1. Heartbeat – Sept 2003 ESC 2003 ESC 2003: Confirming knowledge Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, MA James Ferguson MD Associate Director, Cardiology St Luke's Episcopal Hospital and Texas Heart Institute Houston, TX Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, NY

2. Heartbeat – Sept 2003 ESC 2003 Use of an oral antithrombin post MI ESTEEM Role of an ARB in cardiac failure CHARM ACE inhibitor for chronic stable CAD EUROPA Topics

3. Heartbeat – Sept 2003 ESC 2003 ESTEEM Oral ximelagatran for secondary prophylaxis after myocardial infarction (Lancet 2003; 362: 789–97) 1883 patients with recent MI (<14 days) Ximelagatran (24, 36, 48, or 60 mg twice daily) and aspirin (160 mg once daily) vs aspirin alone Primary end point: all-cause death, nonfatal MI, and severe recurrent ischemia Six-month follow-up

4. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 789–97 ESTEEM: Results

5. Heartbeat – Sept 2003 ESC 2003 ACC 2003 SPORTIF III: Primary events p=0.018p=NS

6. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Well-done trial Cannon A properly sized dose-ranging trial It supports the notion that anticoagulation plus aspirin is better than aspirin alone "Just aspirin is no longer the optimal long-term management strategy."

7. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Raising questions This moves beyond the level of previous studies that showed long-term secondary-prevention benefit Ximelagatran gives us something at least as good as warfarin therapy, without all the downside There was no dose effect seen in the doses used in the study Ferguson

8. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 789–97 ESTEEM: Liver function

9. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Not surprised "I could say I am pleased and not particularly surprised." It was already known to compare well to warfarin in efficacy while being easier to use How does this compare with using two antiplatelet drugs together? Weber

10. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Warfarin + aspirin Warfarin + aspirin is similar to aspirin + clopidogrel We need to compare these strategies side by side "One gets a sense that the data are actually very similar in terms of the combinations of end points." Fuster

11. Heartbeat – Sept 2003 ESC 2003 ESTEEM: What do we choose? "This is the big question as we have more and more options available: which to choose?" ESTEEM is a phase 2, hypothesis- generating, study Ximelagatran is not yet ready for use in this patient population Cannon

12. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Stents Patients with stents have an absolute indication for clopidogrel The next question will be safety and tolerability of clopidogrel, aspirin, and ximelagatran together "Lots of testing and trial work needs to be done." Cannon

13. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 789–97 ESTEEM: Results

14. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 789–97 ESTEEM: Major bleeding

15. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 789–97 ESTEEM: Total bleeding

16. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Dosing questions As you push the dose, you could expect more bleeding issues "You go with the most effective drug with the least number of complications." All the doses seem to be above a threshold for efficacy Bleeding is comparable to warfarin, and so ximelagatran still works as a replacement Ferguson

17. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 789–97 ESTEEM: Alanine transaminase

18. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Liver enzyme tests "I'd rather not see [a liver enzyme increase], but at the same time it isn't really worrying me too much." Threefold increases in ALT aren't unusual; the FDA seems to get worried around an increase of six- to eightfold normal The increase seems to be an early- warning signal Weber

19. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Dose response Dose-response curve appears flat "Did they get the dose-response curve in completely the wrong place and instead of looking at 24 mg and above, should they have been looking at 6 and 12 and 24?" Would different doses have produced comparable efficacy but with a better side-effect profile? Weber

20. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Administering the drug GP IIb/IIIa inhibitors Fantastic given parenterally Terrible given orally Thrombin inhibitors Question mark given parenterally Fantastic given orally Fuster

21. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Dosing Oral GP IIb/IIIa inhibitors are hard to dose properly The very high level of inhibition needed is not tolerated long term One can titrate oral thrombin inhibitors to the right dose Dose is well tolerated in the long-term Cannon

22. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Excitement level "I am very excited, actually, [by the results of the ESTEEM trial]." Are you all only moderately excited because SPORTIF III has already convinced you and this is just SPORTIF III in the arterial system? Fuster

23. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Cannon summary "I'm extremely excited [about ximelagatran] on the venous side, because we desperately need therapies there." In the arterial system, we already have other theories that are effective Adding options is good, but exactly where it fits in is still unknown Cannon

24. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Ferguson summary SPORTIF III presented an alternative to warfarin therapy and where warfarin works, an alternative to warfarin will work "I continue to be excited about the opportunity to ultimately replace warfarin with a better drug." Ferguson

25. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Weber summary ESTEEM is a nice alternative to good therapies we already had SPORTIF III presented a breakthrough for treatment of atrial fibrillation with antithrombin therapy "This is an exciting study, but perhaps doesn't have quite the impact that we've seen earlier with the SPORTIF results." Weber

