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1、The Role of Drugs in Prevention of Sudden Cardiac Death Weimin Li Professor of Medicine CardiovascularDepartment,theFirstClinicalHospital,HarbinMedicalUniversity，Harbin 药物对心脏性猝死（SCD）的预防作用Presentation Overview SuddenCardiacDeathEpidemiology,etiology,pathophysiologyOverviewofICDtherapytopreventSCD Rol
2、es of Drugs in SCD Prevention Summaryandconclusions药物对心脏性猝死（SCD）的预防作用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.Vol51(6)Feb.15,2002.MyerbergRJ,CatellanosA.CardiacArrestandSuddenCardiacDeath.In:Braun
3、waldE,ed.Heart Disease: A Textbook of Cardiovascular Medicine.5thEd.NewYork:WBSaunders.1997:742-779.ZhengZ.Circulation.2001;104:2158-2163.Vreede-SwagemakersJJetal.J Am Coll Cardiol1997;30:1500-1505.GeographyGeographyIncidenceIncidenceWorldwideUS300,000350,0003,000,000W.Europe400,000药物对心脏性猝死（SCD）的预防作
4、用MagnitudeofSCDinChina0.1%0.04%0.2%ChinaUS544,000300,000350,000ChinaUSIncidence RateAbsolute Number0.04%0.1%0.2%药物对心脏性猝死（SCD）的预防作用Incidence of SCD in Specific Populations Adapted from: Myerburg RJ. Sudden Cardiac Death: Exploring the Limits of Our Knowledge. J Cardiovasc Electrophysiol Vol. 12, pp.
5、369-381, March 2001. 300,000200,000100,000Absolute number of SCD Per Year Multiple risk subgroupsPatients with any previous coronary eventPatients with ejectionfraction 35% or CHFCardiac arrest, VT/VF survivorsHigh-risk post-MI subgroupsGeneral adult population3025201050Incidence of SCD(% of group)
6、MADIT II SCD-HeFT AVID, CASH, CIDS MADIT, MUSTT, 药物对心脏性猝死（SCD）的预防作用nSudden death was the first manifestation of coronary heart disease in 50% of men and 63% of women. nCHD accounts for at least 80% of sudden cardiac deaths in Western cultures.80%Coronary Heart Disease15% Cardiomyopathy5% Other Disea
7、se Cause of SCDAmerican 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.Myerberg RJ. Heart Disease, A Textbook of Cardiovascular Medicine. 6th ed. P. 895.药物对心脏性猝死（SCD）的预
8、防作用Arrhythmic Cause of SCDAlbert CM. Circulation. 2003;107:2096-2101.12%Other Cardiac Cause88%Arrhythmic CauseBradycardia16.5%VF62.4%Primary VT8.3%Torsades de Pointes12.7%Bays de Luna A. Am Heart J. 1989;117:151-159.药物对心脏性猝死（SCD）的预防作用Application of ICD in China200544,000药物对心脏性猝死（SCD）的预防作用“Even the w
9、ealthiest nations cannot afford to pay to use every medical advance in any patient who might benefit.”Thomas Bigger, Lancet, 2001药物对心脏性猝死（SCD）的预防作用Roles of Drugs in SCD Prevention药物对心脏性猝死（SCD）的预防作用Roles of Drugs in SCD PreventionValue of Antiarrhythmic Drugs Class I antiarrhythmics Beta Blockers Ami
10、odarone SotalolValue of Non-antiarrhythmic Drugs Electrolytes ACE inhibitors, ARBs and aldosterone blockers Antithrombotic and antiplatelet agents Statins n-3 Fatty acids药物对心脏性猝死（SCD）的预防作用SCD Prevention by Antiarrhythmic Drugs药物对心脏性猝死（SCD）的预防作用All-cause mortalityDays after randomization050100 150 20
11、0 250 300 350 400 450 500859095100Survival(%)Placebo (n=725)Encainide or flecainide (n=730):406CAST Investigators. N Engl J Med 1989;32112.P=0.000380 Roles of Class I antiarrhythmics in SCD PreventionCAST: Cardiac Arrhythmia Suppression Trial药物对心脏性猝死（SCD）的预防作用CAST II: Cardiac Arrhythmia Suppression
12、Trial 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.药物对心脏性猝死（SCD）的预防作用Roles of
