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 Roles
2、 of Drugs in SCD Prevention Summary and conclusionsEpidemiology 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:Braunwald E,ed.He
3、art 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.WorldwideUS300,000350,0003,000,000W.Europe400,000Magnitude of SCD in China0.1%0.04%0.2%ChinaUS544,000300,0
4、00350,000ChinaUSIncidence RateAbsolute Number0.04%0.1%0.2%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.369-381,March 2001.300,000200,000100,000Absolute number of SCD Per Year Multipl
5、e 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)MADIT II SCD-HeFT AVID,CASH,CIDS MADIT,MUSTT,nSudden death was the first manifestatio
6、n 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 Disease Cause of SCDAmerican Heart Association.Heart Disease and Stroke Statistics2003 Update.Dallas,Tex.:American Hea
7、rt 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.Arrhythmic Cause of SCDAlbert CM.Circulation.2003;107:2096-2101.12%Other Cardiac Cause88%Arrhythmic CauseBradycardia16.5%VF62.4%Primary VT8.3%Tor
8、sades de Pointes12.7%Bays de Luna A.Am Heart J.1989;117:151-159.Application of ICD in China200544,000“Even the wealthiest nations cannot afford to pay to use every medical advance in any patient who might benefit.”Thomas Bigger,Lancet,2001Roles of Drugs in SCD PreventionRoles of Drugs in SCD Prevent
9、ionValue of Antiarrhythmic Drugs Class I antiarrhythmics Beta Blockers Amiodarone SotalolValue of Non-antiarrhythmic Drugs Electrolytes ACE inhibitors,ARBs and aldosterone blockers Antithrombotic and antiplatelet agents Statins n-3 Fatty acidsSCD Prevention by Antiarrhythmic DrugsAll-cause mortality
10、Days after randomization050100 150 200 250 300 350 400 450 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 TrialCAST II:Cardiac Arrhythmi
11、a Suppression 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.Roles of Beta
12、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 25 b
13、id 10 qd25m17m15m2.4y1.3y10.4m19822000199919992001 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-Blocker Heart Attack)Trial (P
14、ost-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.BHATNorwegianAverage incidence of SC
15、D in long term trials comparing blockers with placebo after MINuttall SL,Toescu V,Kendall MJ.BMJ.2000;320:581.Average incidence of sudden death in long term trials comparing -blockers with placebo after myocardial infarction Placebo treatment Blocker treatment Norwegian timolol trialBlocker heart at
16、tack trialTotal No of patients 9391921Total No of deaths152188No(%)of sudden deaths95(63)89(47)Total No ofpatients 9451916Total No of deaths 98138No(%)of sudden deaths47(48)64(46)PlaceboCarvedilolHazard Ratio(95%CI)Cardiovascular Death1391040.75(0.58-0.96)Sudden Death69510.74(0.51-1.06)Death Due to
17、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.CIBIS II:Cardiac Insufficiency Bisoprolol Study II -RESULTS-PPrimary endpoint All-cause mortality Secondary endpoints All-cause hospital
18、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(0.39-0.80)0.64(0.53 0.79)0.0001 0.0006 0.0049 0.0004 0.0011 0.0001Prim
19、ary and secondary outcomesPlacebo(n=1320)(%)(n=1327)(%)Hazard ratio(95%CI)CIBIS-II Investigators and Committees.Lancet 1999;353MERIT-HF:Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure -RESULTS-MERIT-HF Study Group.Lancet 1999;353:20017.00.51.01.5Relative risk for mortality
20、Relative risk(95%CI)MortalityMetoprolol CR/XL betterRiskreduction(%)Total mortalityCardiovascular mortalitySudden deathDeath from worseningheart failure343841490.00620.000030.00020.0023PCOPERNICUS:Carvedilol Prospective Randomized Cumulative Survival trial-SUMMARY-In patients with severe chronic hea
21、rt failure,carvedilol in addition to standard therapy reduced:l All-cause mortalityl Combined endpoint of all-cause mortality and hospitalization for any reasonPacker M,Coats AJ,Fowler MB et al.N Engl J Med 2001;344:16518.Roles of Beta Blockers in SCD PreventionStudyBHATNorwegianCOPERNICUSCIBIS-IICA
22、PRICORNMERIT-HFSCD Risk Reduction(p-value)DrugPropranoloTimololmetoprololcarvedilolbisoprololcarvedilolTotal Death Risk Reduction(p-value)34%(0.00009)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 Roles of Amiodarone in SCD Pre
23、ventionConnolly 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-analysisof 13 trials of amiodaron
24、eAmiodaroneControlTotal mortalityArrhythmic/sudden death29%reduction inarrhythmic deathP=0.0003Meta-analysis of the ICD secondary prevention trialsConnolly SJ.et al.Meta-analysis of the implantable cardioverter defibrillator secondary prevention trialsEuropean Heart Journal.2000;20712078Meta-analysi
25、s of effects of amiodarone on SCD -RESULTS-Cumulative 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.MortalityFolow-up(m)Morta
26、lity by Intention-to-TreatSCD-HeFT-2004 HR 97.5%CI PAmiodarone vs placebo1.060.86,1.30 0.529ICD therapy vs placebo0.770.62,0.96 0.007AmiodaroneICD therapyPlaceboBardy GH,Lee KL,Mark DB,et al.N Engl J Med,2005,352:225ICD+AADsPercent Arrhythmia-Free26%reduction inevent ratethe time to first event exte
27、nded median 1.3 months to median 4.4 monthsSteinberg JS,Martins J,Sadanandan S,et al.Am Heart J.2001;142:520-529 ICD ICD+AADs Roles of Sotalol in SCD PreventionSWORD Survival Results1.000Time from randomisation(days)Z=-2.5,P=0.006Proportion event-freePlacebod-sotalol60120180240300.99.98.97.96.95.94.
