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1、The Role of Drugs in Prevention of Sudden Cardiac Death Weimin Li Professor of Medicine CardiovascularDepartment,theFirstClinicalHospital,HarbinMedicalUniversity，Harbin Presentation Overview SuddenCardiacDeathEpidemiology,etiology,pathophysiologyOverviewofICDtherapytopreventSCD Roles of Drugs in SCD
2、 Prevention SummaryandconclusionsEpidemiology 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:BraunwaldE,ed.Heart Disease: A Textbook o
3、f 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.Europe400,000MagnitudeofSCDinChina0.1%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 Yea
5、r 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) MADIT II SCD-HeFT AVID, CASH, CIDS MADIT, MUSTT, nSudden death was the f
6、irst 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 Disease Cause of SCDAmerican Heart Association. Heart Disease and Stroke Statistics2003 Update.
7、 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.Arrhythmic Cause of SCDAlbert CM. Circulation. 2003;107:2096-2101.12%Other Cardiac Cause88%Arrhythmic Cau
8、seBradycardia16.5%VF62.4%Primary VT8.3%Torsades 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
9、in SCD PreventionRoles of Drugs in SCD PreventionValue 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 Preven
10、tion by Antiarrhythmic DrugsAll-cause mortalityDays 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 Ar
11、rhythmia Suppression TrialCAST II: Cardiac Arrhythmia 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
12、 not only ineffective but also harmful.Roles of Beta Blockers in SCD PreventionStudyBHATNorwegianCOPERNICUSCIBIS-IICAPRICORNMERIT-HFPublished1981Follow upTarget Dosage(mg/day)Patientsmild/moderate HFPost-MI LVDPost-MI LVDPost-MI LVDmoderate/severe HFsevere HFDrugPropranoloTimololmetoprololcarvedilol
13、bisoprololcarvedilol 200 qd 25 bid 10 bid 180240 25 bid 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 T
14、imolol Trialand BHAT(Beta-Blocker 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.
15、 JAMA. 1982;247:1707-1714.BHATNorwegianAverage 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 Blocke
16、r treatment TotalNoofpatientsTotalNoofdeathsNo(%)ofsuddendeathsTotalNoofpatientsTotalNoofdeathsNo(%)ofsuddendeathsNorwegiantimololtrial93915295(63)9459847(48)Blockerheartattacktrial192118889(47)191613864(46)PlaceboCarvedilolHazard Ratio(95% CI)Cardiovascular Death1391040.75(0.58-0.96)Sudden Death695
17、10.74(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. CIBIS II: Cardiac Insufficiency Bisoprolol Study II - RESULTS -PPrimary endpoint All-cause mortality
18、 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 (0.39 -0.80) 0.64 (0.53
19、 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; 353MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure - RESULTS -MERIT-HF Study Group. L
20、ancet 1999;353:20017.00.51.01.5Relative risk for mortalityRelative risk (95% CI)MortalityMetoprolol CR/XL betterRiskreduction(%)Total mortalityCardiovascular mortalitySudden deathDeath from worseningheart failure343841490.00620.000030.00020.0023PCOPERNICUS: Carvedilol Prospective Randomized Cumulati
21、ve 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, Coats AJ, Fowler MB et al. N Engl J Med 2001;344:16518.Roles of
22、Beta Blockers in SCD PreventionStudyBHATNorwegianCOPERNICUSCIBIS-IICAPRICORNMERIT-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 rep
23、orted26% ( 0.099) 41% ( 0.0002)44% ( 0.001)Not reported Roles of Amiodarone in SCD PreventionConnolly 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
24、 total mortality and arrhythmic/sudden death from a meta-analysisof 13 trials of amiodaroneAmiodaroneControlTotal mortalityArrhythmic/sudden death29% reduction inarrhythmic deathP=0.0003Meta-analysis of the ICD secondary prevention trialsConnolly SJ. et al.Meta-analysis of the implantable cardiovert
25、er defibrillator secondary prevention trialsEuropean Heart Journal. 2000; 20712078Meta-analysis 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 amiodaron
26、e appears to be dependent upon the degree of left ventricular dysfunction.MortalityFolow-up(m)Mortality 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 therapyPlaceboBardyGH,LeeKL,MarkDB,etal.NEnglJMed,2
27、005,352:225ICD + AADsPercent Arrhythmia-Free26%reduction inevent ratethe time to first event extended 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
28、 randomisation (days)Z = -2.5, P = 0.006Proportion event-freePlacebod-sotalol60120180240300.99.98.97.96.95.94.93.92.91.90.89.88.87Patients at riskPlacebo15721170874551330d-sotalol15491150844544323Study stopped prematurely in Nov. 1994 due to increased mortality in patient population treated with d-s
29、otalolWaldo AL. Lancet. 1996;348:7-12. Roles of Sotalol in SCD PreventionKuhlkamp 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/sotalolsotalolICDRoles of Antiarrhythmic Drugs in SCD Pr
30、eventionValue 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 survival benefit; some studies have shown reductionin SCD in patient
31、s 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 benefit clearly shown Conclusions: Antiarrhythmic drugs (except fo
32、r 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 therapySCD Prevention by Non-antiarrhythmic DrugsRoles of angiotensin converting enzyme inhibitors (ACEI) angiotensin receptor blockers(ARB) and aldo
33、sterone blocker in SCD PreventionRamiprilhigh-risk patients not known to have low ejection fraction or heart failure2000DrugPatientsStudyPublishedHOPESOLVDTEnalapril chronic heart failure1991EPHESUSEplerenonePost-MILV dysfunction2003RALESSpironolactonechronic heart failure1999CHARMCandesartanchronic
34、 heart failure2004SOLVDPEnalaprilchronic heart failure1991Meta-analysis of 15 randomized controlled trial - RESULTS -Domanski MJ, Exner DV, Borkowf CB, et al. JACC Vol. 33, No. 3,1999:598604ACEIACEIACEIACEIACEIMeta-analysis of 15 randomized controlled trial - RESULTS -The overall OR for SCD in patie
35、nts 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 Prevention Evaluation study- RESULTS -PPrimary outcome and deaths from any cause342The Hope Study Investigators. N Engl J Med 2000;:14553.Relative risk
36、(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)0.68 (0.560.84)1.03 (0.851.26)0.
