sudden cardiac death prevention: clinical trials

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Sudden Cardiac Death Prevention: Clinical Trials. Alena Goldman, MD September 9, 2004. Introduction. SCD: common problem in patient with: -CAD -LV dysfunction -asymptomatic ventricular arrhythmias. Introduction. Most sudden deaths and cardiac arrests are due to reentrant VT or VF - PowerPoint PPT Presentation

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  • Sudden Cardiac Death Prevention: Clinical TrialsAlena Goldman, MDSeptember 9, 2004

  • Introduction SCD: common problem in patient with:

    -CAD-LV dysfunction-asymptomatic ventricular arrhythmias

  • IntroductionMost sudden deaths and cardiac arrests are due to reentrant VT or VF ICD (implantable cardioverter defibrillator) has become primary therapeutic modality for secondary prevention of SCD, and in some patients groups, for primary prevention

  • Secondary PreventionCASH trial (Cardiac Arrest Survival in Hamburg): 23% reduction in mortality in survivors of cardiac arrest receiving ICD vs amiodarone/metoprololCIDS trial (Canadian Implantable Defibrillator Study): ICD vs amiodarone; no mortality differenceAVID trial (Antiarrhythmic Drug vs Defibrillator): 1016 pts; trial stopped when survival benefit noted in patients treated with ICD vs amiodarone and d,l sotalol

  • Risk Stratification StrategiesSubgroup analysis of AVID trial:LVEF>35%: no difference in survival between ICD and antiarrhythmic drugsEtiology of Heart Disease (most evidence for coronary heart disease and dilated cardiomyopathy)Effects of shock: recurrence of shocks is independent predictor of poor outcome

  • Risk Stratification Strategies, contdEffects of Electrical Storm: >3 episodes of VT/VF in 24 hours; increased risk for cardiac nonsudden death (MI)Mode of Death: ? Due to electromechanical dissociation rather than recurrent ventricular tachyarrhythmias

  • Primary Prevention: Who is at High Risk?ACC/AHA/NASPE task force recommendations:Patients with CHD; prior MI; LV dysfunction; h/o NSVT; with inducible sustained VT/VF at EPS (without suppression by class I antiarrhythmic)Patients with syncope with inducible sustained VT/VF at EPS when antiarrhythmic therapy not effective, not tolerated, not preferred

  • Ischemic Cardiomyopathy Primary Prevention TrialsMADIT IMUSTTMADIT IICABG PatchCAT

  • MADIT I (NEJM, December 1996)Why care?

    30% 2 year mortality in patients with unsustained VT and h/o previous MI and LV dysfunction

    Aim of trial:To show that prophylactic implantation of ICD, as compared to conventional medical therapy, would improve survival in high risk patients

  • MADIT I, ContdMethods/Inclusion Criteria:-25-80 yo-h/o MI 3 weeks prior to study-NYHA class I,II,or III-LVEF
  • MADIT I; ContdExclusion criteria:-previous cardiac arrest or VT/syncope not associated with MI-symptomatic hypoT while in stable rhythm-recent MI (within 3 weeks)-CABG within past 2 months-coronary angioplasty within past 3 months-pts with cerebrovascular disease

  • MADIT I Eligible Patients

    EPS

    Induced VT yes no Suppression with Procainamide conventional therapy (n=101)yes no (n=196) ICD (n=95)

  • MADIT IStatistical Analysis:-designed to have 85% power to detect 46% reduction in mortality rate-Triangular sequential design modified for two sided alternatives in order to terminate trial once one of boundaries is reached -transthoracic and transvenous ICDs used; analysis stratified based on device type

  • MADIT I: Results-efficacy boundary of sequential design crossed when 51 deaths were reported study stopped-superiority of ICD vs conventional therapy, i. e. survival difference (p 0.009); 95% CI 0.26-0.82-Kaplan-Meier curves separate early and remain separated for 5 years Conventional ICDCardiac death 27 11Noncardiac 6 4Unknown 6 0Total 39 15

  • MADIT I: Discussion-significant reductions in incidence of overall mortality, cardiac mortality and arrhythmic deaths in patients with ICD group-subset analysis:Survival benefit only in patients with more severe heart disease (LVEF12 sec)

  • MADIT I: Limitations-Selected patients are less likely to respond to antiarrhythmic drug (since selected only non-reponders to procainamide)-More patients in ICD group were receiving beta-blocker-antiarrhythmics may increase mortality via proarrhythmic effect-no treatment free group

  • MADIT II; NEJM Mar 2002Why care?Criticism of MADIT I: prognostic value of negative EPS is uncertain