26. Heartbeat – Sept 2003 ESC 2003 ESTEEM: Fuster summary Our laboratory has been involved since the beginnings of antithrombin "[These are] new types of drugs, which certainly are going to be very successful in the future." Critical issues for the future: Effect on liver Cost Fuster

27. Heartbeat – Sept 2003 ESC 2003 CHARM: Trials Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity 7601-patient trial divided into smaller studies of three populations: Patients with LV dysfunction intolerant to ACE inhibitors (the CHARM-Alternative trial) Patients with LV dysfunction already taking ACE inhibitors (the CHARM-Added trial) Patients with preserved LV function (the CHARM- Preserved trial)

28. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 759–66 CHARM-Overall: Results

29. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 772–76 CHARM-Alternative: Results

30. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 767–71 CHARM-Added: Results

31. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 777–81 CHARM-Preserved: Results

32. Heartbeat – Sept 2003 ESC 2003 CHARM: Is candesartan the answer? We still think for LV dysfunction, ACE inhibitors were the drug of choice But in patients who cannot tolerate ACE inhibitors, is candesartan the answer? Fuster

33. Heartbeat – Sept 2003 ESC 2003 CHARM: Support for ARBs Effective inhibition of the angiotensin- renin system is mandatory in patients with heart failure and coronary disease "This really boosts enormously the evidence base on the efficacy side for the ARBs." Cannon

34. Heartbeat – Sept 2003 ESC 2003 N Engl J Med 2001;345:1667-75 CHARM: Val-HeFT results

35. Heartbeat – Sept 2003 ESC 2003 CHARM: ARB popularity The high tolerability of ARBs may make them very popular even if a patient hasn't exhausted the possibility of ACE inhibitors In CHARM-Added, is the effect of the combination any different from simply upping the dose of the ACE inhibitor? Weber

36. Heartbeat – Sept 2003 ESC 2003 CHARM: Physiology CHARM confirms ARBs as an alternative to ACE-inhibitors The physiological axis here is the renin- angiotensin-aldosterone axis, and the aldosterone receptor antagonists will also have effects "ACE inhibitors alone are not necessarily enough." Ferguson

37. Heartbeat – Sept 2003 ESC 2003 CHARM: Side effects Cough was major reason for intolerance to ACE inhibitor ARB blockers had minimal side effects What will the side effects be of two drugs both working in the ACE pathway? "It's very striking data but I'm not sure how applicable it is going to be in the real world." Fuster

38. Heartbeat – Sept 2003 ESC 2003 CHARM: Compliance Difficult to persuade patients to stay on six or eight drugs for their heart failure Patients are so worried about their symptoms and possible hospitalization that most are very motivated The ARBs do seem to not add to the side- effect burden Weber

39. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 759–66 CHARM: New-onset diabetes

40. Heartbeat – Sept 2003 ESC 2003 End pointCandesartan (n=1514) Placebo (n=1509) Adjusted HR (95% CI) p CV death/CHF hospitalization 22.0%24.3%0.86 (0.74-1.00) 0.051 CV death11.2%11.3%0.95 (0.76-1.18) 0.635 CHF hospitalization 15.9%18.3%0.84 (0.70-1.00) 0.047 CHARM-Preserved: Major results Lancet 2003; 362: 777–81

41. Heartbeat – Sept 2003 ESC 2003 CHARM-Preserved: Very promising This is an effect in a population where we have nothing that works right now This was the lowest-risk group of the CHARM trial, so a larger trial would be needed "I think we can really look forward to that as finally a therapy that will be helpful for this group." Cannon

42. Heartbeat – Sept 2003 ESC 2003 CHARM-Preserved: Age Average age in CHARM-Preserved was 67 This type of heart failure is usually found in the elderly, age >70 We don't have much guidance outside of diuretic therapy, so why not use an ARB? 14-15% reduction of hospitalization is very worthwhile in HF Weber

43. Heartbeat – Sept 2003 ESC 2003 CHARM: Enthusiasm Excitement seems based on two issues: Adding an ARB to the conventional ACE inhibitor A hope for patients with preserved LV function Fuster

44. Heartbeat – Sept 2003 ESC 2003 CHARM: Ferguson summary Moderate-plus level excitement No huge surprises in the overall trial CHARM-Preserved sets the stage for the future "It was not earth-shattering, but I think it's very, very encouraging." Ferguson

45. Heartbeat – Sept 2003 ESC 2003 CHARM: Weber summary CHARM suggests the Val-HeFT finding that adding an ARB on top of an ACE inhibitor wasn't effective if a beta blocker was in place was an aberrant finding "That to me is very helpful because I had a lot of trouble explaining why the three drugs didn't work so well together; now I don't have to worry about it anymore." Weber

