心源性猝死scd

1、The Role of Drugs in Prevention of Sudden Cardiac Death,Presentation Overview,? Sudden Cardiac Death Epidemiology, etiology, pathophysiology? Overview of ICD therapy to prevent SCD ? Roles of Drugs in SCD Preventio

2、n ? 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,

3、2002. Myerberg RJ, Catellanos A. Cardiac Arrest and Sudden Cardiac Death. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 5th Ed. New York: WB Saunders. 1997: 742-779. Zheng Z. Cir

4、culation. 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 Specific Populations,Adapted from: Myerburg RJ

5、. 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,Pat

6、ients with any previous coronary event,Patients with ejectionfraction <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 gr

7、oup),,,,,,,,,,MADIT II SCD-HeFT,AVID, CASH, CIDS,MADIT, MUSTT,,Sudden death was the first manifestation of coronary heart disease in 50% of men and 63% of women. CHD accounts for at least 80% of sudden cardiac deaths i

8、n Western cultures.,Disease Cause of SCD,American Heart Association. Heart Disease and Stroke Statistics—2003 Update. Dallas, Tex.: American Heart Association; 2002. Adapted from Heikki et al. N Engl J Med, Vol. 345

9、, No. 20, 2001.Myerberg 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,Bradycar

10、dia16.5%,VF62.4%,Primary VT8.3%,Torsades de Pointes12.7%,,Bayés de Luna A. Am Heart J. 1989;117:151-159.,Application of ICD in China,,200,544,000,,,“Even the wealthiest nations cannot afford to pay to use e

11、very 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 antiarrhythmics ? Beta Block

12、ers ? Amiodarone? SotalolValue of Non-antiarrhythmic Drugs? Electrolytes? ACE inhibitors, ARBs and aldosterone blockers ? Antithrombotic and antiplatelet agents? Statins? n-3 Fatty acids,SCD Prevention by Antiar

13、rhythmic Drugs,,All-cause mortality,Days after randomization,0,50,,,,,100,,150,,200,250,,300,,350,,400,,450,,500,,,,,,,85,90,95,100,Survival,(%),Placebo (n=725),Encainide or flecainide (n=730),,,:406,CAST Investigators.,

14、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 Trial II,As with the antiarrhythmic agent

15、s 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 infar

16、ction is not only ineffective but also harmful.,Roles of Beta Blockers in SCD Prevention,Norwegian Multicentre Study Group. N Engl J Med. 1981;304:801-807.,Overview of Norwegian Timolol Trialand BHAT(Beta-B

17、locker 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.,BHAT,Norwegian,Average incidence of SCD in long

18、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.

19、Eur J Heart Fail. 2000;2:325-332.,,CIBIS II: Cardiac Insufficiency Bisoprolol Study II - RESULTS -,,,,CIBIS-II Investigators and Committees.,Lancet,1999;,353,–

20、,–,–,–,,,MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure - RESULTS -,,MERIT-HF Study Group.,L

21、ancet,1999;,353,:2001,–,7.,0,0.5,1.0,1.5,Relative risk for mortality,Relative risk (95% CI),,,Mortality,Metoprolol CR/XL better,Risk,reduction,(%),,,,,Total mortality,Cardiovascular mortality,Sudden death,Death from wors

22、ening,heart failure,34,38,41,49,,,,,,,,,,,,,0.0062,0.00003,0.0002,0.0023,P,,,COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival trial- SUMMARY -,In patients with severe chronic heart failure, carvedilol

23、 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;3

24、44:1651–8.,Roles of Beta Blockers in SCD Prevention,Roles of Amiodarone in SCD Prevention,,Connolly SJ. Meta-analysis of antiarrhythmic drug trials. Am J Cardiol 1999;84:90R–3R.,A meta-analysis of effects of amiodarone o

25、n SCD,,Meta-analysis of effects of amiodarone on SCD-RESULTS-,Cumulative risk of total mortality and arrhythmic/sudden death from a meta-analysisof 13 trials of amiodarone,Meta-analysis of the ICD secondary preventi

26、on trials,Connolly SJ. et al.Meta-analysis of the implantable cardioverter defibrillator secondary prevention trialsEuropean Heart Journal. 2000; 2071–2078,,Meta-analysis of effects of amiodarone on SCD - RESULTS -,C

27、umulative risk of fatal events or the amiodarone and treatment arms.,Hazard ratio:0.73P<0.001,Hazard ratio:0.49P<0.001,,,,Meta-analysis of effects of amiodarone on SCD - RESULTS -,Cumulative risk of death for pa

28、tients with LVEF >35% and ≤35%,,The efficacy of the ICD over amiodarone appears to be dependent upon the degree of left ventricular dysfunction.,,Mortality,Folow-up(m),Mortality by Intention-to-TreatSCD-HeFT-2004,H

