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从房颤指南看房颤实践 ---- 差距与方向

从房颤指南看房颤实践 ---- 差距与方向. 北京大学人民医院 张海澄. 美国心律失常住院概况. Paroxysmal Supraventricular Tachycardia - 6%. Premature beats - 6%. Atrial Flutter - 4%. Atrial Fibrillation - 21%. Sick Sinus Syndrome - 9%. Conduction Abnormailites - 8%. Ventricular Fibrillation - 2%. Miscellaneous - 21%.

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从房颤指南看房颤实践 ---- 差距与方向

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  1. 从房颤指南看房颤实践----差距与方向 北京大学人民医院 张海澄

  2. 美国心律失常住院概况 Paroxysmal Supraventricular Tachycardia - 6% Premature beats - 6% Atrial Flutter - 4% Atrial Fibrillation - 21% Sick Sinus Syndrome - 9% Conduction Abnormailites - 8% Ventricular Fibrillation - 2% Miscellaneous - 21% Ventricular Tachycardia - 10% Stroke rate is approximately 1-3% without anticoagulation Adapted from Bialy et al.

  3. 非瓣膜性房颤 • 美国每年50万卒中 • 约20%发生于房颤患者 房颤引起的卒中 % Stroke 22(18), 1991 3000838-7

  4. By 2050, atrial fibrillation (AF) may affect 12 million Americans AF is a powerful risk factor for stroke AF independently raises risk 5-fold in all age groups AF is responsible for ≈ 15%-20% of all strokes AF is also an independent risk factor for recurrence and severity Severe strokes cost twice as much as mild strokes, despite similar diagnostic testing Comorbidities like AF and ischemic heart disease predict higher costs Risk for 55-year-old adults who smoke, have diabetes, and have blood pressures of 138-148 mm Hg AHA: Heart Disease and Stroke Statistics2010 Update Lloyd-Jones DM, et al. Circulation. 2010;121:e1-e170.

  5. 先抗栓 再评估抗栓治疗贯穿始终

  6. 房颤的治疗原则 抗栓防栓 心率控制 节律控制 防止血栓栓塞 控制症状 控制症状 减少出血风险 防治心动过速性心肌病 减少住院 治疗目标 减少住院 C B A 9

  7. 房颤的治疗原则 心率控制 节律控制 抗栓防栓 控制症状 控制症状 防止血栓栓塞 防治心动过速性心肌病 减少住院 减少出血风险 治疗目标 减少住院 A B C 10

  8. Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate -100% 50% -50% 100% 0 房颤抗凝与卒中风险 Hart et al. Ann Intern Med. 1999;131:492-501.

  9. 非瓣膜性房颤患者华法林应用情况 %  • 在近3个月内无抗凝禁忌证的房颤患者仅55%应用华法林 • 其他研究：17%-50% Ann Int Med 131(12), 1999 3000838-13

  10. Enrollment End of registry Rhythm Control Rate Control 100 100 80 80 60 60 Patients assigned rhythm control receiving warfarin (%) Patients assigned rate control receiving warfarin (%) 40 40 20 20 0 0 0 n=279 1 n=383 2 n=214 3 n=38 4 n=21 5 n=7 6 n=0 ≥ 2 n=280 0 n=124 1 n=182 2 n=150 3 n=35 4 n=24 5 n=3 6 n=1 ≥ 2 n=213 CHADS2 score CHADS2 score AFFECTS Registry: Warfarin Use in AF Patients Is Not Yet in Line With Evidence-Based Recommendations Anticoagulant use was high among participating cardiologists, but still did not match guidelines and evidence-based recommendations for AF patients. The AFFECTS study did not report the reasons that physicians chose against providing anticoagulation. AFFECTS: Atrial Fibrillation: Focus on Effective Clinical Treatment Strategies Kowey PR, et al. Am J Cardiol. 2010;105:1130-1134.

  11. Low risk (n=34,338) 40.1% treated Moderate risk (n=105,563) 43.5% treated High risk (n=31,492) 42.1% treated 60 50 40 30 Patients receiving warfarin (%) 20 10 0 0 1 2 3 4 5 6 n=34,338 n=58,004 n=47,559 n=20,589 n=7711 n=2625 n=567 CHADS2 score Total (n=171,393) Newly diagnosed AF/flutter (n=51,907) Pre-existing diagnosed AF/flutter (n=119,486) Anticoagulation Is Still Underutilized in AF Patients With High Stroke Risk Warfarin use within 30 days of the first diagnosis assessed according to stroke risk, estimated by CHADS2 score 17.1万人 Zimetbaum PJ, et al. Am J Med. 2010;123:446-453.

