Transcript Sudden Cardiac Death Prevention: Clinical Trials

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
- ICD (implantable cardioverter defibrillator)
has become primary therapeutic modality
for secondary prevention of SCD, and in
some patients groups, for primary
prevention
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
Risk Stratification Strategies
Subgroup analysis of AVID trial:
1. LVEF>35%: no difference in survival
between ICD and antiarrhythmic drugs
2. Etiology of Heart Disease (most
evidence for coronary heart disease and
dilated cardiomyopathy)
3. Effects of shock: recurrence of shocks is
independent predictor of poor outcome
Risk Stratification Strategies, cont’d
• Effects 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:
1. Patients with CHD; prior MI; LV dysfunction;
h/o NSVT; with inducible sustained VT/VF at
EPS (without suppression by class I
antiarrhythmic)
2. Patients with syncope with inducible sustained
VT/VF at EPS when antiarrhythmic therapy not
effective, not tolerated, not preferred
Ischemic Cardiomyopathy Primary
Prevention Trials
•
•
•
•
•
MADIT I
MUSTT
MADIT II
CABG Patch
CAT
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, Cont’d
Methods/Inclusion Criteria:
-25-80 yo
-h/o MI 3 weeks prior to study
-NYHA class I,II,or III
-LVEF <0.35
-documented asymptomatic unsustained VT
(3-30 beats)
-no indications for CABG
MADIT I; Cont’d
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
MADIT I
Eligible Patients
EPS
Induced VT
yes
no
Suppression with
Procainamide
yes
conventional
therapy (n=101)
no (n=196)
ICD (n=95)
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
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
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 (LVEF<26%; CHF
requiring therapy; QRS duration >12 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 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
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 II
Adverse 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: Methods
Inclusion Criteria:
-CAD
-LVEF of 40% or less
-asymptomatic nonsustained VT
Exclusion 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
N 154
ICD
after at least one
unsuccessful drug
n 161
No therapy
n 353
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: 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
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
18%
28%
32%
48%
EPG therapy 12%
22%
25%
42%
p 0.04
p 0.06
No therapy
MUSTT: Results
-Lower rates of arrhythmic events in EPG therapy
largely attributed to ICD:
EPG therapy with ICD
EPG therapy without ICD
5 yr rate
primary end point
9%
37%
p<0.001
5 yr rate
overall mortality
24%
55%
p<0.001
-No Difference in outcome between people
receiving no therapy and treated with
antiarrhythmc drugs
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, Cont’d
-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 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)