    Aim:To show potential survival benefit of a prophylactically implanted ICD (in the absence of EPS) in patients with prior MI and LVEFof 0.30 or less

  • MADIT II: Inclusion Criteria -age >21-h/o prior MI (one month or more before trial)-LVF of .30 or less

    Random assignment in 3:2 ratio to get either ICD or conventional medical therapy

  • MADIT II: Exclusion Criteria-FDA approval for ICD-NYHA class IV at enrollment-CABG within 3 months-MI within past month-Cerebrovascular disease

  • MADIT II: Analysis-death from any cause as primary end point-intention-to-treat analysis-95% power to detect 38% reduction in 2 year mortality rate among patients in defibrillator group-triangular sequential design-trial stopped in 2001 after the upper boundary (ICD superiority) was reached (p=0.027)

  • MADIT II: Results-1232 patients enrolled: 742 patients in ICD group; 490 patients in conventional medical therapy group-mean follow up 20 months# deaths ICD group Conventional group 105(14.2%) 97(19.8%)-Superiority of ICD therapy (p 0.016)-Kaplan-Meier survival curves diverge at 9 months -no difference in effects on survival in subgroups based on age, sex, ef, NYHA class or QRS interval (with exception of less benefit with EF>25%)

  • MADIT IIAdverse effects:

    -Higher incidence of new or worsened heart failure in ICD group (p 0.09)

  • MADIT II: Discussion-31% risk reduction in risk of death with prophylactic ICD implantation in patients wit h/o MI and LVEF of 0.30 or less-benefits begin 9 months after device implantation (? Due to absence of stratification for arrhythmia vs better medical management vs lower EF cut-off as compared to MADIT I)-more CHF in ICD group (? Higher inidence pf progression to heart failure as a result of SCD prevention vs result of multiple ICD shocks) -Criticism: cost effectiveness/need for other invasive/noninvasive markers of risk for further stratification

  • MUSTT Trial (NEJM, Dec 1999)Why care?No reduction in mortality with empirical antiarrhythmic therapy in patients with CAD and asymptomatic ventricular arrhythmias

    Aim:To investigate whether antiarrhythmic therapy guided by EPS might reduce risk of SCD

  • MUSTT: MethodsInclusion Criteria:-CAD-LVEF of 40% or less-asymptomatic nonsustained VTExclusion Criteria:-h/o syncope or sustained VT/VF >48 hours after onset of MI-unsustained VT in the setting of ischemia, metabolic disorders, or drug toxicity

  • MUSTT: Methods Patients

    EPS negative registry n 1435 induced VT/VF (n 704)

    Antiarrhythmic ICD No therapyN 154 after at least one n 353 unsuccessful drug n 161

  • MUSTT: Statistics

    -intention to treat analysis-primary end point: cardiac arrest or death from arrhythmia-secondary end point: all cause mortality; cardiac causes; sustained VT

  • MUSTT: ResultsNonantiarrhythmic medical therapy:

    -use of beta-blockers: more frequent in nonantiarrhthmic group

    Antiarrhythmic therapy:

    -medications (class I agents, 26%; amiodarone, 10%; sotalol, 9%) and ICD

    Mean of 39 months of follow up

  • MUSTT: ResultsKaplan-Meier Curve: rate of cardiac arrest or death (primary end point) and overall mortality (secondary end point) 2yrs 5yrs primary secondary primary secondaryNo therapy 18% 28% 32% 48%

    EPG therapy 12% 22% 25% 42% p 0.04 p 0.06

  • MUSTT: Results-Lower rates of arrhythmic events in EPG therapy largely attributed to ICD: 5 yr rate 5 yr rate primary end point overall mortalityEPG therapy with ICD 9% 24%

    EPG therapy without ICD 37% 55% p

  • MUSTT: Discussion-EPG antiarrhythmic therapy leads to absolute reduction in the risk of cardiac arrest or death of 7% at 5 years-Survival benefit is solely due to use of ICD-ICD was shown to improve overall survival-Rate of cardiac arrest or death from arrhythmia in group assigned to no antiarrhythmics is 18% per 2 years (similar to reported studies)

  • MUSTT: Discussion, Contd-Patients who had at least one unsuccessful antiarrhythmic drug test have poorer prognosis if they did not receive ICD-Antiarrhythmic drug therapy did not improve survival-? Whether EPS is more useful in patients with EF of 30 to 40 %

  • Take Home PointsProphylactic ICD is most cost effective in patients with lower LVEFQRS width is importantEPS is important for risk stratification (although negative EPS does not rule out risk of SCD)ICD is superior to antiarrhythmic drugs in preventing SCD in post MI patients with depressed EFNeed for other methods of risk stratification in MADIT II patients (TWA)