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 Prevention Summary and conclusionsEpidemiology of SCD Accounts for 63% of all cardiac related deaths

2、 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. Heart Disease: A Textbook of Cardiovascular Medicine. 5th Ed. New York: WB Saunders. 1997: 742-779. Zheng

3、 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%ChinaUS544,000300,000350,000ChinaUSIncidence RateAbsolute Number0.04%0.1%0.2%Incidence of SCD in Specific Pop

4、ulations 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 Multiple risk subgroupsPatients with any previous coronary eventPatients with ejectionfr

5、action 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 manifestation of coronary heart disease in 50% of men and 63% of women. nCHD accounts

6、 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 Heart Association; 2002. Adapted from Heikki et al. N Engl J Med,

7、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%Torsades de Pointes12.7%Bays de Luna A. Am Heart J.

8、 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 PreventionValue of Antiarrhythmic Drugs Class I ant

9、iarrhythmics 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 mortalityDays after randomization050100 150 200 250

10、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 Arrhythmia Suppression Trial II As with the ant

11、iarrhythmic 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 PreventionStudyBHATNo

12、rwegianCOPERNICUSCIBIS-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 bid 10 qd25m17m15m2.4y1.3y10.4m1982200

13、0199919992001 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 (Post-MI LVD patients) 39% Reduced m

14、ortality 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 SCD in long term trials compar

15、ing 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 Total No of patientsTotal No of deathsNo (%) of sudden deathsT

16、otal No ofpatientsTotal No of deathsNo (%) of sudden deathsNorwegian timolol trial 93915295 (63) 945 9847 (48)Blocker heart attack trial192118889 (47)191613864 (46)PlaceboCarvedilolHazard Ratio(95% CI)Cardiovascular Death1391040.75(0.58-0.96)Sudden Death69510.74(0.51-1.06)Death Due to Pump Failure30

17、180.60(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 adm

18、ission 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.

19、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. Lancet 1999;353:20017.00.51.01.5Relative ris

20、k for mortalityRelative 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 wi

21、th 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 reasonPacker M, Coats AJ, Fowler MB et al. N Engl J Med 2001;344:16518.Roles of Beta Blockers in SCD PreventionStudyBHATNorw

22、egianCOPERNICUSCIBIS-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 reported26% ( 0.099) 41% ( 0.0002)44% ( 0.001)N

23、ot 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 total mortality and arrhythmic/sudden death

24、 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 cardioverter defibrillator secondary prevention trials

25、European 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 amiodarone appears to be dependent upon the degree of

26、 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 therapyPlaceboBardy GH, Lee KL, Mark DB, et al. N Engl J Med, 2005, 352:225ICD + AADsPercent Ar

27、rhythmia-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 randomisation (days)Z = -2.5,

28、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-sotalolWaldo AL. Lancet. 1996;34

29、8:7-12. 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 PreventionValue of Antiarrhythmic

30、 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 patients with LV dysfunction, especial

31、ly 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 for BB) should not be used as pri

32、mary 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 aldosterone blocker in SCD Preventi

33、onRamiprilhigh-risk patients not known to have low ejection fraction or heart failure2000DrugPatientsStudyPublishedHOPESOLVDTEnalapril chronic heart failure1991EPHESUSEplerenonePost-MILV dysfunction2003RALESSpironolactonechronic heart failure1999CHARMCandesartanchronic heart failure2004SOLVDPEnalapr

34、ilchronic 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 patients randomized to ACE inhibitor

35、 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(95% CI)MI, stroke, or death fr

36、omcardiovascular 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)0.84 (0.750.95)0.0010.0010.0010.0

37、010.740.005Ramipril reduced the risk of SCD about 38% (0.02)-RESULTS N Engl J Med 1991;325:293-30216% Risk Reduction in All Cause Mortality p = 0.00360102030405006 12 18 24 30 36 42 48MonthsMortality%Placebo EnalaprilAll Cause Mortality and SCD SOLVD Treatment TrialSOLVD Prevention Trial10% Risk Red

38、uction in SCD p = NS 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 and morbidity - RESULTs -yrs3.50123010203052515CandesartanPlaceboNon CV deathp=0.6016% reductionp=0.005CV deathCV death

39、s and Non CV deaths (%)PlaceboCandesartanNumber at riskCandesartan2289210518941382580Placebo2287202318111333548CHARM 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 candesarta

40、n 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(n=1514) Placebo (n=1508)Candecartan(n=3803) Placebo (n=3796)Hazard Ratioand 95% Ci8011115016869652993443.04.33.94.51.6

41、1.52.73.2SCD*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 death0.001 Cardiovascular deathSpironolactone group(n=822)3141891101522622782170.69 (0.580.82)0.64 (0.510.80)Placebo gr

42、oup(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 Failure Efficacy and Survival Study - RESULTs -EPHESUSAll-cause MortalityRR 0.85p=0.008EplerenonePlaceboN Engl J Med 2003;348:1309-21

43、Eur 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 of 33% for SCD (P=0.008) Roles of angiotensin converting enzyme inhibitors (ACEI) angiotensin receptor blockers(ARB) and a

44、ldosterone 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)EPHESUSEplerenone8% (=0.02)58% (P=0.008) RALESSpironolactone30% (0.001)29% (0.02)CHARMCandesartan12% (p=0.018)Not reportedS

45、OLVDPEnalapril8% (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 Death, and All-Cause Mortality According to Antithrombotic TherapyNeither 225 2.76 1.0 754 9.24 1.0

46、 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 interval for the point estimate of the relative risk.Cardiovascular deaths include sudden cardiac dea

47、th, 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 DeathCardiovascular Death All Cause MortalityNo. Rate RR No. Rate RR No. Rate RR Dries DL, et al. Am

48、 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 therapy with a 24% reduction. anticoagulant therapy with a 32% reduction. Thus, in patient

49、s 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 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%Statin