 华发林

抗血小板药物＋华发林 --- 增加出血并发症率 FFAACS　(French Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane) 有卒中史、>65岁的房颤患者157例 华法林（INR2.0～2.6）＋安慰剂 VS.　　　 华法林＋阿司匹林100mg/d 严重出血并发症的发生率 华法林＋阿司匹林组：13.1% 华法林组：1.2% 研究仅进行了0.84年提前结束 Thérapie 2000;55:681-9

房颤合并冠心病 房颤合并冠心病多见 华法林足以预防冠脉事件 华法林＋阿司匹林—IIb类适应证（房颤指南） 同时应用中等强度的抗凝治疗和阿司匹林也可以接受（ACCP7） 注意出血并发症

房颤的抗栓治疗 单个抗血小板药物（阿斯匹林） 复合抗血小板药（阿斯匹林＋氯吡格雷） 单个抗血小板药物＋华发林 复合抗血小板药物＋华发林（PCI后） 肝素（暂时替代性措施） 直接凝血酶抑制剂(功败垂成) 华发林

PCI后＋房颤 复合抗血小板药物（ASA+Plavix）＋华发林

房颤的抗栓治疗 单个抗血小板药物（阿斯匹林） 复合抗血小板药（阿斯匹林＋氯吡格雷） 单个抗血小板药物＋华发林 复合抗血小板药物＋华发林（PCI后） 肝素（暂时替代性措施） 直接凝血酶抑制剂(功败垂成) 华发林

房颤的抗栓治疗 单个抗血小板药物（阿斯匹林） 复合抗血小板药（阿斯匹林＋氯吡格雷） 单个抗血小板药物＋华发林 复合抗血小板药物＋华发林（PCI后） 肝素（暂时替代性措施） 直接凝血酶抑制剂 华发林 XIMELEGATRAN 口服 固定剂量 不需监测INR 起效快 肝毒性 功败垂成

房颤的抗栓治疗 单个抗血小板药物（阿斯匹林） 复合抗血小板药（阿斯匹林＋氯吡格雷） 单个抗血小板药物＋华发林 复合抗血小板药物＋华发林（PCI后） 肝素（暂时替代性措施） 直接凝血酶抑制剂(功败垂成) 华发林!

抗凝治疗溶解血栓 31例合并左心房血栓患者 小剂量华发林（2mg/d） 左心房血栓均由经食道超声心动图证实和随访 体积最大者3cm×4cm×6cm，最小者1cm×1cm×0.5cm 3例失访，28例随访到血栓消失 血栓消失的时间在2～12个月，85.7%血栓消失的时间<６个月 马长生, 刘旭, 董建增, 王乐丰, 胡大一.　二尖瓣狭窄合并左心房血栓患者小 剂量华法令抗凝溶栓作用评价.中华心血管病杂志, 1996, 24( 4): 285-287

抗凝治疗溶解血栓 123例待复律房颤TEE，11例有左房血栓（9％） 华发林抗凝(INR>2)治疗平均4周(4～9周)后9例血栓消失（81.8％） Figure 1. TEEs (horizontal plane) of the left atrium and left atrial appendage (patient No. 4 of the table). Panel A shows the left atrium and appendage in a 60-year-old woman affected by mitral stenosis and aortic regurgitation. The duration of atrial fibrillation was unknown. Note the pedunculated thrombus (white arrow) at the mouth of left atrial appendage. Panel B shows the same patient after 4 weeks of warfarin. The thrombus had completely resolved. Scant spontaneous echocontrast can be seen in left atrial appendage. Atrial Thrombi Resolution After Prolonged Anticoagulation in Patients With Atrial Fibrillation* A Transesophageal Echocardiographic Study CHEST 1999;115:140~143

抗凝治疗使血栓溶解 174例左房血栓患者 华法林抗凝治疗48±18天后，80.1%的患者TEE检查左房血栓溶解 未溶解的血栓即使延长抗凝治疗时间也很少溶解？ Am Heart J 2000;140:150-6

房颤抗凝主要指南 7th ACCP: Oct. 2004 Singer DE,Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ: Antithrombotic and thrombolytic therapy. Chest 2004;126;429-456 ACC/AHA/ESC Sep. 2001 (undergoing revision) Fuster V, Rydén LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) developed in collaboration with the North American Society for Pacing and Electrophysiology. J Am Coll Cardiol 2001;38:1231-1266 AF Guideline, Royal College of Physicians Oct.2005 (draft)

