Transcript Do Bolus Thrombolytics Carry a Higher Risk of

MADIT II
The EP Show:
MADIT II
Eric Prystowsky MD
Director, Clinical Electrophysiology Laboratory
St Vincent Hospital
The Care Group (private clinic)
Indianapolis, Indiana
Arthur Moss MD
Professor of Medicine
University of Rochester Medical Center
Rochester, New York
EP Show – April 2002
MADIT II
Background
Identified low EF as primary determinant of
mortality post-MI in 1970s
Repetitive ventricular ectopic beats (salvos)
also contribute to risk
•BHAT (JAMA 1982;247:1707-1714)
•ACE inhibitors (NEJM 1992;327:669-77)
•CAST (NEJM 1991;324:781-788)
EP Show – April 2002
MADIT II
1990's
In 1990s we had good treatment for left
ventricular dysfunction but no effective
therapy for preventing sudden cardiac
death
Moss
EP Show – April 2002
MADIT II
ICD benefit in previous studies
Relative reduction
2-year all-cause mortality (%)
40
39%
51%
54%
Control
30
ICD
20
10
0
AVID
EP Show – April 2002
MUSTT
MADIT
MADIT II
MADIT II: Description
Multicenter Automatic Defibrillator
Implantation Trial II
•MI > 4 weeks
•LVEF 30%
1232 patients randomized to ICD or
conventional medical therapy
Arrhythmia was not an inclusion criteria,
did not require previous EP testing
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MADIT II
MADIT II: All-cause mortality
25%
P=0.016
20%
15%
19.8%
14.2%
10%
5%
0%
ICD
EP Show – April 2002
Medical therapy
Moss et al. N Engl J Med
2002;346(12):877-83.
MADIT II
Serial drug testing
EP testing began in Philadelphia in the early
1980s
•Arrhythmias could be induced and then
suppressed by anti-arrhythmic agents
•Despite no long-term follow-up, it
made physiologic sense to think this
provided survival benefit
Moss
EP Show – April 2002
MADIT II
MUSTT
Entry Criteria
• EF < 40%
• CAD
• spontaneous nonsustained
ventricular tachycardia (VT-NS)
Total mortality (5 years)
ICDs
(n=161)
Drug therapy
(n=153)
P value
24%
55%
<0.001
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Buxton et al. N Engl J Med
1999;341(25):1882-90.
MADIT II
EP testing
MUSTT and CAST have shaken the
confidence in EP testing as a good risk
stratifier in coronary disease
•MADIT II sub-study is looking for any
patients who did benefit from EP studies
Moss
EP Show – April 2002
MADIT II
MADIT II: Medications
ICD
(n=742)
Medical
therapy
(n=490)
ACE-inhibitors
68%
72%
Beta-blockers
70%
70%
Statins
67%
64%
Diuretics
72%
81%
Medication at last
contact
EP Show – April 2002
Moss et al. N Engl J Med
2002;346(12):877-83.
MADIT II
ICD benefit in MADIT and MUSTT
2-year all-cause mortality (%)
40
Relative reduction
51%
54%
Control
30
ICD
20
10
0
MUSTT
EP Show – April 2002
MADIT
MADIT II
Patient populations
MUSTT and MADIT both required
documented ventricular arrhythmias and
had to be inducible in the lab
•A higher risk population
•Medical therapy available to control
group was not as good as in MADIT II
Moss
EP Show – April 2002
MADIT II
MADIT II: Medications
ICD
(n=742)
Medical
therapy
(n=490)
ACE-inhibitors
68%
72%
Beta-blockers
70%
70%
Statins
67%
64%
Diuretics
72%
81%
Medication at last
contact
EP Show – April 2002
Moss et al. N Engl J Med
2002;346(12):877-83.
MADIT II
ICD benefit
ICDs benefit is now superimposed on very
aggressive drug management
•The control group has an improved
outcome
•The relative ICD benefit is now only
30% compared to 50% in earlier trials
Moss
EP Show – April 2002
MADIT II
MADIT II vs MADIT and MUSTT
2-year all-cause mortality (%)
40
Relative reduction
31%
51%
54%
Control
30
ICD
20
10
0
MADIT II
EP Show – April 2002
MUSTT
MADIT
MADIT II
Inducible patients
“There probably is a little more, not
dramatic, additive risk stratification if
you are inducible positive in the lab.”
Prystowsky
“I think [EP testing] does add an
increment. Its not as large an increment
as what we thought and one needs a
larger population now to see it.”
Moss
EP Show – April 2002
MADIT II
Two peculiarities
Two peculiarities noted in the MADIT-II
manuscript
•Superimposable survival curves for the
first 6-7 months
•Increased heart failure in the ICD
group
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MADIT II
MADIT II: Diverging curves
Probability of survival
Time
ICD patients
Control
1 year
0.91
0.90
2 years
0.84
0.78
3 years
0.78
0.69
EP Show – April 2002
Moss et al. N Engl J Med
2002;346(12):877-83.
