1. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Clinical trial commentary: REMATCH, MADIT-II, and pricey technology Eric J Topol MD Provost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, Ohio Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, North Carolina

2. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology New technology Bx-Velocity Stent Source: Cordis HeartMate LVAD Source: Thoratec VENTAK PRIZM 2 ICD Source: Guidant

3. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Outline REMATCH LVADs as destination therapy MADIT-II ICDs for MI survivors with low EF Crisis of technology costs How will we pay for all this effective technology?

4. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology REMATCH Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure 129 Class IV heart failure patients randomized to either HeartMate LVAD or medical therapy Non-transplant candidates

5. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Time pointLVAD (n=68) medical therapy (n=61) p value 1 year52%25%0.002 2 years23%8%0.09 Kaplan-Meier estimates of survival at 1 and 2 years REMATCH: survival Rose EA, et al. NEJM 2001; 345:1435-43

6. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology REMATCH: quality of life 1-year quality of life assessment LVAD group Medical therapy groupp value Median NYHA functional class IIIV<0.001 SF-36 (physical function) 46  1921  21 0.01 Minnesota Living with Heart Failure 41  2258  21 0.11 Rose EA, et al. NEJM 2001; 345:1435-43

7. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology REMATCH: adverse events Event LVAD (n=67) Medical therapy (n=60) Rate ratio (95% CI) rate/patient-year Sepsis0.600.302.03 (0.99-4.13) Nonneurologic bleeding 0.560.069.47 (2.30-38.90) Suspected LVAD malfunction 0.75N/A Rose EA, et al. NEJM 2001; 345:1435-43

8. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Cost-effectiveness HeartMate® VE LVAD Some estimates put it at >$160,000 per year of life saved. If 100,000 patients eligible, that's $16 billion per year Source: Thoratec

9. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Cost-effectiveness HeartMate® VE LVAD Formal cost-effectiveness has not yet been done Cost-effectiveness may drive the interpretation of the devices usefulness At $160,000 per year of life, it may not be covered, but would be at $60,000 per year of life Source: Thoratec

10. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Interpretation "What does it mean when you save a lot of lives, but in a short period of time, everyone is dead?" Califf REMATCH median improved survival is 250 days Median improved survival of many pharmacological therapies is <3 months but in a larger patient population

11. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Is it worth it? In pharmacologic therapies, most patients live 10- 12 years of life after the intervention After REMATCH most were dead in 2 years This is an early stage in the technology still, it will get better "Maybe REMATCH is truly a segue into something that's going to be more important for a more broadly applicable patient population in the years ahead.” Topol

12. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology What do you do now? "The genie's out of the bottle here, unfortunately. And this as well as the other device trials we're talking about today are really putting an inordinate stress on the system, on our ability to survive from a financial point of view." Topol

13. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology End therapy Jarvik 2000 Source: Texas Heart Institute LionHeart LVAD Source: Arrow International

14. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Who gets the device? Will it be possible to deny this technology to an eligible patient? The estimate of 100,000 patients may be low, especially if you go beyond the end-stage patient "Now we have a technology that can do it, should we do it?" Topol

15. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Califf: 2 thumbs up for REMATCH "It raises a series of really interesting future questions." Califf

16. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Topol: 2 thumbs up for REMATCH "I think this is an enormously difficult trial for the medical community to absorb from a financial standpoint, from an ethical standpoint." Topol

17. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology MADIT-II Multicenter Automatic Defibrillator Implantation Trial II 1232 post-MI patients with moderate LV dysfunction (EF 30%) randomized to ICD or medical therapy Arrhythmia was not an inclusion criteria

18. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Mortality in MADIT-II 30% total reduction of mortality 0 5 10 15 20 25 ICD Medical therapy Percent mortality

19. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Potential patient population MADIT-II entry criteria would lead to an additional 300,000 patients for ICDs, a $9 billion market ICDs cost $25-35,000 The only thing holding back the numbers of implants are the numbers of electrophysiologists Topol VENTAK PRIZM 2 ICD Source: Guidant

20. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Obligatory ICDs From databases, we could identify people who are post-MI with EF <30 – should we automatically bring them in to get ICDs? At 6 lives saved for every 100 treated, are we ethically obligated to implant no matter what?

21. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Cheap ICDs for everyone? "For some patients, a sophisticated ICD that could be used to treat comorbidities and monitor a variety of physiological functions may be indicated, whereas in others, an inexpensive ICD in the $10,000 to $15,000 range might be preferable." Zipes Dr Douglas Zipes Source: Indiana University School of Medicine Zipes DP, Circulation 2001;103:1372-4

22. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology SCD-HeFT 2500 patients with either ischemic heart failure or dilated cardiomyopathy in proportions of roughly 50-50, EF 35% Randomized to 3 arms: ICD, amiodarone, or placebo

23. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Estimated costs of new technology 0 2 4 6 8 10 12 14 16 18 LVAD (REMATCH) ICD (MADIT-II) Coated stents (RAVEL) US dollars (in billions)

24. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Money "For us, [the medical community], to be able to live in this new world… we can't do it without more subsidy, and I don't know how that's going to happen." Topol Bx-Velocity Stent Source: Cordis

25. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology A culture shift We have a culture that is aggressively unaccepting of death That culture demands a lot of financial support `"Otherwise we need a culture shift and an acceptance of lesser survival, lesser quality of life. That's not something that seems to be very acceptable." Topol

26. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Life-saving stents State-of-the-art stent implantaion Pre-procedural dual anti-platelet Intra-procedural IV GP IIb/IIIa inhibition Coated stents to reduce repeat procedures This is a strategy that improves survival, not just reduces restenosis Topol

27. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology A new crisis The last medical cost crisis was about medical waste, this one will be about proven benefit that is very expensive "I think it is going to be the cardiovascular devices that will force the issue because of the epidemic proportions of the disease in the midst of an ageing population." Califf

28. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Rationing Vice President Dick Cheney Source: GWU hospital If Cheney can get his ICD, why can't everyone?

29. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Califf: final thoughts "With these expensive technologies, how are we going to fairly allocate resources? And obviously this is going to come to the forefront in the hospitals we all work in well before healthcare policy will have caught up to where it needs to be." Califf

30. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Topol: final thoughts "I don't think that [delivering high-tech strategies to patients at large] is likely to be accomplished without some redesign of how medicine is supported by our government." Topol

31. Thumbs up/Thumbs down – January 2002 REMATCH, MADIT-II, and pricey technology Bx-Velocity Stent Source: Cordis HeartMate LVAD Source: Thoratec VENTAK PRIZM 2 ICD Source: Guidant