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

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Sudden Cardiac Death Prevention Clinical Trials

• Alena Goldman, MD
• September 9, 2004

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Introduction

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

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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

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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

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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

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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

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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

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Ischemic Cardiomyopathy Primary Prevention Trials

• MADIT I
• MUSTT
• MADIT II
• CABG Patch
• CAT

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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

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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

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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

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MADIT I

• Eligible Patients
• EPS
• Induced VT
• yes no
• Suppression with
• Procainamide
  conventional
• 
  therapy (n101)
• yes no (n196)
• 
  ICD (n95)

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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

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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

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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)

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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

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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

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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

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MADIT II Exclusion Criteria

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

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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)

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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)

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MADIT II

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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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)