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1、The Role of Drugs in Prevention of Sudden Cardiac Death Weimin Li Professor of Medicine Cardiovascular Department, the First Clinical Hospital, Harbin Medical University，Harbin,Presentation Overview, Sudden Cardiac Death Epidemiology, etiology, pathophysiology Overview of ICD therapy to prevent SCD
2、Roles of Drugs in SCD Prevention Summary and conclusions,Epidemiology of SCD,Accounts for 63% of all cardiac related deaths in the US. One of the most common causes of death in developed countries:,MMWR. Vol 51(6) Feb. 15, 2002. Myerberg RJ, Catellanos A. Cardiac Arrest and Sudden Cardiac Death. In:
3、 Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 5th Ed. New York: WB Saunders. 1997: 742-779. Zheng Z. Circulation. 2001;104:2158-2163. Vreede-Swagemakers JJ et al. J Am Coll Cardiol 1997; 30: 1500-1505.,Geography,Magnitude of SCD in China,0.04%,0.1%0.2%,Incidence of SCD in S
4、pecific Populations,Adapted from: Myerburg RJ. Sudden Cardiac Death: Exploring the Limits of Our Knowledge. J Cardiovasc Electrophysiol Vol. 12, pp. 369-381, March 2001.,300,000,200,000,100,000,Absolute number of SCD Per Year,Multiple risk subgroups,Patients with any previous coronary event,Patients
5、 with ejection fraction 35% or CHF,Cardiac arrest, VT/VF survivors,High-risk post-MI subgroups,General adult population,30,25,20,10,5,0,Incidence of SCD (% of group),MADIT II SCD-HeFT,AVID, CASH, CIDS,MADIT, MUSTT,Sudden death was the first manifestation of coronary heart disease in 50% of men and 6
6、3% of women. CHD accounts for at least 80% of sudden cardiac deaths in Western cultures.,Disease Cause of SCD,American Heart Association. Heart Disease and Stroke Statistics2003 Update. Dallas, Tex.: American Heart Association; 2002. Adapted from Heikki et al. N Engl J Med, Vol. 345, No. 20, 2001. M
7、yerberg RJ. Heart Disease, A Textbook of Cardiovascular Medicine. 6th ed. P. 895.,Arrhythmic Cause of SCD,Albert CM. Circulation. 2003;107:2096-2101.,12%Other Cardiac Cause,88% Arrhythmic Cause,Bradycardia 16.5%,VF 62.4%,Primary VT 8.3%,Torsades de Pointes 12.7%,Bays de Luna A. Am Heart J. 1989;117:
8、151-159.,Application of ICD in China,200,544,000,“Even the wealthiest nations cannot afford to pay to use every medical advance in any patient who might benefit.”,Thomas Bigger, Lancet, 2001,Roles of Drugs in SCD Prevention,Roles of Drugs in SCD Prevention,Value of Antiarrhythmic Drugs Class I antia
9、rrhythmics Beta Blockers Amiodarone Sotalol Value of Non-antiarrhythmic Drugs Electrolytes ACE inhibitors, ARBs and aldosterone blockers Antithrombotic and antiplatelet agents Statins n-3 Fatty acids,SCD Prevention by Antiarrhythmic Drugs,All-cause mortality,Days after randomization,0,50,100,150,200
10、,250,300,350,400,450,500,85,90,95,100,Survival,(%),Placebo (n=725),Encainide or flecainide (n=730),:406,CAST Investigators.,N Engl J Med,1989;,321,12.,P=0.0003,80,Roles of Class I antiarrhythmics in SCD Prevention,CAST: Cardiac Arrhythmia Suppression Trial,CAST II: Cardiac Arrhythmia Suppression Tri
11、al II,As with the antiarrhythmic agents used in CAST-I, the use of moricizine in CAST-II to suppress asymptomatic or mildly symptomatic ventricular premature depolarizations to try to reduce mortality after myocardial infarction is not only ineffective but also harmful.,Roles of Beta Blockers in SCD
