Opening doors to new therapies: Clinical trials at AHA 2001

1. Opening doors to new therapies:Clinical trials at AHA 2001 Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, New York Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, Massachusetts James Ferguson MD Associate Director, Cardiology St Luke's Episcopal Hospital and Texas Heart Institute Houston, Texas Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, New York

2. Studies INTERVENTIONAL REMATCH COPPA II PRESTO PHAMACOLOGICAL HPS IONA PENTUA

3. REMATCH • Randomized Evaluation of Mechanical Assistance Therapy for Congestive Heart Failure • 129 Class IV heart failure patients randomized to either Heartmate LVAD or medical therapy • 2-year follow-up

4. REMATCH results Kaplan-Meier estimates of survival at 1 and 2 years Rose EA et al. AHA 2001

5. Lessons from REMATCH • Life expectancy among transplant-ineligible CHF patients is dismal • An option for patients, but not for everyone • Technical improvements will minimize device failures (35% failure at 24 months) • Economic issues will become important if extended beyond transplant-ineligible patients • "We are not saving lives here, we are prolonging life." Ferguson

6. A year of life • We are only giving these people 1 year of life, but that is not much different from pharmacological trials • "Everything we are doing, which is fantastically statistically significant, in fact when you look at what we are accomplishing, it is really not much." • Fuster

7. Survival plateau • We have hit a plateau in survival, but anything to improve quality of life is helpful • "The real benefit isn't making people live that much longer, but hopefully improving their quality of life during whatever time is left to them." Weber

8. REMATCH: quality of life Rose EA et al. AHA 2001

9. Potential LVAD candidates • Who would be getting this? • Younger patients who had a massive MI and developed heart failure • New options are needed because there are still too few donors • Cannon

10. Recovery on LVAD • A feasible device that might be combined with cell transplantation to improve the heart muscle • Fuster • Some evidence for recovery of heart muscle function in some patients on LVADs Ferguson

11. COPPA II • Decrease atrial fibrillation post bypass • 293 patients (half on beta-blockers, half on propafenone postoperatively)

12. Postoperative atrial fibrillation • Was 50% before beta-blockers • 25% with beta-blockers • COPPA II: • 12.4% AF in propafenone group22.7% AF in control group

13. Caution • A lot of AF goes away on its own • Propafenone is not a totally benign drug "Maybe we should not necessarily be routinely prophylaxing these people all the time." Ferguson

14. Red flags "I have big red flags that go off clinically in treating with anything other than amiodarone." • We won't see anything until we get 2-4000 patients • Every class IA or IC antiarrhythmic has been associated with sudden death when studied in a very large trial Cannon

15. Are there real benefits? • Issues to look at with propafenone • Only the highest dose did anything • No difference in hospital length of stay between groups Ferguson

16. PREVENT 2 • PRoject of Ex-Vivo Vein Graft ENgineering Via Transfection 2 • 200 patients undergoing CABG randomized to receive E2F Decoy-treatment of their autologous vein grafts or to receive their grafts untreated

17. PREVENT 2 results Park S-J et al. TCT 2001

18. Gene therapy • "This has been one area where there has been almost nothing developed in the last 2 decades." • Encouraging to have a more direct approach • Cannon

19. An exciting advance • First major advance in years with real potential to impact the biology of the bypass graft • "What has always been the real Achilles' heel of the procedure is the biology of venous conduits." • Ferguson

20. PRESTO • Prevention of REStenosis with Tranilast and its Outcomes • 11 500 patients were randomized • 4 treatment arms with tranilast or 1 placebo arm • "This is the largest trial I know with the largest disappointment." Fuster

21. PRESTO results Holmes D et al. AHA 2001

22. Problems with PRESTO • What data led to the clinical trial • Animal models • Small-scale human studies • Treatment analysis, not intention-to-treat analysis • "[This] points out the hazards of basing large-scale clinical trials on small populations of patients." Ferguson

23. Understand the biology • "To my way of thinking, it really reinforces our need, before we go jumping into mega-million dollar clinical trials, that we really need to understand a little bit about the biology of what is going on." Ferguson

24. Coated stents • If coated stents hold their promise, the issue of using an oral drug to treat a local problem may be moot • Cannon