13、Beta Blockers in SCD PreventionStudyBHATNorwegianCOPERNICUSCIBIS-IICAPRICORNMERIT-HFPublished1981Follow upTarget Dosage(mg/day)Patientsmild/moderate HFPost-MI LVDPost-MI LVDPost-MI LVDmoderate/severe HFsevere HFDrugPropranoloTimololmetoprololcarvedilolbisoprololcarvedilol 200 qd 25 bid 10 bid 180240
14、 25 bid 10 qd25m17m15m2.4y1.3y10.4m19822000199919992001药物对心脏性猝死（SCD）的预防作用 Norwegian Multicentre Study Group. N Engl J Med. 1981;304:801-807.36333027242118151296300.000.050.100.150.200.25TimololPlaceboMonthCumulative Mortality Raten=945n=939P0.0005Overview of Norwegian Timolol Trialand BHAT(Beta-Bloc
15、ker Heart Attack) Trial (Post-MI LVD patients) 39% Reduced mortality Placebo n=1921061824303612024681012N=383737063647395921631310406Cumulative Mortality (%)Months of Follow-upPropranolol n=1916P0.00526% Decreased mortalityBeta-Blocker Heart Attack Trial Research Group. JAMA. 1982;247:1707-1714.BHAT
16、Norwegian药物对心脏性猝死（SCD）的预防作用Average incidence of SCD in long term trials comparing blockers with placebo after MINuttall SL, Toescu V, Kendall MJ. BMJ. 2000;320:581.Averageincidenceofsuddendeathinlongtermtrialscomparing-blockerswithplaceboaftermyocardialinfarction Placebo treatment Blocker treatment
17、TotalNoofpatientsTotalNoofdeathsNo(%)ofsuddendeathsTotalNoofpatientsTotalNoofdeathsNo(%)ofsuddendeathsNorwegiantimololtrial93915295(63)9459847(48)Blockerheartattacktrial192118889(47)191613864(46)药物对心脏性猝死（SCD）的预防作用PlaceboCarvedilolHazard Ratio(95% CI)Cardiovascular Death1391040.75(0.58-0.96)Sudden De
18、ath69510.74(0.51-1.06)Death Due to Pump Failure30180.60(0.33-1.07) CAPRICORN: Carvedilol Post-Infarct Survival Control in LV Dysfunction - TRIAL RESULTS - Dargie HJ et al. Eur J Heart Fail. 2000;2:325-332.药物对心脏性猝死（SCD）的预防作用 CIBIS II: Cardiac Insufficiency Bisoprolol Study II - RESULTS -PPrimary endp
19、oint All-cause mortality Secondary endpoints All-cause hospital admission All cardiovascular deaths Combined endpoint Exploratory analyses Sudden death Hospital admission for worsening heart failure17 39 12 35 6 1812 33 9 29 4 120.66 (0.54 0.81) 0.80 (0.71 0.91) 0.71 (0.56-0.90)0.79 (0.69 0.90) 0.56
20、 (0.39 -0.80) 0.64 (0.53 0.79)0.0001 0.0006 0.0049 0.0004 0.0011 0.0001Primary and secondary outcomesPlacebo(n=1320)(%)(n=1327)(%)Hazard ratio(95% CI)CIBIS-II Investigators and Committees. Lancet 1999; 353药物对心脏性猝死（SCD）的预防作用MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart
21、Failure - RESULTS -MERIT-HF Study Group. Lancet 1999;353:20017.00.51.01.5Relative risk for mortalityRelative risk (95% CI)MortalityMetoprolol CR/XL betterRiskreduction(%)Total mortalityCardiovascular mortalitySudden deathDeath from worseningheart failure343841490.00620.000030.00020.0023P药物对心脏性猝死（SCD
22、）的预防作用COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival trial- SUMMARY - In patients with severe chronic heart failure, carvedilol in addition to standard therapy reduced:l All-cause mortalityl Combined endpoint of all-cause mortality and hospitalization for any reason Packer M, Coat
23、s AJ, Fowler MB et al. N Engl J Med 2001;344:16518.药物对心脏性猝死（SCD）的预防作用Roles of Beta Blockers in SCD PreventionStudyBHATNorwegianCOPERNICUSCIBIS-IICAPRICORNMERIT-HFSCD Risk Reduction (p-value)DrugPropranoloTimololmetoprololcarvedilolbisoprololcarvedilolTotal Death Risk Reduction (p-value)34% (0.00009)
