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ESC 2003: Confirming knowledge

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

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ESC 2003: Confirming knowledge

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  1. 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. Topics Use of an oral antithrombin post MI ESTEEM Role of an ARB in cardiac failure CHARM ACE inhibitor for chronic stable CAD EUROPA

  3. 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. ESTEEM: Results Lancet 2003; 362: 789–97

  5. SPORTIF III: Primary events p=NS p=0.018 ACC 2003

  6. ESTEEM: Well-done trial 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." Cannon

  7. 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. ESTEEM: Liver function Lancet 2003; 362: 789–97

  9. 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. 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. 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. 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. ESTEEM: Results Lancet 2003; 362: 789–97

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

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

  16. 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. ESTEEM: Alanine transaminase Lancet 2003; 362: 789–97

  18. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. CHARM-Overall: Results Lancet 2003; 362: 759–66

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

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

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

  32. 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. 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. CHARM: Val-HeFT results N Engl J Med 2001;345:1667-75

  35. 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. 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. 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. 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. CHARM: New-onset diabetes Lancet 2003; 362: 759–66

  40. CHARM-Preserved: Major results Lancet 2003; 362: 777–81

  41. 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. 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. 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. 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. 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. 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. 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. EUROPA: Results Lancet 2003; 362: 782–88

  49. EUROPA: HOPE results ESC 1999

  50. 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

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