Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY

1. ACC 2003: Biomarkers and devices Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, MA Robert Harrington MD Professor, Cardiology Duke University Medical Center Durham, NC Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, NY

2. Topics Biomarkers Calcium score Lp-PLA2 Dual-chamber pacemakersCOMPANION trial Drug-eluting stentsTAXUS II and SIRIUS

3. EBCT: St Francis Heart Study • Assessment of prognostic accuracy of EBCT • Prospective, longitudinal, population-based study, scanning 5585 asymptomatic men and women aged 50 to 70 years of age and with no prior history of CV disease • Risk factors for CV disease were measured in 1817 patients. • High calcium scores: >80th percentile for age and gender and were compared with controls (<80th) • Follow-up 4.3 years

4. EBCT:Calcium score threshold RR of CV event for calcium score >100 vs <100 = 9.5 Guerci AD.ACC 2003

5. EBCT: What do you do with it? • 26% sensitivity is not very high • What to do with patients with high calcium score? • Asymptomatic patients • High calcium score only leads back to treating known risk factors Weber

6. EBCT: What for? • What are we using the test for? • Not very effective for screening a population • Standard risk factors are still cheaper and easier to evaluate Harrington

7. EBCT: Reacting to a high score Do you take a high-calcium-score patient to get an angiogram? Do you revascularize patients based on anatomy? What do we want to use this test for? Start with classical risk factors and maybe look at other, cheaper biomarkers Harrington

8. EBCT: Beyond the evidence Patient with a score of >600 means there may be a problem, but you go back to traditional approaches A potential use of EBCT is to convince someone with risk factors that there really is a problem "To go beyond doing risk-factor modification goes way beyond the data." Cannon

9. EBCT: A warning sign • A high calcium score is like having diabetes • Once identified, you aggressively approach all the risk factors • "It puts people on alert that perhaps you have to be much more aggressive in the approach to the patient." Fuster

10. EBCT: Reacting to a low score A calcium score of zero implies no anatomical disease at that moment "It shouldn't give you carte blanche to go out and ignore the other conventional risk factors." A good sign, but it doesn't negate the fact you should monitor traditional risk factors Harrington

11. Lp-PLA2: WOSCOPS • Lipoprotein-associated phospholipase A2: enzyme that hydrolyzes phospholipids • WOSCOPS found Lp-PLA2 to be an important predictor of nonfatal MI, death from cardiac causes, or revascularization as a first event Fuster

12. Lp-PLA2: ARIC CHD risk ratio by Lp-PLA2 tertiles in ARIC (lowest tertile is reference) ACC 2003

13. Lp-PLA2: Biomarkers Marker approach to risk-stratification is "taking off" Risk markers in ACS are expanding, here we have some in a stable population Inexpensive tests that refine and expand identification of high-risk patients "This is a very promising area in general." Cannon

14. Lp-PLA2: What do you do? Promising—but unclear what to do with a result "What do we do if we know someone has an elevated Lp-PLA2? What are we going to treat? What are we going to do to make these patients better?" We are increasing our awareness of risk, and maybe motivating the patient, but we aren't sure how to treat this Weber

15. Lp-PLA2: Exciting times Biomarker approach is expanding our diagnostic and prognostic capabilities "We are at the cusp of a very exciting time to be able to offer more and more for this population of patients, but clearly a lot of work needs to be done." Harrington

16. Lp-PLA2: Active elements • Perhaps in the future this will be computerized, where the assembly of factors are analyzed at once • We will need to determine which are active and which are just markers Fuster

17. Lp-PLA2: Applications Biomarkers started to gain traction with troponin but became popular only when linked to a treatment strategy "When you can link up doing something differently based on a new marker, this is when people find it very useful and it will get into guidelines." Cannon

18. COMPANION: Trial design Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure • 1600 patients with QRS >120 ms, P-R interval >150 ms, class 3 or 4 heart failure, and hospitalization for HF in past 12 months • Randomized to optimal medical therapy, cardiac resynchronization, or resynchronization with an ICD • Primary end point: all-cause mortality and all-cause hospitalization

19. COMPANION: Results ACC 2003

20. COMPANION: Very preliminary data The total number of events were relatively small There wasn't a real difference between CRT and CRT+ICD, so do you need both? This was a highly selected population and those selection criteria might be used to decide who gets these devices Weber

21. COMPANION: When to present data? With modern technology, we can present data to practicing clinicians in many ways "When you have preliminary data, which are not fully complete, when you have data that are complicated . . . it takes a bit more to digest it and to determine if these are the kind of data that ought to impact practice." Harrington

22. COMPANION: Too soon • We don't have enough information yet • Not all rehospitalizations were counted as part of the end point • We need to see the final trial results • These are complicated data and there are huge financial-resources issues here Harrington

23. COMPANION: A new avenue Devices in HF have advanced while neurohormonal inhibition seems to be leveling off "Cardiac synchronization is for real." Novel data suggesting ICD in nonischemic cardiomyopathy Cannon