24、23% ( 0.031) 26%(0.005)39%(0.0005)35% ( 0.001)34% ( 0.0001)Not reportedNot reported26% ( 0.099) 41% ( 0.0002)44% ( 0.001)Not reported药物对心脏性猝死（SCD）的预防作用 Roles of Amiodarone in SCD PreventionConnolly SJ. Meta-analysis of antiarrhythmic drug trials. Am J Cardiol 1999;84:90R3R. A meta-analysis of effect
25、s of amiodarone on SCD 药物对心脏性猝死（SCD）的预防作用 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 amiodaroneAmiodaroneControlTotal mortalityArrhythmic/sudden death29% reduction inarrhythmic deathP=0.000
26、3药物对心脏性猝死（SCD）的预防作用Meta-analysis of the ICD secondary prevention trialsConnolly SJ. et al.Meta-analysis of the implantable cardioverter defibrillator secondary prevention trialsEuropean Heart Journal. 2000; 20712078药物对心脏性猝死（SCD）的预防作用Meta-analysis of effects of amiodarone on SCD - RESULTS - Cumulativ
27、e risk of fatal events or the amiodarone and treatment arms.Hazard ratio:0.73P0.001Hazard ratio:0.49P35% and 35% The efficacy of the ICD over amiodarone appears to be dependent upon the degree of left ventricular dysfunction.药物对心脏性猝死（SCD）的预防作用MortalityFolow-up(m)Mortality by Intention-to-TreatSCD-He
28、FT-2004 HR 97.5% CI PAmiodarone vs placebo1.060.86, 1.30 0.529ICD therapy vs placebo0.770.62, 0.96 0.007AmiodaroneICD therapyPlaceboBardyGH,LeeKL,MarkDB,etal.NEnglJMed,2005,352:225药物对心脏性猝死（SCD）的预防作用ICD + AADsPercent Arrhythmia-Free26%reduction inevent ratethe time to first event extended median 1.3
29、months to median 4.4 monthsSteinberg JS, Martins J, Sadanandan S, et al. Am Heart J. 2001;142:520-529 ICD ICD + AADs药物对心脏性猝死（SCD）的预防作用 Roles of Sotalol in SCD PreventionSWORD Survival Results1.000Time from randomisation (days)Z = -2.5, P = 0.006Proportion event-freePlacebod-sotalol60120180240300.99.
30、98.97.96.95.94.93.92.91.90.89.88.87Patients at riskPlacebo15721170874551330d-sotalol15491150844544323Study stopped prematurely in Nov. 1994 due to increased mortality in patient population treated with d-sotalolWaldo AL. Lancet. 1996;348:7-12.药物对心脏性猝死（SCD）的预防作用 Roles of Sotalol in SCD PreventionKuhl
31、kamp 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/sotalolsotalolICD药物对心脏性猝死（SCD）的预防作用Roles of Antiarrhythmic Drugs in SCD PreventionValue of Antiarrhythmic Drugs Class I antiarrhythmi
32、cs: not only ineffective but also harmful Beta Blockers: Effective in suppressing ventricular ectopic beats and arrhythmias; reduce incidence of SCD Amiodarone: No definite survival benefit; some studies have shown reductionin SCD in patients with LV dysfunction, especially when given in conjunction
33、 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 benefit clearly shown Conclusions: Antiarrhythmic drugs (except for BB) should not be used as primary therapy of the preventi
34、on of SCD. Both sotalol and amiodarone have been shown to reduce the frequency of ICD shock therapy药物对心脏性猝死（SCD）的预防作用SCD Prevention by Non-antiarrhythmic Drugs药物对心脏性猝死（SCD）的预防作用Roles of angiotensin converting enzyme inhibitors (ACEI) angiotensin receptor blockers(ARB) and aldosterone blocker in SCD
35、PreventionRamiprilhigh-risk patients not known to have low ejection fraction or heart failure2000DrugPatientsStudyPublishedHOPESOLVDTEnalapril chronic heart failure1991EPHESUSEplerenonePost-MILV dysfunction2003RALESSpironolactonechronic heart failure1999CHARMCandesartanchronic heart failure2004SOLVD