  12. 中国不同危险的急诊房颤患者抗凝治疗情况 中国房颤CHADS2≥2的患者仅有19%接受华法林抗凝治疗

  13. 非瓣膜性房颤患者华法林应用情况 Low INR <1.6 Efficacy  4-fold TherapeuticINR 2-3 High INR >3.2 % Bungard: Pharmacotherapy 20:1060, 2001 3000838-14

  14. INR与颅内出血风险 20 15 颅内出血 脑栓塞 10 Odds ratio 5 1 1.0 2.0 3.0 4.0 5.0 6.0 7.0 INR 1Fuster V, et al. Circulation 2006;114:e257-e354. 2Oden A, et al. Thromb Res 2006;117:493-499.

  15. 血栓栓塞风险评估与出血风险评估

  16. 非瓣膜性AF 年龄65-95岁 n = 1733 n=120 n=463 n=523 n=337 n=220 n=65 n=5 CHADS2未抗栓患者的卒中风险 CHADS:congestive heart failure (CHF), hypertension, age >75 years, diabetes, stroke 1Fuster V, et al. Circulation. 2006;114:e257-e354. 2Gage BF, et al. JAMA. 2001;285:2864-2870.

  17. CHA2DS2-VASc评分

  18. CHA2DS2-VAS评分 • 评分≥2：口服抗凝治疗，INR 2.0~3.0 • 评分=1：口服抗凝或阿司匹林75~325mg/日，但更推荐口服抗凝治疗 • 评分=0：阿司匹林75~325mg/日或不采取抗栓治疗，但更推荐不采取抗栓治疗

  19. OBRI Score 0: low risk 1-2: moderate risk 3-4: high risk Outpatient Bleeding Risk Index: A Simple Index for Bleeding Risk Evaluation 8 • OBRI: • History of stroke • Age > 65 years • History of gastrointestinal bleeding • Presence of ≥ 1 comorbid condition • Recent myocardial infarction • Renal insufficiency • Severe anemia • Diabetes 6 4 *Incidence (%) 2 0 Triple therapy OAC + 1 antiplatelet OAC *Incidence: number of major bleeding events during antithrombotic treatment per 100 months of treatment OBRI: outpatient bleeding risk index Airaksinen KE, et al. Am J Cardiol. 2010;106:175-179.

  20. 房颤患者出血风险评估表（HAS-BLED评分法）

  21. 对达比加群酯的特殊推荐

  22. New Anticoagulants ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecogin alfa) sTM (ART-123) RivaroxabanApixaban LY517717 YM150 DU-176b Betrixaban TAK 442 IXa VIIIa Va AT Xa FondaparinuxIdraparinux II DX-9065a IIa Dabigatran Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2007

  23. RE-LY:试验设计 R 伴有中度至高度卒中或全身性栓塞风险的非瓣膜性房颤 (至少伴有一项额外的风险因素)* 华法林 1 mg, 3 mg, 5 mg (INR 2.0–3.0) n=6000 达比加群酯 110 mg BID n=6000 达比加群酯 150 mg BID n=6000 • 主要目的：脑卒中和体循环栓塞的发生率非劣效于华法林 • 随访期最少为1年，最多为3年，平均为2年 *Severe heart-valve disorder, stroke ≤14 days or severe stroke ≤6 months before screening, increased haemorrhage risk, creatinine clearance <30 mL/min, active liver disease, pregnancy; BID = twice daily; INR = international normalized ratio Ezekowitz MD et al. Am Heart J 2009;157:805–10; Connolly SJ et al. N Engl J Med 2009;361:1139–51 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation in China

  24. RE-LY主要终点：卒中或全身性栓塞发生率 1.8 1.5 1.2 卒中/全身性栓塞 (%/年) 0.9 0.6 0.3 0.0 达比加群110 mg BID 达比加群150 mg BID 华法林 事件数量: 183/6015 134/6076 202/6022 RR 0.90 (95% CI: 0.74–1.10) P<0.001 (NI) RR 0.65 (95% CI: 0.52–0.81) P<0.001 (Sup) 1.71 1.54 35% 1.11 BID = 每日两次; NI = 非劣效性; RR = 相对危险度; RRR =相对危险降幅; Sup = 优效性 Connolly SJ et al. N Engl J Med 2010;363:1875–6 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation in China

  25. RE-LY主要终点：卒中或全身性栓塞发生率 华法林 达比加群 110 mg BID 达比加群 150 mg BID RR 0.90 (95% CI: 0.74–1.10) P<0.001 (NI) P=0.30 (Sup) RRR 35% RR 0.65 (95% CI: 0.52–0.81) P<0.001 (NI) P<0.001 (Sup) BID = 每日两次; NI = 非劣效性; RR = 相对危险度; RRR =相对危险降幅; Sup = 优效性 Connolly SJ et al. N Engl J Med 2010;363:1875–6 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation in China