房颤患者抗凝治疗指南-ACCP7 以一言蔽之: 65岁以下无危险因素者不用,其余均用 年龄 危险因素 建议 年龄 危险因素 建议 <65岁 无 阿司匹林/No 有 华法林 65-75岁 无 阿司匹林或华法林 >75岁 所有病人 华法林 以一言蔽之: 65岁以下无危险因素者不用,其余均用 低危个体如患者本人更担心卒中并发症，也可选用华法林 Chest 2004;126;429-456

房颤抗凝治疗 ACC/AHA/ESC 2001版2006更新 华发林抗凝强度INR 2-3（房扑同房颤） 华发林 卒中史、TIA、全身栓塞 ≥ 2个以下因素（＞ 75岁、高血压、心衰、LVEF＜ 35%、糖尿病） 阿斯匹林 325mg 或华发林 以下任意一个因素（＞ 65岁、女性、高血压、心衰、LVEF＜ 35%、糖尿病、CAG）

华发林应用

抗凝治疗强度与血栓和出血事件 Figure 7. Adjusted odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation in randomized trials of antithrombotic therapy for patients with AF. The data are from Hylek et al (203,207). Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996;335:540–6. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994;120:897–902.

华法林发生“缺血性卒中”时的INR INR 1.8 4.0 1.7 3.0 1.6 1.5 2.0 1.4 1.3 PT比值 1.0 1.2 1.1 1.0 4.0 3.0 2.0 1.0 PT比值 ISI 2.4 INR AFASAK CAFA SPAFI BAATAF SPINAF 指南推荐INR ：2-3 不同研究INR的目标范围

华法林发生“出血性卒中”时的INR INR 4.0 1.8 3.0 1.7 1.6 2.0 1.5 1.4 PT比值 1.0 1.3 1.2 1.1 1.0 PT比值 ISI 2.4 INR AFASAK CAFA SPAF II BAATAF SPINAF 指南推荐INR ：2-3 不同研究INR的目标范围

日本房颤卒中二级预防试验 严重出血指颅内出血、视网膜出血、需要输血或住院的大出血 Stroke 2000;31:817-21

3482 次INR值分布 2378（INR 2~3 , 68.3% ） 70 60 50 40 30 20 10 Follow-up period :median 19m（2～24m） Mean dose of warfarin: 3.19±0.69 mg（1.5-5mg） % <1.0 1.0-1.4 1.5-1.9 2.0-2.4 2.5-2.9 3.0-3.4 3.5-3.9 >4.0 INR

Combined Endpoint Occurrence (%) 华发林组血栓栓塞事件 INR 2.0 N=15 N=4 3.0 2.5 There were 19 cases of thromboembolic events, most of them occurred in INR <2.0. 2.0 Combined Endpoint Occurrence (%) 1.5 1.0 华法林的平均剂量为3.19±0.69 mg（1.5-5）。华法林达到目标范围的时间，平均为23日，（18-43天） 总血栓栓塞事件（缺血性卒中合并体循环栓塞）19例（5.4%），与INR的关系 INR<2 占15例，INR2-3 占4例 0.5 <1.0 1.0-1.4 1.5-1.9 2.0-2.4 2.5-2.9 >3.0 INR

华发林组出血事件 5例严重出血的INR 颅内3例 3.85, 4.89, 5.76 消化道2例 4.75, 4.89, 5.24 % INR Minor bleeding Major bleeding 10 8 6 4 2 5例严重出血的INR 颅内3例 3.85, 4.89, 5.76 消化道2例 4.75, 4.89, 5.24 % 华法林组总出血发生率为23例6.87%，其中严重出血5例（脑出血3例，上消化道出血2例），2例导致死亡；轻微出血18例（占5.37%）。但华法林组5例严重出血的INR值均>3.0。牙龈出血5例，鼻2例，皮肤粘膜瘀斑7例，血尿2例，球结膜出血1例，阴道出血1例。 <1.0 1.0-1.9 2.0-2.9 3.0-3.9 4.0-4.9 5.0-5.9 INR

抗凝治疗现状 美国前10名处方药,全美年3百万人(3千2百万处方) 用华发林,当然也是麻烦最多的药物之一 　抗凝治疗现状 美国前10名处方药,全美年3百万人(3千2百万处方) 用华发林,当然也是麻烦最多的药物之一 ATRIA研究（2001）：美国适合抗凝治疗的患者 年龄(岁) <55 55~64 65~74 75~84 >85 华法林率 43% 58.1% 60.7% 57.3% 34.5% 总应用率 55% 中国部分地区回顾性调查（2003）: 住院患者抗凝治疗率 6.6% 胡大一等全国人群流调（2003）: 房颤患者抗凝治疗率 2%

普通门诊华法林治疗 门诊就诊患者138例,至少有5次INR记录 INR<1.8者占63％ INR>2.5者占13.8％ DU Xin, et al. Chin Med J 2005;118( 14):1206-1209