37、84 (0.750.95)0.0010.0010.0010.0010.740.005Ramipril reduced the risk of SCD about 38% (0.02)SOLVD Trial -RESULTS NEnglJMed1991;325:293-30216% Risk Reduction in All Cause Mortality p = 0.00360102030405006 12 18 24 30 36 42 48MonthsMortality%Placebo EnalaprilAll Cause Mortality and SCD SOLVD Treatment
38、TrialSOLVD Prevention Trial10% Risk Reduction in SCD p = NS8%8% RiskRisk Reduction in All Cause Mortality Reduction in All Cause Mortality P=0.30051015202506 12 18 24 30 36 42 48MonthsMortality (%)7% Risk Reduction in SCD p = NSCHARMCandesartan in Heart failure Assessment of Reduction in Mortality a
39、nd morbidity - RESULTs -yrs3.50123010203052515CandesartanPlaceboNon CV deathp=0.6016% reductionp=0.005CV deathCV deaths and Non CV deaths (%)PlaceboCandesartanNumber at riskCandesartan2289210518941382580Placebo2287202318111333548CHARM Candesartan in Heart failure Assessment of Reduction in SCD- RESU
40、LTs -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) Placebo (n=1272)Candecartan(
41、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 heart failureSudden d
42、eath0.001 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) EPHESUSEPHESUS Eplerenone Post-AMI Heart
43、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 Engl J Med 2003;348:1309-21EurEur J Heart Fail. 2006;8 :295-301 J Heart Fail. 2006;8 :295-301CV DeathCV DeathRR 0.87RR 0.8
44、7p=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) Roles of angiotensin converting enzyme inhibitors (ACEI) angiotensin receptor blockers(ARB) and aldosterone blockerinSCD
45、PreventionDrugTotal Death Risk Reduction (p-value)StudySCD Risk Reduction (p-value)HOPERamipril26% (0.005)38% (0.02)SOLVDTEnalapril 16% (0.004)10% (NS)EPHESUSEplerenone8% (=0.02)58% (P=0.008) RALESSpironolactone30% (0.001)29% (0.02)CHARMCandesartan12% (p=0.018)Not reportedSOLVDPEnalapril8% (0.3)7% (
46、NS)Roles of Antithrombotic Therapy in SCD PreventionData from SOLVD prevention and treatment trials Incidence and Crude Relative Risk of Sudden 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
47、 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 interval for the point estimate of the relative risk.Cardiovascular deaths include sudden cardiac death, death due to progressi
48、ve 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 DeathCardiovascular Death All Cause MortalityNo. Rate RR No. Rate RR No. Rate RR Dries DL, et al. Am J Cardiol. 1997;79: 909-9
49、13Roles 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% reduction. Thus, in patients with moderate to severe
50、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 PreventionStatins in the MADIT-II Study.Vyas AK, Hongsh
51、eng Guo, Moss AJ, et al. J Am Coll Cardiol 2006; 47: 769-773 1%2%3%4%StatinsStatinsPlacebo 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 Ca
52、rdiol. 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 mortalitymay result from reducti
53、on in SCD 2y1989273m70% reduction in mortality 199433.5y59% reduction 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
54、-arrhythmic properties, but conflicting data exist for the prevention of SCDWith ICDs12m prolonged the time to the first ICD event reduced death from any cause20035PublishedNon-antiarrhythmic Drugs-SUMMARY- ACEI, ARB and aldosterone blockers can improvethe myocardial substrate through reverse remode
55、ling 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 ex
56、ist for the prevention of SCD Angiotensin II(Renin-Angiotensin System RAS) Norepinephrine(Sympathetic Nervous System SNS)RAS Inhibition -BlockadeDisease ProgressionNeurohormonal Blockade Across theCardiovascular Disease ContinuumOne-year Mortality (%)More drugs, More SurvivalAs 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
