ep show – april 2002 madit ii the ep show: madit ii eric prystowsky md director, clinical...

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