  26. 出血性卒中发生率 50 40 30 出血性卒中 (事件数量) 20 10 0 华法林 达比加群110 mg BID 达比加群150 mg BID n: 6015 6076 6022 RR 0.31 (95% CI: 0.17–0.56) P<0.001 (Sup) RR 0.26 (95% CI: 0.14–0.49) P<0.001 (Sup) 45 0.38% 74% 69% 14 0.12% 12 0.10% BID = 每日两次; RR = 相对危险度; RRR = 相对危险降幅; Sup = 有效性 Connolly SJ et al. N Engl J Med 2009;361:1139–51; Connolly SJ et al. N Engl J Med 2010;363:1875–6 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation in China

  27. 大出血发生率 4.0 3.5 3.0 2.5 大出血 (%/年) 2.0 1.5 1.0 0.5 0.0 达比加群110 mg BID 达比加群150 mg BID 华法林 事件/数量 342/6015 399/6076 421/6022 RR 0.80 (95% CI: 0.70–0.93) P=0.003 (Sup) RR 0.93 (95% CI: 0.81–1.07) 20% P=0.32 (Sup) 3.57 3.32 2.87 BID = 每日两次; RR = 相对危险度; RRR = 相对危险降幅; Sup = 优效性 Connolly SJ et al. N Engl J Med 2010;363:1875–6 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation in China

  28. 危及生命的出血发生率 2.0 1.5 危及生命的出血(%/年) 1.0 0.5 0.0 达比加群110 mg BID 达比加群150 mg BID 华法林 事件/数量: 147/6015 179/6076 218/6022 RR 0.67 (95% CI: 0.54–0.82) P<0.001 (Sup) RR 0.80 (95% CI: 0.66–0.98) 33% P=0.03 (Sup) 1.85 RRR 20% 1.49 1.24 BID = 每日两次; RR = 相对危险度; RRR = 相对危险降幅; Sup = 优效性 Connolly SJ et al. N Engl J Med 2010;363:1875–6 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation in China

  29. 颅内出血发生率 0.9 0.8 0.7 0.6 0.5 颅内出血(%/年) 0.4 0.3 0.2 0.1 0 达比加群110 mg BID 达比加群150 mg BID 华法林 事件/数量: 27/6015 38/6076 90/6022 RR 0.30 (95% CI: 0.19–0.45) P<0.001 (Sup) RR 0.41 (95% CI: 0.28–0.60) P<0.001 (Sup) 0.76 59% 70% 0.32 0.23 BID = 每日两次; RR = 相对危险度; RRR = 相对危险降幅; Sup = 优效性 Connolly SJ et al. N Engl J Med 2010;363:1875–6 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation in China

  30. 总体出血事件 25 20 15 总体出血事件 (%/年) 10 5 0 达比加群110 mg BID 达比加群150 mg BID 华法林 事件/数量: 1754/6015 1993/6076 2166/6022 RR 0.78 (95% CI: 0.73–0.83) RR 0.91 (95% CI: 0.85–0.96) P<0.001 (Sup) 22% P=0.002 (Sup) 18.37 16.56 14.74 BID = 每日两次; RR = 相对危险度; RRR = 相对危险降幅; Sup = 优效性 Connolly SJ et al. N Engl J Med 2010;363:1875–6 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation in China

  31. Stroke or Systemic Embolism Superiority Non-inferiority p-value p-value Dabigatran 110 vs. Warfarin <0.001 0.34 <0.001 <0.001 Dabigatran 150 vs. Warfarin Margin = 1.46 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Dabigatran better Warfarin better

  32. 达比加群酯与华法林的比较 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation in China

  33. 对无人工心脏瓣膜、无血流动力学改变瓣膜病、无严重肝肾（肌酐清除率<15ml/min)损害的阵发性、持续性、永久性房颤及伴有卒中和体循环栓塞风险的患者，达比加群可替代华法林用来预防卒中和体循环栓塞。 （I类推荐，B级证据） 2011年 ACCF/AHA/HRS房颤指南更新

  34. WATCHMAN LAA Closure Device in situ 3000838-18

  35. 持续时间<48小时房颤转复前也需抗栓

  36. 心室率控制：严格 vs 宽松

  37. RACE II • 持久性房颤614例，随机入组 • 宽松控制组 (静息HR <110bpm) • 严格控制组 (静息HR <80 bpm；中等运动 <110 bpm) • 一级终点：心血管死亡、心衰住院、卒中、动脉栓塞、出血、致命性心律失常事件 • 随访2~3年 Van Gelder, et.al, for the RACE II Investigators NEJM April 15, 2010, No. 15, Vol 362: 1363-1373

  38. RACE II 14.9% 12.9% Van Gelder, et.al, for the RACE II Investigators NEJM April 15, 2010, No. 15, Vol 362: 1363-1373

  39. RACE II P<0.001 97.7% 67% Van Gelder, et.al, for the RACE II Investigators NEJM April 15, 2010, No. 15, Vol 362: 1363-1373

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