MADIT II
Delay in survival benefit
A physiological explanation
•Curves are almost identical to original
ACE inhibitor trials
•Patients were probably enrolled with
previous symptoms
•The patients are high enough risk that
the ICD doesn't show a difference in the
first 6 months
Moss
EP Show – April 2002
MADIT II
Delay in survival benefit
A statistical explanation
•Statisticians find the effect is just part
of the "wobble" of a clinical trial
•Pattern of difference between the
curves is consistent over time
Moss
EP Show – April 2002
MADIT II
Explaining the delay
Two ongoing explanations
•Physiological effect – the sickest
patients die equally in both arms in the
first 6 months
•Statistical effect – the overlap is just
an artifact that resolves itself over time
Moss
EP Show – April 2002
MADIT II
Explaining the delay
Third possible explanation
•Drug treatment effect – it took some
time for medical therapy to reach the
appropriate level, and the delay is
reflected in the overlap of the curves
Moss
EP Show – April 2002
MADIT II
MADIT II: Increased hospitalizations
Patient
group
# patients
hospitalized
# patients
hospitalized/1000
hours follow-up
Conventional
therapy group
73 (14.9%)
9.4
148 (19.9%)
11.3
Defibrillator
group
Nominal p=0.09
EP Show – April 2002
Moss et al. N Engl J Med 2002;346(12):877-83.
MADIT II
Explaining the rise in CHF
We encourage physicians who put in ICDs
to be vigilant for the development of subtle
heart failure
•Patients who live longer have more
chances to develop heart failure
•Backup ventricular pacing may
contribute to LV dysfunction
•Each shock releases myocardial
enzyme, this may signal damage
Moss
EP Show – April 2002
MADIT II
A disease of medical progress
AVID trial also had an increased number of
hospitalizations for heart failure in the ICD
patients
“I would look upon this is a disease of
medical progress. That is, as you reduce
mortality due to one cause, you're
naturally going to have morbidity and
mortality from other causes that will
creep up. But over time, it takes longer
for that to become manifest."
Doctor
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MADIT II
Effect of pacing rate
Do people who developed heart failure have
a greater percentage of time pacing?
•Could be an important clinical
observation
•Data on this should be available in the
near future
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MADIT II
Cardiac death in the USA
Endpoint
# Deaths
Death rate
(per 100 000)
1998
724 859
268.2
1999
725 192
265.9
2000*
709 894
257.9
*preliminary data
EP Show – April 2002
National Vital Statistics Reports. CDC 2002
MADIT II
The future
Sudden death remains a major
epidemiological problem
•We are moving toward AEDs
everywhere
•Should we consider ICDs before people
present with serious problems?
Prystowsky
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MADIT II
Should everyone get ICDs?
"One can raise a similar type of
question, 'Should everyone have a
coronary angiogram or should everyone
have an exercise tolerance test?' And I
think one has to put this in good clinical
judgment and the answer is 'no' "
Moss
EP Show – April 2002
MADIT II
Risk stratification
We are required as good clinicians to do
risk stratification
•Do they have symptoms?
•Exercise tolerance tests after 50
We need appropriate, relevant, clinical risk
stratification
Moss
EP Show – April 2002
MADIT II
Risk stratification
Should everyone with an MI have an ICD?
•Not at that level of evidence yet
•Previous MI and LVEF 30% probably
should get one
Moss
EP Show – April 2002
MADIT II
MADIT III
Multicenter Automatic Defibrillator
Implantation Trial III
•Adults with type 2 diabetes
•LVEF 30%-40%
Planned trial for the future to look at this
risk population
EP Show – April 2002
MADIT II
Other risk populations
Populations outside of coronary disease
may benefit from ICDs
•Hypertrophic cardiomyopathy
•Brugada syndrome
•Long-QT syndrome
•Arrhythmagenic right ventricular
dysplasia
EP Show – April 2002
Moss
MADIT II
Progress
We will continue to identify populations
where the ICD is useful
•An expanding population, but not likely
to become a cure-all
"I wouldn't put [an ICD] in yet but I
think you ought to have an exercise
tolerance test, just like I think President
Bush ought to have an exercise
tolerance test."
Moss
EP Show – April 2002
MADIT II
Money
We in the US have not had quotas on lifesaving therapies
•MADIT II opens up a large population
for ICD implantation
•Talk of how it is too expensive and
might bankrupt the health care system
Prystowsky
EP Show – April 2002
MADIT II
Repeat of the CABG debate
This is the same argument that appeared in
1982 about CABG
•Editorials said CABG would bankrupt
the system
•CABG continued and is now a multibillion dollar part of health care
Moss
EP Show – April 2002
MADIT II
Future of ICDs
Future ICD market in the range of 300 000
per year
•3 million by prevalence alone
•2-300 000 new cases meet MADIT II
criteria every year
As volume increases, market forces will
bring the cost down to pacemaker range
($3000)
Moss
EP Show – April 2002
MADIT II
Future costs
As the volume increases, market forces
should lower the cost
•ICD cost in 5 years should be $3000
"I'm not an economist, I'm a clinician
and an investigator and I think the first
thing we have to do is show the clear
cut benefit and then the market forces
will come into play."
Moss
EP Show – April 2002
MADIT II
The EP Show:
MADIT II
Eric Prystowsky MD
Director, Clinical Electrophysiology Laboratory
St Vincent Hospital
The Care Group (private clinic)
Indianapolis, Indiana
Arthur Moss MD
Professor of Medicine
University of Rochester Medical Center
Rochester, New York
EP Show – April 2002