ep show – april 2002 madit ii the ep show: madit ii eric prystowsky md director, clinical...
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EP Show – April 2002
MADIT II
The EP Show:MADIT II
Eric Prystowsky MDDirector, Clinical Electrophysiology Laboratory
St Vincent Hospital The Care Group (private clinic)Indianapolis, Indiana
Arthur Moss MDProfessor of MedicineUniversity of Rochester Medical CenterRochester, 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
Control
ICD
ICD benefit in previous studies
0
10
20
30
40
AVID
2-y
ear
all-c
au
se m
ort
ality
(%
)
39%
MUSTT MADIT
54%51%
Relative reduction
EP Show – April 2002
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
EP Show – April 2002
MADIT II
Moss et al. N Engl J Med 2002;346(12):877-83.
MADIT II: All-cause mortality
0%
5%
10%
15%
20%
25%
ICD Medical therapy
14.2%
19.8%P=0.016
EP Show – April 2002
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
• EF < 40% • CAD • spontaneous nonsustained ventricular tachycardia (VT-NS)
MUSTT
ICDs (n=161)
Drug therapy (n=153)
P value
24% 55% <0.001
Buxton et al. N Engl J Med 1999;341(25):1882-90.
Entry Criteria
Total mortality (5 years)
EP Show – April 2002
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
64%67%Statins
Medication at last contact
70%70%Beta-blockers
72%68%ACE-inhibitors
Medical therapy (n=490)
ICD (n=742)
81%72%Diuretics
Moss et al. N Engl J Med 2002;346(12):877-83.
EP Show – April 2002
MADIT II
Control
ICD
ICD benefit in MADIT and MUSTT
0
10
20
30
40
2-y
ear
all-c
au
se m
ort
ality
(%
)
MUSTT MADIT
54%51%
Relative reduction
EP Show – April 2002
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
64%67%Statins
Medication at last contact
70%70%Beta-blockers
72%68%ACE-inhibitors
Medical therapy (n=490)
ICD (n=742)
81%72%Diuretics
Moss et al. N Engl J Med 2002;346(12):877-83.
EP Show – April 2002
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
Control
ICD
MADIT II vs MADIT and MUSTT
0
10
20
30
40
MADIT II
2-y
ear
all-c
au
se m
ort
ality
(%
)
31%
MUSTT MADIT
54%51%
Relative reduction
EP Show – April 2002
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
EP Show – April 2002
MADIT II
MADIT II: Diverging curves
Probability of survival
0.690.783 years
Time
0.780.842 years
0.900.911 year
ControlICD patients
Moss et al. N Engl J Med 2002;346(12):877-83.
EP Show – April 2002
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
11.3148 (19.9%)Defibrillator group
9.473 (14.9%)Conventional therapy group
# patients hospitalized/1000
hours follow-up# patients
hospitalized
Moss et al. N Engl J Med 2002;346(12):877-83.
Nominal p=0.09
EP Show – April 2002
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
EP Show – April 2002
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
EP Show – April 2002
MADIT II
Cardiac death in the USA
Endpoint # DeathsDeath rate
(per 100 000)
1998 724 859 268.2
1999 725 192 265.9
2000* 709 894 257.9
*preliminary data
National Vital Statistics Reports. CDC 2002
EP Show – April 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
EP Show – April 2002
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
Moss
EP Show – April 2002
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 life-saving 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 multi-billion 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 MDDirector, Clinical Electrophysiology Laboratory
St Vincent Hospital The Care Group (private clinic)Indianapolis, Indiana
Arthur Moss MDProfessor of MedicineUniversity of Rochester Medical CenterRochester, New York