影响华法林应用的原因 116200非瓣膜性房颤患者及医生的调查 华法林的处方率48％ 遇到消化道和颅内出血后，医生给其他患者开华法林的处方率90天内减少21％， 90～180天减少40％ 遇到血栓栓塞后，医生给其他患者开华法林的处方率没有显著改变 BMJ 2006；332：141

华法林的起始剂量 美国指南推荐以5mg/日开始华法林治疗 我国患者？ 53例NVAF患者，随机分为以5mg 和3mg 起始治疗 连续服用1周后， 5mg组71.4%的患者INR达目标范围, 3mg组仅有44.0%的患者INR达标

华法林INR变化规律 华发林3mg QN 华发林5mg QN 天 安贞医院房颤中心

华法林过量时的处理 INR <5，无明显出血，减量或停服一次 INR 5-9，停华法林l-2次；如病人出血危险性高，停用一次同时口服维生素K1（1-2.5mg） INR>9但无明显出血，口服维生素K13-5mg，INR将在24-48小时内降低，必要时可重复使用 严重出血或INR>20时，应用维生素K110 mg，静脉输注新鲜血浆和凝血酶原浓缩物

华法林过量时INR的回落情况 INR 3~4，平均需要停药2天; INR>4.0，需要停药4~5天 安贞医院房颤中心

华法林应用注意事项 可空腹也可和食物混食 尽可能晚上用 剂量差异大 INR3天,每周2次至稳定,每周1次,每2周1次,每月1次 头日漏食,第2日不需加量;连续2日以上漏食,应监测 忌易伤运动 食物相对固定,忌中草药及茶 大手术5-7天前停,拔牙提前3天停 房颤有血栓栓塞危险因素者肝素替代 厂家区别 ……

病例 1 M64，PAF，HPN,华法林1年， 医生告之服用华法林“太麻烦”，建议改用阿司匹林治疗 1年内发生3次TIA

病例2 45岁阵发性房颤患者，无危险因素 每次房颤发作持续2～3天，房颤病史10年 近一周房颤持续，准备行电转复 TEE左房内大血栓

病例3 男性79岁，体检时发现房颤 第一位医生建议他应用华法林抗凝治疗，3mg QN，并告之3天后查INR 患者请另外一个医生帮他看了化验单，医生看到INR在治疗范围后，告之继续按原来的方案服药，每月复查一次INR 半个月后，患者出现昏迷，磁共振检查证实为颅内出血，当时INR为13.8，昏迷10天后，患者死亡

病例4 男性，35岁，DCM、CHF 4年，持续性房颤6月，TEE左房血栓 给予华法林抗凝治疗3mg/d，因肺部感染同时给予左旋氧氟沙星0.2 iv drip bid， 6天后INR达3.5 停用左旋氧氟沙星，华法林仍以3mg/d口服，4天后INR逐渐降至1.56 将华法林调整至3.75mg，并以此剂量维持，INR控制在1.90

病例5 女性，73岁，冠心病，稳定性心绞痛，一直服用阿司匹林，近来出现阵发性房颤，既往无溃疡病史，医生建议加用华法林 服药3个月后，发生上消化道大出血，出血时INR为2.3

病例6 女性，62岁，风湿性心脏病，二尖瓣狭窄40余年，持续性房颤10余年 曾因肢体动脉栓塞及肠系膜动脉栓塞前后接受了动脉拉栓、小肠切除、截肢等共7次手术，还曾经发生过一次脑卒中 一直未用华法林抗凝治疗 在最后一次术前请心内科会诊，才开始应用华法林抗凝治疗。连续口服3mg/晚，3天后INR为4.12，停用华法林，停药后第3天复查INR，为6.08 最后以1mg/天，隔日一次，使INR维持在2.5左右

病例7 复律之前三后四问题 INR 可达龙 200 mg tid, 华发林 3mg qd, 倍他乐克 25mg bid 蒙诺 10mg qd 男性，62岁，阵发房颤５年，近 半年增多，每周1～2次，每次持 续1～9小时，21小时前再次发作 ，ECG房颤,110BPM 高血压、糖尿病，甲状腺功能正常 INR 华发林3周后用可达龙　　 华发林　　3mg qd, 倍他乐克　25mg bid 蒙诺　　　10mg qd 心律平　 450 mg PO. 华发林　　3mg qd, 倍他乐克　25mg bid 蒙诺　　　10mg qd DC. 心律平　 150 mg tid　或可达龙 华发林　 3mg qd, 倍他乐克 25mg bid 蒙诺　　 10mg qd

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