1. 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

2. 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)

3. 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

4. EP Show – April 2002 MADIT II Control ICD ICD benefit in previous studies 0 10 20 30 40 AVID 2-year all-cause mortality (%) 39% MUSTT MADIT 54% 51% Relative reduction

5. 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

6. EP Show – April 2002 MADIT II Moss et al. N Engl J Med 2002;346(12):877-83. MADIT II: All-cause mortality 14.2% 19.8% P=0.016

7. 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

8. 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)

9. 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

10. EP Show – April 2002 MADIT II MADIT II: Medications 64%67% Statins Medication at last contact 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.

11. EP Show – April 2002 MADIT II Control ICD ICD benefit in MADIT and MUSTT 0 10 20 30 40 2-year all-cause mortality (%) MUSTT MADIT 54% 51% Relative reduction

12. 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

13. EP Show – April 2002 MADIT II MADIT II: Medications 64%67% Statins Medication at last contact 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.

14. 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

15. EP Show – April 2002 MADIT II Control ICD MADIT II vs MADIT and MUSTT 0 10 20 30 40 MADIT II 2-year all-cause mortality (%) 31% MUSTT MADIT 54% 51% Relative reduction

16. 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

17. 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

18. EP Show – April 2002 MADIT II MADIT II: Diverging curves Probability of survival 0.69 0.78 3 years Time 0.78 0.84 2 years 0.90 0.91 1 year ControlICD patients Moss et al. N Engl J Med 2002;346(12):877-83.

19. 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

20. 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

21. 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

22. 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

23. EP Show – April 2002 MADIT II MADIT II: Increased hospitalizations Patient group 11.3 148 (19.9%)Defibrillator group 9.4 73 (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

24. 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

25. 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

26. 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

27. EP Show – April 2002 MADIT II Cardiac death in the USA Endpoint# Deaths Death rate (per 100 000) 1998724 859268.2 1999725 192265.9 2000*709 894257.9 *preliminary data National Vital Statistics Reports. CDC 2002

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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