12、 Prevention,Norwegian Multicentre Study Group. N Engl J Med. 1981;304:801-807.,Overview of Norwegian Timolol Trial and BHAT(Beta-Blocker Heart Attack) Trial (Post-MI LVD patients),39% Reduced mortality,26% Decreased mortality,Beta-Blocker Heart Attack Trial Research Group. JAMA. 1982;247:1707-1714.,
13、BHAT,Norwegian,Average incidence of SCD in long term trials comparing blockers with placebo after MI,Nuttall SL, Toescu V, Kendall MJ. BMJ. 2000;320:581.,CAPRICORN: Carvedilol Post-Infarct Survival Control in LV Dysfunction - TRIAL RESULTS -,Dargie HJ et al. Eur J Heart Fail. 2000;2:325-332.,CIBIS I
14、I: Cardiac Insufficiency Bisoprolol Study II - RESULTS -,CIBIS-II Investigators and Committees.,Lancet,1999;,353,MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure - RESULTS -,MERIT-HF Study Group.,Lancet,1999;,353,:2001,7.,0,0.5,1.0,1.5,Relative risk for mortality,
15、Relative risk (95% CI),Mortality,Metoprolol CR/XL better,Risk,reduction,(%),Total mortality,Cardiovascular mortality,Sudden death,Death from worsening,heart failure,34,38,41,49,0.0062,0.00003,0.0002,0.0023,P,COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival trial - SUMMARY -,In patie
16、nts with severe chronic heart failure, carvedilol in addition to standard therapy reduced: All-cause mortality Combined endpoint of all-cause mortality and hospitalization for any reason,Packer M, Coats AJ, Fowler MB et al. N Engl J Med 2001;344:16518.,Roles of Beta Blockers in SCD Prevention,Roles
17、of Amiodarone in SCD Prevention,Connolly SJ. Meta-analysis of antiarrhythmic drug trials. Am J Cardiol 1999;84:90R3R.,A meta-analysis of effects of amiodarone on SCD,Meta-analysis of effects of amiodarone on SCD -RESULTS-,Cumulative risk of total mortality and arrhythmic/sudden death from a meta-ana
18、lysis of 13 trials of amiodarone,Meta-analysis of the ICD secondary prevention trials,Connolly SJ. et al.Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials European Heart Journal. 2000; 20712078,Meta-analysis of effects of amiodarone on SCD - RESULTS -,Cumulative
19、 risk of fatal events or the amiodarone and treatment arms.,Hazard ratio:0.73 P0.001,Hazard ratio:0.49 P0.001,Meta-analysis of effects of amiodarone on SCD - RESULTS -,Cumulative risk of death for patients with LVEF 35% and 35%,The efficacy of the ICD over amiodarone appears to be dependent upon the
20、 degree of left ventricular dysfunction.,Mortality,Folow-up(m),Mortality by Intention-to-Treat SCD-HeFT-2004,HR 97.5% CI P Amiodarone vs placebo 1.06 0.86, 1.30 0.529 ICD therapy vs placebo 0.77 0.62, 0.96 0.007,Bardy GH, Lee KL, Mark DB, et al. N Engl J Med, 2005, 352:225,ICD + AADs,Percent Arrhyth
21、mia-Free,26%reduction in event rate the time to first event extended median 1.3 months to median 4.4 months,Steinberg JS, Martins J, Sadanandan S, et al. Am Heart J. 2001;142:520-529,ICD,ICD + AADs,Roles of Sotalol in SCD Prevention,SWORD Survival Results,Study stopped prematurely in Nov. 1994 due t
22、o increased mortality in patient population treated with d-sotalol,Waldo AL. Lancet. 1996;348:7-12.,Roles of Sotalol in SCD Prevention,Kuhlkamp V. Suppression of sustained ventricular tachyarrhythmias: a comparison of d,l-sotalol with no antiarrhythmic drug treatment. J Am Coll Cardiol.1999;33: 46-5