28、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.Roles of Sotalol in SCD PreventionKuhlkamp V.Suppression of sustained ventr
29、icular tachyarrhythmias:a comparison of d,l-sotalol with no antiarrhythmic drug treatment.J Am Coll Cardiol.1999;33:46-52.ICD/sotalolsotalolICDRoles of Antiarrhythmic Drugs in SCD PreventionValue of Antiarrhythmic Drugs Class I antiarrhythmics:not only ineffective but also harmful Beta Blockers:Effe
30、ctive 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 with BB.but it has complex drug interactions and many adverse si
31、de 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 prevention of SCD.Both sotalol and amiodarone have been shown to reduce the frequ
32、ency of ICD shock therapySCD Prevention by Non-antiarrhythmic DrugsRoles of angiotensin converting enzyme inhibitors(ACEI)angiotensin receptor blockers(ARB)and aldosterone blocker in SCD PreventionRamiprilhigh-risk patients not known to have low ejection fraction or heart failure2000DrugPatientsStud
33、yPublishedHOPESOLVDTEnalapril chronic heart failure1991EPHESUSEplerenonePost-MILV dysfunction2003RALESSpironolactonechronic heart failure1999CHARMCandesartanchronic heart failure2004SOLVDPEnalaprilchronic heart failure1991Meta-analysis of 15 randomized controlled trial-RESULTS-Domanski MJ,Exner DV,B
34、orkowf CB,et al.JACC Vol.33,No.3,1999:598604ACEIACEIACEIACEIACEIMeta-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 about 20%in post-MI patientsHOPE:Heart Outcomes Prev
35、ention Evaluation study-RESULTS-PPrimary outcome and deaths from any cause342The Hope Study Investigators.N Engl J Med 2000;:14553.Relative risk(95%CI)MI,stroke,or death fromcardiovascular causesDeath from cardiovascular causesMIStrokeDeath from noncardiovascular causesDeath from any causeRamipriln=
36、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)0.68(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)-RESULTS N Engl J Med 1991;325:293-30216%Risk Reduction in All Cause Mortal
37、ity p=0.00360102030405006 12 18 24 30 36 42 48MonthsMortality%Placebo EnalaprilAll Cause Mortality and SCD SOLVD Treatment TrialSOLVD Prevention Trial10%Risk Reduction in SCD p=NS P=0.30051015202506 12 18 24 30 36 42 48MonthsMortality (%)7%Risk Reduction in SCD p=NSCHARMCandesartan in Heart failure
38、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 riskCandesartan2289210518941382580Placebo2287202318111333548CHARM Candesartan in Heart failure Ass
39、essment 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-OverallCandecartan(n=1013)Placebo (n=1015)Candecartan(n=1276)Pla
40、cebo (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 rateRALES:the Randomized Aldactone Evaluation Study-RESULTs-PCardiac causesProgression of hea
41、rt 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)0.020.001Pitt,N Engl J Med 1999;SCD Risk Reduction:29%(p0.02)Eplerenone Post-AMI Heart Failur
42、e Efficacy and Survival Study-RESULTs-EPHESUSAll-cause MortalityRR 0.85p=0.008EplerenonePlaceboN Engl J Med 2003;348:1309-21Eur J Heart Fail.2006;8:295-301CV DeathRR 0.87p=0.002EplerenonePlacebo Treatment with eplerenone in the subgroup of patients with LVEF 30%resulted in relative risk reductions o
43、f 33%for SCD(P=0.008)Roles of angiotensin converting enzyme inhibitors(ACEI)angiotensin receptor blockers(ARB)and aldosterone blocker in SCD PreventionDrugTotal Death Risk Reduction(p-value)StudySCD Risk Reduction(p-value)HOPERamipril26%(0.005)38%(0.02)SOLVDTEnalapril 16%(0.004)10%(NS)EPHESUSEpleren
44、one8%(=0.02)58%(P=0.008)RALESSpironolactone30%(0.001)29%(0.02)CHARMCandesartan12%(p=0.018)Not reportedSOLVDPEnalapril8%(0.3)7%(NS)Roles of Antithrombotic Therapy in SCD PreventionData from SOLVD prevention and treatment trials Incidence and Crude Relative Risk of Sudden Coronary Death,Cardiovascular
45、 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%CI the 2-sided 95%confidence inte
46、rval 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.RR relative risk.Sudden Coronary DeathCa
47、rdiovascular Death All Cause MortalityNo.Rate RR No.Rate RR No.Rate RR Dries DL,et al.Am J Cardiol.1997;79:909-913Roles of Antithrombotic Therapy in SCD Prevention Antiplatelet and anticoagulant monotherapy each remained independently associated with a reduction in the risk of SCD:antiplatelet thera
48、py 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 each associated with a reduction in the risk of SCD.Data from SOLVD preven
49、tion and treatment trials 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 1%2%3%4%StatinsPlacebo or no treatmentSCD Mortality19%risk reduction p=0.003Levantesi G et al.Meta-analysis of effect of statin treatment on
50、 risk of sudden death.Am J Cardiol.2007;100:1644-1650.Roles of Statins in SCD PreventionMeta-analysis of effect of statin treatment on risk of SCD Roles of n-3 Fatty Acid in SCD Prevention.PatientsStudyOutcomeFollow up1the secondary prevention of myocardial infarction Published29%reduction in mortal
