1. EP show – June 2004 EP show The EP show: Risk stratification for sudden death Eric Prystowsky MD Director, Clinical Electrophysiology Laboratory St Vincent Hospital Indianapolis, IN Arthur Moss MD Professor of Medicine and Cardiology University of Rochester Rochester, NY Michael Gold MD Chief, Division of Cardiology Medical University South Carolina Charleston, SC

2. EP show – June 2004 EP show Risk stratification for sudden death

3. EP show – June 2004 EP show Historical look at early markers Began during the mid-1980s with a prospective study of about 1000 postinfarction patients Measured 24-hour Holter recordings for ventricular premature beat frequency Determined ejection fraction Ascertained several other routine clinical parameters Moss

4. EP show – June 2004 EP show Historical look at early markers Found inverse relationship between the ejection fraction and total mortality as well as sudden death Cut point between 30% and 40% Recent studies, including MADIT I and II, grew out of this early work Moss

5. EP show – June 2004 EP show Serial electrophysiology testing Mechanistically driven Sudden death in postinfarction patients predominately due to ventricular tachycardia If you could induce ventricular tachycardia and introduce a drug that suppresses this ability, you could monitor efficacy Gold

6. EP show – June 2004 EP show Reviewing CAST Cardiac Arrhythmia Suppression Trial (CAST) Large randomized trial that looked at whether suppressing ventricular ectopy after MI reduces sudden death Trial stopped because antiarrhythmic agents associated with increased mortality

7. EP show – June 2004 EP show Reviewing CAST "This set the stage for moving from antiarrhythmic agents to device therapy." Moss

8. EP show – June 2004 EP show Reviewing CAST Could these results be related to the drugs selected? Subsequent trials confirmed that this was not the case Prystowsky

9. EP show – June 2004 EP show MADIT I Would an ICD or conventional therapy improve survival in this high-risk population? Randomly assigned 196 patients with prior MI and: NYHA functional class 1, 2, or 3 A left ventricular ejection fraction <35% An episode of asymptomatic unsustained ventricular tachycardia Inducible, nonsuppressible ventricular tachyarrhythmia on electrophysiologic study

10. EP show – June 2004 EP show MADIT I findings Group Total deaths Cardiac deaths Defibrillator1511 Conventional therapy3927 * Average 27-month follow-up

11. EP show – June 2004 EP show MADIT I In high-risk patients with prior MI, prophylactic therapy with an ICD leads to improved survival compared with conventional medical therapy

12. EP show – June 2004 EP show MUSTT Multicenter Unsustained Tachycardia Trial (MUSTT), a randomized controlled trial Can electrophysiologically guided antiarrhythmic therapy reduce the risk of sudden death? Looked at coronary artery disease patients with a left ventricular ejection fraction <40% and asymptomatic unsustained ventricular tachycardia

13. EP show – June 2004 EP show MUSTT End pointCardiac arrest or arrhythmia death EP-guided therapy (%) 25 No antiarrhythmic therapy (%) 32 Relative risk0.73 95% CI0.53-0.99

14. EP show – June 2004 EP show MUSTT Therapy with implantable defibrillators, but not with antiarrhythmic drugs, reduces the risk of sudden death in high-risk patients with coronary disease

15. EP show – June 2004 EP show Unsustained VT "I think it's a relatively weak risk stratifier. And as you point out, it was both frustrating and cumbersome." Gold

16. EP show – June 2004 EP show MADIT II Randomized trial evaluating the effect of an implantable defibrillator on survival 1232 patients with prior MI and a left ventricular ejection fraction of <30% Patients randomly assigned in a 3:2 ratio to receive ICD or conventional medical therapy

17. EP show – June 2004 EP show MADIT mortality rates

18. EP show – June 2004 EP show MADIT II "This really introduced a simplified stratification approach." Moss

19. EP show – June 2004 EP show MADIT II and CMS "They took a conservative position and said that they were going to reimburse only for MADIT II patients who had a QRS duration >120 milliseconds and that they would revisit this when SCD-HeFT data were presented." Moss

20. EP show – June 2004 EP show SCD-HeFT Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Largest of the trials involving ICD therapy with a longer patient follow-up than previous studies

21. EP show – June 2004 EP show SCD-HeFT Compared all-cause mortality in >2500 patients With NYHA class 2 to 3 HF LVEF <35% Patients randomized to receive ICD, amiodarone, or placebo on top of standard medical therapy

22. EP show – June 2004 EP show SCD-HeFT all-cause mortality

23. EP show – June 2004 EP show SCD-HeFT ICD cuts all-cause mortality by 23% in NYHA class 2 to 3 heart failure

24. EP show – June 2004 EP show What's a payer to do? "The trials were designed specifically to answer the major question of defibrillators and their role to reduce total mortality. I think the trials, as you point out, are concordant in that regard, and I think that it would be reasonable that that would be an indication for paying." Gold

25. EP show – June 2004 EP show What's a payer to do? "Getting into subsets when it's not really prespecified that's what you're looking for is potentially very treacherous and can be misleading." Moss

26. EP show – June 2004 EP show The future Many have become cynical as noninvasive test after noninvasive test failed to live up to its expectations But I remain optimistic Gold

27. EP show – June 2004 EP show Question Are there patients in MADIT II who are: "Too healthy" to benefit from an ICD? "Too sick" for one? Prystowsky

28. EP show – June 2004 EP show Latest look at MADIT II The benefit from ICD was entirely in the patients who carried one or more risk factors The 20% of the population that carried no risk factors achieved no benefit whatsoever Moss

29. EP show – June 2004 EP show Summary Several decades of research have put risk stratifiers to the test Ejection fraction remains supreme as a noninvasive test We've identified the benefactors of ICD therapy And realized that antiarrhythmic drugs to prevent sudden death are not as important as once thought

30. EP show – June 2004 EP show In conclusion Despite so many noninvasive tests failing to live up to expectations, many still show promise Hot off the press! New soon-to-be- published data will show that combinations of risk stratifiers may help pinpoint patients who will derive the most and least benefit from an ICD Prystowsky