29、R 97.5% CI PAmiodarone vs placebo1.060.86, 1.300.529ICD therapy vs placebo0.770.62, 0.960.007,Bardy GH, Lee KL, Mark DB, et al. N Engl J Med, 2005, 352:225,ICD + AADs,Percent Arrhythmia-Free,26%

30、reduction inevent ratethe 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 Preve

31、ntion,SWORD Survival Results,,Study stopped prematurely in Nov. 1994 due to increased mortality in patient population treated with d-sotalol,Waldo AL. Lancet. 1996;348:7-12.,Roles of Sotalol in SCD Prevention,,Kuhlkamp

32、V. Suppression of sustained ventricular tachyarrhythmias: a comparison of d,l-sotalol with no antiarrhythmic drug treatment. J Am Coll Cardiol.1999;33: 46-52.,ICD/sotalol,sotalol,,,ICD,,Roles of Antiarrhythmic Drugs in

33、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

34、SCD ? Amiodarone: No definite survival 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 ma

35、ny adverse side effects.? Sotalol: Suppresses ventricular arrhythmias; is more pro-arrhythmic than amiodarone, no survival benefit clearly shown? Conclusions: Antiarrhythmic drugs (except for BB) should not be use

36、d 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

37、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

38、, No. 3,1999:598–604,,,,,,Meta-analysis of 15 randomized controlled trial - RESULTS -,,The 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 a

39、bout 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 death from,cardiovascular causes,Death

40、 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,&

41、lt;0.001,<0.001,<0.001,0.74,0.005,Ramipril reduced the risk of 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 Tria

42、l,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 Reduction in SCD p = NS,CHARMCandesartan i

43、n 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

44、.,Treatment of heart failure patients with candesartan resulted in a reduction in SCD (p=0.036),,,RALES : the Randomized Aldactone Evaluation Study- RESULTs -,,,,P,Cardiac causes,Progression of heart failure,Sudden de

45、ath,＜0.001,Cardiovascular death,,Spironolactone group,(n=822),,314,189,110,15,226,227,82,17,0.69 (0.58–0.82),0.64 (0.51–0.80),,Placebo group,(n=841),Raletive risk,(95% CI),,,,VARIABLE,Myocardial infarction,0.71 (0.54–0.9

46、5),0.02,＜0.001,Pitt, N Engl J Med 1999;,SCD Risk Reduction: 29% (p<0.02),EPHESUS Eplerenone Post-AMI Heart Failure Efficacy and Survival Study - RESULTs -,,All-cause MortalityRR 0.85p=0.008,Eplerenone,Placebo

47、,N Engl J Med 2003;348:1309-21Eur J Heart Fail. 2006;8 :295-301,CV DeathRR 0.87p=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

48、),,,,Roles of angiotensin converting enzyme inhibitors (ACEI) angiotensin receptor blockers(ARB) and aldosterone blocker in SCD Prevention,,Roles of Antithrombotic Therapy in SCD Prevention,Data from SOLVD prevention

49、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

50、 754 9.24 1.0 853 10.45 1.0Antiplatelet 149 1.82 0.66 470 5.75 0.63 534 6.48 0.63Anticoagulant 40 1.8

51、6 0.70 155 7.21 0.82 185 8.56 0.87Both 10 2.24 0.81 34 7.61 0.83 37 8.28 0.80,95

52、% CI the 2-sided 95% confidence interval for the point estimate of the relative risk.Cardiovascular deaths include sudden cardiac death, death due to progressive pump failure, fatal myocardial infarction, and cerebrova

53、scular 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 R

54、R No. Rate 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 associat

55、ed with a reduction in the risk of SCD: antiplatelet therapy with a 24% reduction. anticoagulant therapy with a 32% reduction. Thus, in patients with moderate to severe left ventricular systolic

56、 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

57、 Prevention,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 Mortality19% risk reduction p=0.003,Levantesi G et al .Meta-a

58、nalysis of effect of statin treatment on risk of sudden death.Am J Cardiol. 2007;100:1644-1650.,Roles of Statins in SCD Prevention,Meta-analysis of effect of statin treatment on risk of SCD,Roles of n-3 Fatty Acid in SC

59、D Prevention,.,,,Patients,Study,Outcome,Follow up,1,the secondary prevention of myocardial infarction,Published,29% reduction in mortalitymay result from reduction in SCD,2y,1989,2,73m,70% reduction in mortality,199

60、4,3,3.5y,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 VFAnd ICD,24m,does not reduce the risk of VT/VF and may be

61、proarrhythmic in some patients,2005,have 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,Publ

62、ished,Non-antiarrhythmic Drugs-SUMMARY-,? ACEI, ARB and aldosterone blockers can improvethe myocardial substrate through reverse remodeling and thus reduce incidence of SCD

63、 ? Antithrombotic and antiplatelet agents may reduce SCD by reducing coronary thrombosis ? Statins have been shown to reduce life-threatening VA in high-risk pat

64、ients with electrical instability ? n-3 Fatty acids have anti-arrhythmic properties, but conflicting data exist for the prevention of SCD,,,Neurohormonal