46. Heartbeat – Sept 2003 ESC 2003 CHARM: Cannon summary It provides stronger evidence to reinforce things we already knew "This is for real and we need to really try to implement effective inhibition of the angiotensin, renin, and aldosterone axis." Cannon

47. Heartbeat – Sept 2003 ESC 2003 EUROPA Adding perindopril to standard therapy in patients with stable CAD 12 218 patients Randomized to perindopril (8 mg once daily) or placebo Primary end point: CV death, MI, and cardiac arrest Four-year follow-up

48. Heartbeat – Sept 2003 ESC 2003 Lancet 2003; 362: 782–88 EUROPA: Results

49. Heartbeat – Sept 2003 ESC 2003 ESC 1999 EUROPA: HOPE results

50. Heartbeat – Sept 2003 ESC 2003 EUROPA: Broader population Very powerful data EUROPA suggests ACE-inhibitor benefit may extend out broadly into an at-risk population "I knew that ACE inhibitors were good, but I had no idea how good they are in a broader population of patients." Ferguson

51. Heartbeat – Sept 2003 ESC 2003 EUROPA: Stroke results

52. Heartbeat – Sept 2003 ESC 2003 EUROPA: Signal to noise The lack of stroke effect may have to do with EUROPA using lower-risk patients "We may be losing the signal in the noise for right now. Two hundred strokes in the overall population is not a lot to be able to try to tease out an effect." Ferguson

53. Heartbeat – Sept 2003 ESC 2003 EUROPA: Blood pressure Possible explanation of the difference between EUROPA and HOPE: Lack of power Blood pressure There was a smaller change in blood pressure in EUROPA than there was in HOPE Fuster

54. Heartbeat – Sept 2003 ESC 2003 EUROPA: Class effect? Salim Yusuf: Does this show anything different from what we saw with ramipril in HOPE? EUROPA investigators: Fantastic results in a very low-risk population that is different from HOPE Sidney Smith: This is adding to the HOPE study Fuster

55. Heartbeat – Sept 2003 ESC 2003 EUROPA: Stronger evidence Cardiologists are always skeptical of new things Guidelines did not adopt full HOPE population for treatment with ACE inhibitors when it came out "There was some reluctance to say, 'put this in the drinking water for coronary disease.' I think that can now go away." Cannon

56. Heartbeat – Sept 2003 ESC 2003 EUROPA: Class effect "It is pretty clear this is a class effect." ACE-inhibitor story started with captopril in the SAVE trial and then continued in the SOLVD study Effect has been seen with captopril, ramipril, and perindopril All CAD patients should be on an ACE inhibitor Cannon

57. Heartbeat – Sept 2003 ESC 2003 EUROPA: Building on previous data EUROPA builds on the HOPE trial Gives us a new ACE inhibitor Extends the population Not a huge advance but it expands our horizons "ACE inhibitors, while not added to the drinking water, maybe ought to be put in the saltshakers." Ferguson

58. Heartbeat – Sept 2003 ESC 2003 EUROPA: Clarifying data EUROPA is confirmatory rather than breakthrough Removes the argument that HOPE was a hypertension trial rather than a high- risk cardiovascular trial "It's confirmatory but very important confirmatory, and I'm delighted it turned out this way." Weber

59. Heartbeat – Sept 2003 ESC 2003 ESTEEM Adds the arterial system as an option for ximelagatran CHARM ARB as an alternative or in addition to ACE inhibitor for CHF patients EUROPA All patients with CAD should be treated with an ACE inhibitor Summary: Topics

60. Heartbeat – Sept 2003 ESC 2003 Final word: The right track These studies show we are on the right track Antithrombotic therapy in coronary disease Treating cardiac failure with the ACE pathway ACE inhibition for CAD patients regardless of risk Fuster

61. Heartbeat – Sept 2003 ESC 2003 Final word: Cannon The inhibition of the renin-angiotensin- aldosterone system is extremely important "I think that has become now a mandatory component of heart failure and coronary disease management." Cannon

62. Heartbeat – Sept 2003 ESC 2003 Final word: Ferguson Older forms of therapy can be used in broader populations (ACE inhibitors in at-risk CAD patients) Newer forms of therapies can extend what we can do (ARBs can add to or substitute for ACE inhibitors) New compounds on the horizon that may supplant older forms of therapy (oral antithrombins can replace warfarin) Ferguson

63. Heartbeat – Sept 2003 ESC 2003 Final word: Weber Confidence: These studies confirm what we predicted "Had the results not turned out the way they had, I think we would have been devastated." These results should give cardiologists confidence they are on the right track Weber

64. Heartbeat – Sept 2003 ESC 2003 GRACIA-2 Immediate thrombolysis plus PCI Aspirin resistance Present in many patients DECOPI Late-artery opening BASEL BNP testing and diagnosing heart failure Next session