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Title: (Cardiac Arrest Survival in Hamburg): 23% reduction in


1
Sudden Cardiac Death Prevention Clinical Trials
  • Alena Goldman, MD
  • September 9, 2004

2
Introduction
  • SCD common problem in patient with
  • -CAD
  • -LV dysfunction
  • -asymptomatic ventricular arrhythmias

3
Introduction
  • Most 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

4
Secondary Prevention
  • CASH trial (Cardiac Arrest Survival in Hamburg)
    23 reduction in mortality in survivors of
    cardiac arrest receiving ICD vs
    amiodarone/metoprolol
  • CIDS trial (Canadian Implantable Defibrillator
    Study) ICD vs amiodarone no mortality
    difference
  • AVID trial (Antiarrhythmic Drug vs
    Defibrillator) 1016 pts trial stopped when
    survival benefit noted in patients treated with
    ICD vs amiodarone and d,l sotalol

5
Risk Stratification Strategies
  • Subgroup analysis of AVID trial
  • LVEFgt35 no difference in survival between ICD
    and antiarrhythmic drugs
  • Etiology of Heart Disease (most evidence for
    coronary heart disease and dilated
    cardiomyopathy)
  • Effects of shock recurrence of shocks is
    independent predictor of poor outcome

6
Risk Stratification Strategies, contd
  • Effects of Electrical Storm gt3 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

7
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

8
Ischemic Cardiomyopathy Primary Prevention Trials
  • MADIT I
  • MUSTT
  • MADIT II
  • CABG Patch
  • CAT

9
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

10
MADIT I, Contd
  • Methods/Inclusion Criteria
  • -25-80 yo
  • -h/o MI 3 weeks prior to study
  • -NYHA class I,II,or III
  • -LVEF lt0.35
  • -documented asymptomatic unsustained VT (3-30
    beats)
  • -no indications for CABG

11
MADIT I Contd
  • Exclusion 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

12
MADIT I
  • Eligible Patients
  • EPS
  • Induced VT
  • yes no
  • Suppression with
  • Procainamide
    conventional

  • therapy (n101)
  • yes no (n196)

  • ICD (n95)

13
MADIT I
  • Statistical 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

14
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
    ICD
  • Cardiac death 27
    11
  • Noncardiac 6
    4
  • Unknown 6
    0
  • Total 39
    15

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 (LVEFlt26 CHF requiring
    therapy QRS duration gt12 sec)

16
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

17
MADIT II NEJM Mar 2002
  • Why 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

18
MADIT II Inclusion Criteria
  • -age gt21
  • -h/o prior MI (one month or more before trial)
  • -LVF of .30 or less
  • Random assignment in 32 ratio to get either ICD
    or conventional medical therapy

19
MADIT II Exclusion Criteria
  • -FDA approval for ICD
  • -NYHA class IV at enrollment
  • -CABG within 3 months
  • -MI within past month
  • -Cerebrovascular disease

20
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 (p0.027)

21
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
    EFgt25)

22
MADIT II
  • Adverse effects
  • -Higher incidence of new or worsened heart
    failure in ICD group (p 0.09)

23
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

24
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

25
MUSTT Methods
  • Inclusion Criteria
  • -CAD
  • -LVEF of 40 or less
  • -asymptomatic nonsustained VT
  • Exclusion Criteria
  • -h/o syncope or sustained VT/VF gt48 hours after
    onset of MI
  • -unsustained VT in the setting of ischemia,
    metabolic disorders, or drug toxicity

26
MUSTT Methods
  • Patients
  • EPS negative
    registry n 1435
  • induced VT/VF (n 704)
  • Antiarrhythmic ICD No therapy
  • N 154 after at least one
    n 353

  • unsuccessful drug
  • n 161

27
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

28
MUSTT Results
  • Nonantiarrhythmic 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

29
MUSTT Results
  • Kaplan-Meier Curve rate of cardiac arrest or
    death (primary end point) and overall mortality
    (secondary end point)
  • 2yrs
    5yrs
  • primary secondary
    primary secondary
  • No therapy 18 28 32 48
  • EPG therapy 12 22 25 42
  • p
    0.04 p 0.06

30
MUSTT Results
  • -Lower rates of arrhythmic events in EPG therapy
    largely attributed to ICD
  • 5 yr rate
    5 yr rate

  • primary end point overall mortality
  • EPG therapy with ICD 9
    24
  • EPG therapy without ICD 37
    55

  • plt0.001 plt0.001
  • -No Difference in outcome between people
    receiving no therapy and treated with
    antiarrhythmc drugs

31
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)

32
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

33
Take Home Points
  • Prophylactic ICD is most cost effective in
    patients with lower LVEF
  • QRS width is important
  • EPS 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
    EF
  • Need for other methods of risk stratification in
    MADIT II patients (TWA)
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