24. COMPANION: CRT ineffective? The ICD data were consistent with the known ICD story The CRT mortality reduction was not statistically significant The combined end point in CRT was driven by the rehospitalizations, but which rehospitalizations were includedwas unclear Harrington

25. COMPANION: Trend on mortality Trend on mortality for CRT "That says that the benefits that have been seen in each of the studies in terms of improving symptoms and reducing hospitalizations may have an even broader impact." Cannon

26. COMPANION: Two questions • If life is prolonged, how many months or years? • In a high-risk patient, how much real gain do you get? • Improvement of symptoms • Stress testing • Oxygen consumption Fuster

27. COMPANION: Additional lifespan • We don't have the data in yet • SOLVD and CONSENSUS showed ACE inhibitors added 3 to 6 months • I expect an increase of less than 3 to 6 months lifespan for these devices Weber

28. COMPANION: Cost effectiveness Given the costs, it is even more important to get the cost-effectiveness analysis done "What is the actual cost per life-year saved?" Industry and investigators should work to include these analyses as part of evaluation of these therapies Harrington

29. COMPANION: Optimism "One important thing here is that we are seeing mortality benefits that are pretty dramatic." This is the highest risk of the heart-failure group "This can be a great therapy to offer to the patients where you've done everything and yet they're still not living a livable life really." Cannon

30. COMPANION: Significant advance We need the cost-effectiveness data Hopefully wide use of these devices will bring the cost down "It’s the constant drum beat—each of these two different devices, and it looks like both together, have been a significant advance." Cannon

31. COMPANION: Mechanical interventions • Mechanical interventions have had a significant impact on CV health • CABG • PCI • Transplantations • Pacemakers • Defibrillators Fuster

32. TAXUS II: 12-month results ACC 2003

33. TAXUS II: Encouraging Not that much new between 6 and 12 months Clinical end point for TVR has gradually moved to 9 months since 6 months doesn't allow long enough follow-up How does it stack up to sirolimus? Trial-to-trial comparisons are hard Cannon

34. TAXUS II: Winning technology • The technology works on both: • The biology (TVR) • The clinical aspect (MACE) • Patients have been mainly low- or moderate-risk patients • We need randomized head-to-head comparisons Harrington

35. TAXUS II: Risk These were patients mainly with single-vessel disease Against historical controls, even bare-metal stents in this trial did reasonably well It would be interesting to see the results in a high-risk group Weber

36. Coated stents:SIRIUS cost analysis Cohen DJ. ACC 2003

37. Coated stents: Cost effectiveness "The good news is, we're not going to bankrupt the healthcare system." Hospitals will pay more up front and get fewer admissions HMOs will benefit by fewer repeat procedures Cannon

38. Coated stents: Perspective "From a national perspective, this looks to be a good thing. Yes, it's an expensive technology up front but it does reduce some serious outcomes that are both important to patients and expensive." Individual health systems will need to grapple with how to deal with this Harrington

39. Coated stents: Other patients • How do we apply the data for patients not yet studied? • Multivessel disease • Diffuse disease • Very small-vessel disease • Chronic total occlusion • Graft disease • Still work to be done on how to incorporate it into practice Harrington

40. Coated stents: Cost issues "You can't look at this from the point of view of hospital costs or pharmacy costs, but you have to look at it as a total integrated concept." With more approvals, that should drive down costs Federal authorities are getting hostile to new technologies that raise initial cost Weber

41. Summary: EBCT Calcium score does seem to have predictive value Calcium score may add to Framingham risk Calcium score should not lead to treatments we wouldn't otherwise do for patients with high-risk factor profiles Fuster

42. Summary: Lp-PLA2 CHD risk ratio by Lp-PLA2 tertiles in ARIC (lowest tertile is reference) ACC 2003

43. Summary: COMPANION CRT with or without ICD for patients with severe heart failure May have meaningful use for a small but very sick group of patients ICDs may be effective in patients with dilated cardiomyopathy Results are still very preliminary Fuster

44. Summary: Drug-eluting stents Results continue to be positive and impressive Should we have a trial comparing paclitaxel vs sirolimus? The sirolimus stents appear to be cost-effective over time when compared with conventional stents Fuster

45. Final word: Cannon Devices are advancing tremendously "There has been a lot of talk about all the various medical therapies, but now in CHF these two different technologies both seem to be very helpful." Cannon

46. Final word: Weber Drug-eluting stents are the way of the future and CRT and ICDs are promising "We can talk about high cost and all the difficulties of selecting the right patients but I think deep down we all know that if we had patients who would fit those criteria we wouldn't hesitate to make this sort of technology available to them." Weber

47. Final word: Harrington • "Our beginning discussion on markers really tells me that we are here in an era of proteomics." • We need to learn how to use biomarkers to improve: • diagnosing patients • risk-stratifying patients • selecting therapies Harrington

48. Final word: Fuster We are entering an era of merging physicists and biologists "This field is evolving like NASA, where all the different people have something to offer." Fuster