23、2.,ICD/sotalol,sotalol,ICD,Roles of Antiarrhythmic Drugs in SCD Prevention,Value of Antiarrhythmic Drugs Class I antiarrhythmics: not only ineffective but also harmful Beta Blockers: Effective in suppressing ventricular ectopic beats and arrhythmias; reduce incidence of SCD Amiodarone: No definite s
24、urvival benefit; some studies have shown reductionin SCD in patients with LV dysfunction, especially when given in conjunction with BB. but it has complex drug interactions and many adverse side effects. Sotalol: Suppresses ventricular arrhythmias; is more pro-arrhythmic than amiodarone, no survival
25、 benefit clearly shown Conclusions: Antiarrhythmic drugs (except for BB) should not be used as primary therapy of the prevention of SCD. Both sotalol and amiodarone have been shown to reduce the frequency of ICD shock therapy,SCD Prevention by Non-antiarrhythmic Drugs,Roles of angiotensin converting
26、 enzyme inhibitors (ACEI) angiotensin receptor blockers(ARB) and aldosterone blocker in SCD Prevention,Meta-analysis of 15 randomized controlled trial - RESULTS -,Domanski MJ, Exner DV, Borkowf CB, et al. JACC Vol. 33, No. 3,1999:598604,Meta-analysis of 15 randomized controlled trial - RESULTS -,The
27、 overall OR for SCD in patients randomized to ACE inhibitor therapy was 0.80 (95% CI 0.70 to 0.92) ACEIs reduce the risk of SCD about 20% in post-MI patients,HOPE: Heart Outcomes Prevention Evaluation study - RESULTS -,P,Primary outcome and deaths from any cause,Relative risk,(95% CI),MI, stroke, or
28、 death from,cardiovascular causes,Death from cardiovascular causes,MI,Stroke,Death from noncardiovascular causes,Death from any cause,0.78 (0.70,0.86),0.74 (0.64,0.87),0.80 (0.70,0.90),0.68 (0.56,0.84),1.03 (0.85,1.26),0.84 (0.75,0.95),0.001,0.001,0.001,0.001,0.74,0.005,Ramipril reduced the risk of
29、SCD about 38% (0.02),SOLVD Trial RESULTS ,N Engl J Med 1991;325:293-302,All Cause Mortality and SCD,SOLVD Treatment Trial,SOLVD Prevention Trial,10% Risk Reduction in SCD p = NS,8% Risk Reduction in All Cause Mortality P=0.30,0,5,10,15,20,25,0,6,12,18,24,30,36,42,48,Months,Mortality (%),7% Risk Redu
30、ction in SCD p = NS,CHARM Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity - RESULTs -,CHARM Candesartan in Heart failure Assessment of Reduction in SCD - RESULTs -,The CHARM study Investigators. Circulation. 2004;110:2618-26.,Treatment of heart failure patients with c
31、andesartan resulted in a reduction in SCD (p=0.036),RALES : the Randomized Aldactone Evaluation Study - RESULTs -,P,Cardiac causes,Progression of heart failure,Sudden death,0.001,Cardiovascular death,Spironolactone group,(n=822),314,189,110,15,226,227,82,17,0.69 (0.580.82),0.64 (0.510.80),Placebo gr
32、oup,(n=841),Raletive risk,(95% CI),VARIABLE,Myocardial infarction,0.71 (0.540.95),0.02,0.001,Pitt, N Engl J Med 1999;,SCD Risk Reduction: 29% (p0.02),EPHESUS Eplerenone Post-AMI Heart Failure Efficacy and Survival Study - RESULTs -,All-cause Mortality RR 0.85 p=0.008,Eplerenone,Placebo,N Engl J Med
33、2003;348:1309-21 Eur J Heart Fail. 2006;8 :295-301,CV Death RR 0.87 p=0.002,Treatment with eplerenone in the subgroup of patients with LVEF 30% resulted in relative risk reductions of 33% for SCD (P=0.008),Roles of angiotensin converting enzyme inhibitors (ACEI) angiotensin receptor blockers(ARB) an