36、PEnalaprilchronic heart failure1991药物对心脏性猝死（SCD）的预防作用Meta-analysis of 15 randomized controlled trial - RESULTS -Domanski MJ, Exner DV, Borkowf CB, et al. JACC Vol. 33, No. 3,1999:598604ACEIACEIACEIACEIACEI药物对心脏性猝死（SCD）的预防作用Meta-analysis of 15 randomized controlled trial - RESULTS -The overall OR for
37、 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药物对心脏性猝死（SCD）的预防作用HOPE: Heart Outcomes Prevention Evaluation study- RESULTS -PPrimary outcome and deaths from any cause342The Hope Study Investigators. N Engl
38、J Med 2000;:14553.Relative risk(95% CI)MI, stroke, or death fromcardiovascular causesDeath from cardiovascular causesMIStrokeDeath from noncardiovascular causesDeath from any causeRamipriln=4645(%)14.06.19.93.44.310.4Placebon=4652(%)17.88.112.34.94.112.20.78 (0.700.86)0.74 (0.640.87)0.80 (0.700.90)0
39、.68 (0.560.84)1.03 (0.851.26)0.84 (0.750.95)0.0010.0010.0010.0010.740.005Ramipril reduced the risk of SCD about 38% (0.02)药物对心脏性猝死（SCD）的预防作用SOLVD Trial -RESULTS NEnglJMed1991;325:293-30216% Risk Reduction in All Cause Mortality p = 0.00360102030405006 12 18 24 30 36 42 48MonthsMortality%Placebo Enal
40、aprilAll Cause Mortality and SCD SOLVD Treatment TrialSOLVD Prevention Trial10% Risk Reduction in SCD p = NS8%8% Risk Reduction in All Cause Mortality Risk Reduction in All Cause Mortality P=0.30051015202506 12 18 24 30 36 42 48MonthsMortality (%)7% Risk Reduction in SCD p = NS药物对心脏性猝死（SCD）的预防作用CHAR
41、MCandesartan in Heart failure Assessment of Reduction in Mortality and morbidity - RESULTs -yrs3.50123010203052515CandesartanPlaceboNon CV deathp=0.6016% reductionp=0.005CV deathCV deaths and Non CV deaths (%)PlaceboCandesartanNumber at riskCandesartan2289210518941382580Placebo2287202318111333548药物对
42、心脏性猝死（SCD）的预防作用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 candesartan resulted in a reduction in SCD (p=0.036)CHARM-AlternativeCHARM-AddedCHARM-PreservedCHARM-Overa
43、llCandecartan(n=1013) Placebo (n=1015)Candecartan(n=1276) Placebo (n=1272)Candecartan(n=1514) Placebo (n=1508)Candecartan(n=3803) Placebo (n=3796)Hazard Ratioand 95% Ci8011115016869652993443.04.33.94.51.61.52.73.2SCD*Per 100 person-years 0.85（0.73-0.99）P=0.036 Incidence rate药物对心脏性猝死（SCD）的预防作用RALES :
44、 the Randomized Aldactone Evaluation Study- RESULTs -PCardiac causesProgression of heart failureSudden death0.001 Cardiovascular deathSpironolactone group(n=822)3141891101522622782170.69 (0.580.82)0.64 (0.510.80)Placebo group(n=841)Raletive risk(95% CI)VARIABLEMyocardial infarction0.71 (0.540.95)0.0
45、20.001Pitt, N Engl J Med 1999; SCD Risk Reduction: 29% (p0.02) 药物对心脏性猝死（SCD）的预防作用EPHESUSEPHESUS Eplerenone Post-AMI Heart Failure Efficacy and Survival Study - RESULTs -All-cause All-cause MortalityMortalityRR 0.85RR 0.85p=0.008p=0.008EplerenoneEplerenonePlaceboPlaceboN Engl J Med 2003;348:1309-21N
46、Engl J Med 2003;348:1309-21Eur J Heart Fail. 2006;8 :295-301Eur J Heart Fail. 2006;8 :295-301CV DeathCV DeathRR 0.87RR 0.87p=0.002p=0.002EplerenoneEplerenonePlaceboPlacebo Treatment with eplerenone in the subgroup of patients with LVEF 30% resulted in relative risk reductions of 33% for SCD (P=0.008
47、) 药物对心脏性猝死（SCD）的预防作用Roles of angiotensin converting enzyme inhibitors (ACEI) angiotensin receptor blockers(ARB) and aldosterone blockerinSCDPreventionDrugTotal Death Risk Reduction (p-value)StudySCD Risk Reduction (p-value)HOPERamipril26% (0.005)38% (0.02)SOLVDTEnalapril 16% (0.004)10% (NS)EPHESUSEp
