室心律失常的药物治疗目前的困惑与挑.ppt

室性心律失常的药物治疗 目前的困惑与挑战,南京医科大学第一附属医院 江苏心血管病临床医学中心 曹克将,Sudden Cardiac Death A Major Public Health Problem,1/2 of all cardiac deaths 1/7 of all deaths,Leading Causes of Death in the US,SCD is a leading cause of death in the U.S., second to all cancers combined,20%,25%,National Vital Statistics Report, Vol 49 (11), Oct. 12, 2001 State-specific mortality from sudden cardiac death United States 1999. MMWR. 2002,51:123-126,15%,10%,5%,0%,At least 335,000 SCD in the U.S. each year Only 5 to 10% survive after first episode of SCD Roughly two-thirds of SCD out-of-hospital,SCD Survival & Mortality Data,Seidl K, Senges J. Card Electrophysiol Rev. 2003;7:5-13 Heart Disease and Stroke Statistics 2005 Update. AHA. Crespo EM, Kim J, Selzman KA. Am J Med Sci. 2005;329:238-246 Zheng ZJ, et al. Circulation. 2001;104:2158-2163 Zipes, DP, et al. 2006 ACC/AHA/ESC Practice Guidelines 5. Circulation. 2006;114;385-484,Arrhythmic Cause of SCD,Albert CM. Circulation 2003,107:2096-2101,12% Other Cardiac Cause,88% Arrhythmic Cause,Bradycardia 17%,Primary VF 8%,VT 62%,Bays de Luna A. Am Heart J 1989,117:151-159,Torsades de Pointes 13%,Underlying Arrhythmias of Sudden Cardiac Arrest,循证医学定义 Evidence-based medicine,慎重、准确、科学、明智地应用目前可获得的最佳研究证据，同时结合临床医生个人专业技能和长期的临床经验，充分考虑病人的价值观和自身意愿，并将三者完美地结合在一起，以制定出具体的治疗方案,循值医学 Value-based medicine,在循证医学最佳证据基础上，将患者的生命质量、自身感受、寿命延长等指标与疾病经济负担最大限度在有机结合起来综合考虑，并且运用成本效用分析方法对生命质量中的“质”进行具体量化的医学，旨在延长患者期望寿命、提高患者生活质量基础上最大限度在减轻患者和社会的疾病经济负担,室性心律失常的治疗措施,药物治疗 电复律和电除颤 心律转复除颤器(ICD) 射频导管消融 外科手术治疗 基因治疗,室性心律失常的药物治疗,药物选择依据 基础心脏病变 心功能状态 药物副作用 总体死亡率,室性心律失常药物治疗的副作用,I类 奎尼丁，普鲁卡因酰胺：毒副作用较大 恩卡尼，氟卡尼：CAST-I研究发现该药虽可控制心肌梗死患者的心律失常，但服药组的死亡率却明显高于安慰剂组 普罗帕酮：消化道不良反应、传导阻滞；致心律失常作用如多形性室速、室颤等；在心肌缺血和心功能不全时耐受性下降；CASH研究中普罗帕酮组死亡率明显高于安慰剂组,CAST-I,Prognosis of Post-MI Patients Treated with Placebo vs. Encainide/Flecainide,80,85,90,95,100,0,91,182,273,364,455,Days after Randomization,Patients without Event (%),Placebo (n = 743),Encainide or Flecainide (n = 755),P = 0.001,Echt DS., et al. N Engl J Med 1991; 324:781-788,CAST,The Cardiac Arrest Study Hamburg (CASH),Assignment to propafenone was discontinued on the request of the Safety Monitoring Board in March 1992, after an interim analysis conducted on 58 patients showed a 61% higher all-cause mortality rate than in 61 ICD patients during a follow-up of 11.3 months,Kuck. et al. Circulation 2000;102:748-754,室性心律失常药物治疗的副作用,II类 受体阻滞剂：心动过缓、传导阻滞、低血压、疲劳、支气管痉挛或哮喘、外周血管阻力增加，糖与脂代谢紊乱 IV类 维拉帕米：负性肌力作用明显，低血压，传导阻滞,From 8th 2008, the Braunwalds Heart Disease,室性心律失常药物治疗的副作用,III类 胺碘酮：主要为心外副作用，肺间质纤维化、角膜色素沉淀、甲状腺功能亢进或减退、皮肤色素沉着、肝功能异常、胃肠道反应，以及神经系统不良反应；心脏副作用主要为窦缓、传导阻滞、Tdp；SCD-HeFT研究发现胺碘酮组与安慰剂组的死亡率无差异 索他洛尔：延长QT间期，可诱发Tdp。SWORD研究中口服索他洛尔组的死亡率较安慰剂组高，致心律失常作用是死亡率增加的主要原因 新III类：TDP发生率高，可达7%,SWORD,Study stopped prematurely in Nov. 1994 due to increased mortality in patient population treated with d-sotalol,Waldo AL. Lancet. 1996; 348: 7-12,d-Sotalol n = 1,549,n = 78 (5.0%)*,3,121 Patients,Placebo n = 1,572,n = 48 (3.1%)*,* 5 month F/U,Mortality,Mortality,p = 0.006,SWORD: Survival Results,Waldo AL. Lancet. 