34、d aldosterone blocker in SCD Prevention,Roles of Antithrombotic Therapy in SCD Prevention,Data from SOLVD prevention and treatment trials,Incidence and Crude Relative Risk of Sudden Coronary Death, Cardiovascular Death, and All-Cause Mortality According to Antithrombotic Therapy,Neither 225 2.76 1.0
35、 754 9.24 1.0 853 10.45 1.0 Antiplatelet 149 1.82 0.66 470 5.75 0.63 534 6.48 0.63 Anticoagulant 40 1.86 0.70 155 7.21 0.82 185 8.56 0.87 Both 10 2.24 0.81 34 7.61 0.83 37 8.28 0.80,95% CI the 2-sided 95% confidence interval for the point estimate of the relative risk. Cardiovascular deaths include
36、sudden cardiac death, death due to progressive pump failure, fatal myocardial infarction, and cerebrovascular deaths. The rate is expressed as events per 100 patient-years of follow-up. RR relative risk.,Sudden Coronary Death,Cardiovascular Death,All Cause Mortality,No. Rate RR No. Rate RR No. Rate
37、RR,Dries DL, et al. Am J Cardiol. 1997;79: 909-913,Roles of Antithrombotic Therapy in SCD Prevention,Antiplatelet and anticoagulant monotherapy each remained independently associated with a reduction in the risk of SCD: antiplatelet therapy with a 24% reduction. anticoagulant therapy with a 32% redu
38、ction. Thus, in patients with moderate to severe left ventricular systolic dysfunction resulting from coronary artery disease, antiplatelet and anticoagulant therapy are each associated with a reduction in the risk of SCD.,Data from SOLVD prevention and treatment trials,Roles of Statins in SCD Preve
39、ntion,Statins in the MADIT-II Study,.,Vyas AK, Hongsheng Guo, Moss AJ, et al. J Am Coll Cardiol 2006; 47: 769-773,Statins,Placebo or no treatment,SCD Mortality 19% risk reduction p=0.003,Levantesi G et al .Meta-analysis of effect of statin treatment on risk of sudden death. Am J Cardiol. 2007;100:16
40、44-1650.,Roles of Statins in SCD Prevention,Meta-analysis of effect of statin treatment on risk of SCD,Roles of n-3 Fatty Acid in SCD Prevention,.,Patients,Study,Outcome,Follow up,1,the secondary prevention of myocardial infarction,Published,29% reduction in mortality may result from reduction in SC
41、D,2y,1989,2,73m,70% reduction in mortality,1994,3,3.5y,59% reduction in mortality 45% reduction in SCD,17y,1999,52% reduction in risk of SCD,4,Without cardiovascular disease,2002,6,With Sustained VT or VF And ICD,24m,does not reduce the risk of VT/VF and may be proarrhythmic in some patients,2005,ha
42、ve anti-arrhythmic properties, but conflicting data exist for the prevention of SCD,With ICDs,12m,prolonged the time to the first ICD event reduced death from any cause,2003,5,Published,Non-antiarrhythmic Drugs -SUMMARY-, ACEI, ARB and aldosterone blockers can improvethe myocardial substrate through
43、 reverse remodeling and thus reduce incidence of SCD Antithrombotic and antiplatelet agents may reduce SCD by reducing coronary thrombosis Statins have been shown to reduce life-threatening VA in high-risk patients with electrical instability n-3 Fatty acids have anti-arrhythmic properties, but conflicting data exist for the prevention of SCD,Neurohormonal Blockade Across the Cardiovascular Disease Continuum,One-year Mortality (%),More drugs, More Survival,As to disease, make a habit of two thingsto help, or at least do no harm！,Hippocrates,谢谢！,