48、lerenone8% (=0.02)58% (P=0.008) RALESSpironolactone30% (0.001)29% (0.02)CHARMCandesartan12% (p=0.018)Not reportedSOLVDPEnalapril8% (0.3)7% (NS)药物对心脏性猝死（SCD）的预防作用Roles of Antithrombotic Therapy in SCD PreventionData from SOLVD prevention and treatment trials Incidence and Crude Relative Risk of Sudde
49、n Coronary Death, Cardiovascular Death, and All-Cause Mortality According to Antithrombotic TherapyNeither 225 2.76 1.0 754 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 1.86 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 0.8095%
50、 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 cerebrovascular deaths.The rate is expressed as events per 100 patient-years of follow-up. R
51、R relative risk.Sudden Coronary DeathCardiovascular Death All Cause MortalityNo. Rate RR No. Rate RR No. Rate RR Dries DL, et al. Am J Cardiol. 1997;79: 909-913药物对心脏性猝死（SCD）的预防作用Roles of Antithrombotic Therapy in SCD Prevention Antiplatelet and anticoagulant monotherapy each remained independently a
52、ssociated 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 dysfunction resulting from coronary artery disease, antiplatelet and anticoagulant therapy are eac
53、h associated with a reduction in the risk of SCD.Data from SOLVD prevention and treatment trials 药物对心脏性猝死（SCD）的预防作用Roles of Statins in SCD PreventionStatins in the MADIT-II Study.Vyas AK, Hongsheng Guo, Moss AJ, et al. J Am Coll Cardiol 2006; 47: 769-773药物对心脏性猝死（SCD）的预防作用 1%2%3%4%StatinsStatinsPlace
54、bo or no treatmentPlacebo or no treatmentSCD MortalitySCD Mortality19% risk reduction19% risk reduction p=0.003p=0.003Levantesi G et al .Meta-analysis of effect of statin treatment on risk of sudden death.Am J Cardiol. 2007;100:1644-1650. Roles of Statins in SCD PreventionMeta-analysis of effect of
55、statin treatment on risk of SCD 药物对心脏性猝死（SCD）的预防作用Roles of n-3 Fatty Acid in SCD Prevention.PatientsStudyOutcomeFollow up1the secondary prevention of myocardial infarction Published29% reduction in mortalitymay result from reduction in SCD 2y1989273m70% reduction in mortality 199433.5y59% reduction
56、in mortality 45% reduction in SCD17y199952% reduction in risk of SCD 4Without cardiovascular disease20026With Sustained VT or VFAnd ICD 24m does not reduce the risk of VT/VF and may be proarrhythmic in some patients 2005 have anti-arrhythmic properties, but conflicting data exist for the prevention
57、of SCDWith ICDs12m prolonged the time to the first ICD event reduced death from any cause20035Published药物对心脏性猝死（SCD）的预防作用Non-antiarrhythmic Drugs-SUMMARY- ACEI, ARB and aldosterone blockers can improvethe myocardial substrate through reverse remodeling and thus reduce incidence of SCD Antithrombotic
58、 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药物对心脏性猝死（SCD）的预防作用 Angi
59、otensin II(Renin-Angiotensin System RAS) Norepinephrine(Sympathetic Nervous System SNS)RAS Inhibition -BlockadeDisease ProgressionNeurohormonal Blockade Across theCardiovascular Disease Continuum药物对心脏性猝死（SCD）的预防作用One-year Mortality (%)More drugs, More Survival药物对心脏性猝死（SCD）的预防作用As to disease, make a habit of two thingsAs to disease, make a habit of two thingsto to helphelp, or at least , or at least do no harmdo no harm！Hippocrates 药物对心脏性猝死（SCD）的预防作用药物对心脏性猝死（SCD）的预防作用