1996;348:7-12.,1.00,0,Time from Randomization (days),Z = -2.75, p = 0.006,Proportion Event-Free,Patients at Risk,Placebo 1,572 1,170 874 551 330 d-sotalol 1,549 1,150 844 544 323,Placebo,d-sotalol,60,120,180,240,300,.99,.98,.97,.96,.95,.94,.93,.92,.91,.90,.89,.88,.87,室性心律失常药物治疗的副作用,许多抗心律失常药物可增加其他药物的血药浓度，降低其他药物的排泄。当心、肝、肾功能不全、酸中毒、休克或老年病人，其半衰期可明显延长 抗心律失常药物联用时，某些副作用增强，可造成严重窦缓、低血压、严重传导阻滞，负性肌力作用的增强可导致心功能恶化甚至心衰：如抗心律失常药物联合应用时的协同负性作用、增加血药浓度影响药物代谢,室性心律失常药物治疗的困惑 新型抗心律失常药物,EURIDIS and ADONIS Two identical multicenter, double-blind, randomized trials EURIDIS: in Europe ADONIS: in the USA, Canada, Australia, South Africa, and Argentina Dronedarone group: 828 pts. 400 mg bid Placebo group: 409 pts. Primary end point: first recurrence of AF or AFL,Bramah NS. et al. N Engl J Med 2007;357:987-99.,DRONEDARONE,Bramah NS. et al. N Engl J Med 2007;357:987-99.,The times to recurrence of AF or AFL for the EURIDIS For the ADONIS For the two trials combined,Bramah NS. et al. N Engl J Med 2007;357:987-99.,室性心律失常药物治疗的困惑 新型抗心律失常药物,EURIDIS and ADONIS Conclusions Dronedarone was more effective than placebo in maintaining sinus rhythm and in reducing the ventricular rate during recurrence of arrhythmia Rates of pulmonary toxic effects and of thyroid and liver dysfunction were not significantly increased in the dronedarone group,室性心律失常药物治疗的困惑 新型抗心律失常药物,ATHENA 4628 patients with AF or AFL Evaluate the efficacy of dronedarone (400 mg bd) for preventing cardiovascular hospitalisation and all-cause mortality Mean follow up: 21 months Conclusion: Dronedarone group was less likely to reach the primary endpoint compared with placebo group The incidence of adverse events was similar in each group,室性心律失常药物治疗的困惑 新型抗心律失常药物,ANDROMEDA TRIAL Multicenter, Double-blind, Placebo-controlled, Randomized, Parallel-group trial of Dronedarone Patients with symptomatic heart failure and severe left ventricular systolic dysfunction End points Primary end point: death from any cause or hospitalization for worsening heart failure,N Engl J Med 2008; 358: 2678-87,N Engl J Med 2008; 358: 2678-87,ANDROMEDA TRIAL,ANDROMEDA TRIAL,All-Cause Mortality: total: 37 pts Dronedarone group: 25 pts Placebo group: 12 pts HR 2.13，P=0.03 In January 2003, the data and safety monitoring board recommended that the trial be terminated for safety reasons, owing to an excess of deaths in the dronedarone group In patients with severe heart failure and left ventricular systolic dysfunction, treatment with dronedarone was associated with increased early mortality related to the worsening of heart failure,N Engl J Med 2008; 358: 2678-87,室性心律失常药物治疗的困惑 非抗心律失常药物的抗心律失常作用,非抗心律失常药物 ACEI/ARB 醛固酮拮抗剂 非醛固酮拮抗剂利尿剂 n-3 fatty acid/lipids Statin 治疗心律失常、降低心脏猝死的机制尚未明确 不可替代抗心律失常药物的治疗 只能作为一级预防,室性心律失常药物治疗的困惑,遗传性室性心律失常 药物治疗常效果不佳甚至无效 Brugada综合征: 奎尼丁仅减少ICD植入后的电风暴现象 LQT综合征: 受体阻滞剂治疗迄今尚无长期随机研究报告，所有推荐的原发性 LQTS 治疗方法均来源于临床经验和非对照性研究；使用阻滞剂者仍有8-