25. HPS • Heart Protection Study • >20 000 patients with previous CV event or diabetes randomized to simvastatin (40 mg) or placebo • 5-year follow-up • Also looked at antioxidant vitamins • Endpoints of vascular events and mortality

26. Primary endpoints in HPS Collins R et al. AHA 2001

27. Events by LDL level Data from www.hpsinfo.org Collins R et al. HPS trial website

28. Vitamins in HPS Collins R et al. AHA 2001

29. Secondary endpoints in HPS Collins R et al. AHA 2001

30. A confirmatory study • What was really new here? • It confirmed suspicions and assumptions we already had due to earlier studies • Secondary prevention patients benefit from statin • Patients with other risk factors benefit Weber

31. Incidence of MI and stroke in diabetic patients without prior disease Collins R et al. AHA 2001

32. Importance of low LDL results • The low-LDL data is impressive. Even if you are at target levels, it is worth taking a statin • Should we even test for cholesterol? • Statin effects other than LDL lowering are becoming more important • Ferguson

33. Impact on care • HPS will impact on care • A statin other than pravachol • Offers new hope for market after the removal of Baycol • Raises possible application in a broader population not focused on lipid status • Ferguson

34. Not enough statin use • The paradox is we don't use statins enough now, and we keep expanding the population it is useful for • Fuster • But all the doctors take statins, so there may be hope for the future • Weber

35. Clinical use of statins • ATP III guidelines suggest 36 million patients receiving statins in the US, but estimates put it at 12 million • A lot of the gap is in primary prevention • "Hopefully this huge trial will make a big impact on the clinical use of this class of drugs." Cannon

36. The vitamin problem • A perception problem, people don't want to take a medicine all their life. But they will take ineffective vitamins • "The bottom line for me is, hopefully people will throw away their vitamins and talk to their doctor about taking a statin." Cannon

37. Price • Insurance means price should not be a problem • Perception of having to take a medicine • People don't want the implication they are ill • People don't realize taking statin would have a huge real effect Cannon

38. Simvastatin use in HPS Collins R et al. AHA 2001

39. Which drug to use • We now have compelling evidence for a number of drugs • Aspirin • ACE inhibitors • Statins • "Now maybe you can get people to take one medicine, and maybe, if you're lucky, you can get them to take two. But you're not going to get them to take three, it's just not going to happen." Ferguson

40. PENTUA • PENtasaccharide in Unstable Angina • A dose study of fondaparinux in 929 patients with unstable angina • Indirect blocker of Factor Xa • Outperformed heparin in preventing venous thrombosis following orthopedic surgery in earlier studies

41. PENTUA: events at 9 and 30 days Simoons ML et al. AHA 2001

42. Upstream in the cascade • The further upstream in both the anticoagulant and antiplatelet cascade you go, the more effective the approach • Enoxaparin was earlier in the cascade than unfractionated heparin • Clopidogrel higher in the cascade than oral IIb/IIIa inhibitors • Pentasaccharide higher than enoxaparin Cannon

43. PENTUA: bleeding Simoons ML et al. AHA 2001

44. Questions about PENTUA • The reverse dose-effect is troubling • We never saw the ST-segment monitoring data • "We still need to have some sort of ability to block thrombin if it is generated." Ferguson

45. More caution on PENTUA • Other questions on PENTUA • Data based on a small number of patients • Why is there no dose-response effect? • A phase III trial may require a huge number of patients • Weber

46. Dose response • No dose response shouldn't be a worry, no anticoagulant has a dose response for efficacy • With heparin, lowest levels of PTT beneficial • No difference found in enoxaprin • Aspirin showed no difference by INR once you get above 1.5 INR • Cannon

47. Feedback mechanisms • Dose effects are unclear in the anticoagulant field • "The clotting systems works with an incredible number of feedback mechanisms." Fuster

48. IONA • Impact of Nicorandil in Angina • 5126 patients with stable angina randomized to nicorandil or placebo • Endpoints death, MI, hospitalization for angina • 1.6 years average follow-up

49. IONA: outcomes Dargie H et al. AHA 2001

50. Interpreting IONA • UK has very low revascularization rate, which may affect interpretation • Antianginal therapy is beneficial, especially for those who cannot be revascularized • "It's a tool in your antianginal armementarium. We just don't happen to have it available in the United States right now." Ferguson