室心律失常的藥物治療目前的困惑與挑.ppt

室性心律失常的藥物治療 目前的困惑與挑戰(zhàn),南京醫(yī)科大學第一附屬醫(yī)院 江蘇心血管病臨床醫(yī)學中心 曹克將,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,循證醫(yī)學定義 Evidence-based medicine,慎重、準確、科學、明智地應(yīng)用目前可獲得的最佳研究證據(jù)，同時結(jié)合臨床醫(yī)生個人專業(yè)技能和長期的臨床經(jīng)驗，充分考慮病人的價值觀和自身意愿，并將三者完美地結(jié)合在一起，以制定出具體的治療方案,循值醫(yī)學 Value-based medicine,在循證醫(yī)學最佳證據(jù)基礎(chǔ)上，將患者的生命質(zhì)量、自身感受、壽命延長等指標與疾病經(jīng)濟負擔最大限度在有機結(jié)合起來綜合考慮，并且運用成本效用分析方法對生命質(zhì)量中的“質(zhì)”進行具體量化的醫(yī)學，旨在延長患者期望壽命、提高患者生活質(zhì)量基礎(chǔ)上最大限度在減輕患者和社會的疾病經(jīng)濟負擔,室性心律失常的治療措施,藥物治療 電復(fù)律和電除顫 心律轉(zhuǎn)復(fù)除顫器(ICD) 射頻導(dǎo)管消融 外科手術(shù)治療 基因治療,室性心律失常的藥物治療,藥物選擇依據(jù) 基礎(chǔ)心臟病變 心功能狀態(tài) 藥物副作用 總體死亡率,室性心律失常藥物治療的副作用,I類 奎尼丁，普魯卡因酰胺：毒副作用較大 恩卡尼，氟卡尼：CAST-I研究發(fā)現(xiàn)該藥雖可控制心肌梗死患者的心律失常，但服藥組的死亡率卻明顯高于安慰劑組 普羅帕酮：消化道不良反應(yīng)、傳導(dǎo)阻滯；致心律失常作用如多形性室速、室顫等；在心肌缺血和心功能不全時耐受性下降；CASH研究中普羅帕酮組死亡率明顯高于安慰劑組,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,室性心律失常藥物治療的副作用,II類 受體阻滯劑：心動過緩、傳導(dǎo)阻滯、低血壓、疲勞、支氣管痙攣或哮喘、外周血管阻力增加，糖與脂代謝紊亂 IV類 維拉帕米：負性肌力作用明顯，低血壓，傳導(dǎo)阻滯,From 8th 2008, the Braunwalds Heart Disease,室性心律失常藥物治療的副作用,III類 胺碘酮：主要為心外副作用，肺間質(zhì)纖維化、角膜色素沉淀、甲狀腺功能亢進或減退、皮膚色素沉著、肝功能異常、胃腸道反應(yīng)，以及神經(jīng)系統(tǒng)不良反應(yīng)；心臟副作用主要為竇緩、傳導(dǎo)阻滯、Tdp；SCD-HeFT研究發(fā)現(xiàn)胺碘酮組與安慰劑組的死亡率無差異 索他洛爾：延長QT間期，可誘發(fā)Tdp。SWORD研究中口服索他洛爾組的死亡率較安慰劑組高，致心律失常作用是死亡率增加的主要原因 新III類：TDP發(fā)生率高，可達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,室性心律失常藥物治療的副作用,許多抗心律失常藥物可增加其他藥物的血藥濃度，降低其他藥物的排泄。當心、肝、腎功能不全、酸中毒、休克或老年病人，其半衰期可明顯延長 抗心律失常藥物聯(lián)用時，某些副作用增強，可造成嚴重竇緩、低血壓、嚴重傳導(dǎo)阻滯，負性肌力作用的增強可導(dǎo)致心功能惡化甚至心衰：如抗心律失常藥物聯(lián)合應(yīng)用時的協(xié)同負性作用、增加血藥濃度影響藥物代謝,室性心律失常藥物治療的困惑 新型抗心律失常藥物,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.,室性心律失常藥物治療的困惑 新型抗心律失常藥物,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,室性心律失常藥物治療的困惑 新型抗心律失常藥物,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,室性心律失常藥物治療的困惑 新型抗心律失常藥物,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,室性心律失常藥物治療的困惑 非抗心律失常藥物的抗心律失常作用,非抗心律失常藥物 ACEI/ARB 醛固酮拮抗劑 非醛固酮拮抗劑利尿劑 n-3 fatty acid/lipids Statin 治療心律失常、降低心臟猝死的機制尚未明確 不可替代抗心律失常藥物的治療 只能作為一級預(yù)防,室性心律失常藥物治療的困惑,遺傳性室性心律失常 藥物治療常效果不佳甚至無效 Brugada綜合征: 奎尼丁僅減少ICD植入后的電風暴現(xiàn)象 LQT綜合征: 受體阻滯劑治療迄今尚無長期隨機研究報告，所有推薦的原發(fā)性 LQTS 治療方法均來源于臨床經(jīng)驗和非對照性研究；使用阻滯劑者仍有8-