1. Heartbeat – Sep 2002 ESC 2002 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 – Sep 2002 ESC 2002 Acute coronary syndromes MAGIC OPTIMAAL RITA-3 BNP prognostics Off-pump surgery Stem cells Topics

3. Heartbeat – Sep 2002 ESC 2002 MAGIC: Trial design MAGnesium In Coronaries (MAGIC) PI: Elliot Antman 6213 MI patients. Randomized to IV magnesium or placebo. Primary end point: all-cause mortality at 30 days.

4. Heartbeat – Sep 2002 ESC 2002 MAGIC: Mortality results No difference in 30-day mortality between magnesium and placebo. No significant differences in any subgroup. No benefit or harm seen in secondary outcomes. “Magnesium is dead in the water.” Rory Collins

5. Heartbeat – Sep 2002 ESC 2002 MAGIC: Time to move on There were intriguing questions generated by earlier trials. “But when you put it to the test, it doesn’t make any difference. So, let’s move on.” Ferguson

6. Heartbeat – Sep 2002 ESC 2002 MAGIC: Rationale for the trial Cannon LIMIT-2: Mg started before thrombolysis. ISIS 4: Mg started several hours after thrombolysis. The negative results in ISIS-4 could have been due to the delay. MAGIC went back to early administration of Mg.

7. Heartbeat – Sep 2002 ESC 2002 MAGIC: A might-have-been? “We really don’t have any information that would allow us to make that judgment.” Did magnesium never have a chance because ACE inhibitors and thrombolysis got there first? Weber

8. Heartbeat – Sep 2002 ESC 2002 OPTIMAAL: Trial design Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) PI: Kenneth Dickstein 5477 patients. Acute MI. Losartan 50 mg once daily vs captopril 50 mg 3 times daily mm Hg. Primary end point: all-cause mortality at 2.7 years follow-up.

9. Heartbeat – Sep 2002 ESC 2002 Lancet 360:752-760 OPTIMAAL: Results p=0.069p=0.032

10. Heartbeat – Sep 2002 ESC 2002 OPTIMAAL: ACE vs ARB The angiotensin axis is important, but ACE inhibitors are still superior to ARBs in the doses we’ve tested. New tools help, but losartan is still just a good alternative therapy. There is interest in higher doses of losartan. Ferguson

11. Heartbeat – Sep 2002 ESC 2002 The results were known well over a year ago. ELITE-2 also had a trend favoring captopril with the same doses. VAL-HeFT used a genuine dose (160 mg twice a day) of valsartan and got FDA approval for heart failure. 50 mg is a nonsense dose. Weber OPTIMAAL: A Greek tragedy

12. Heartbeat – Sep 2002 ESC 2002 The name is ironic because OPTIMAAL tested suboptimal levels of losartan. Dose is critical–-we haven’t tested proper doses of losartan yet. “The whole rationale in this field is moving toward complete blockade of this axis, so to use a very low dose goes counter to the thinking of how this pathway can be best inhibited and outcomes improved.” Cannon OPTIMAAL: Misnamed

13. Heartbeat – Sep 2002 ESC 2002 Losartan as a replacement for captopril should use a minimum of 100 mg. We should push the doses as high as one appropriately can because that goes after the pathophysiology of the problem. Cannon OPTIMAAL: Appropriate dosing

14. Heartbeat – Sep 2002 ESC 2002 Losartan should be used at 50 mg bid. LIFE titrated patients from 50 mg a day to as much as 100 mg daily. The advantage in LIFE was a stroke advantage, not an MI advantage. “For all the excitement with the ARBs they’ve still got to prove themselves as having a cardioprotective effect.” OPTIMAAL: ARBs Weber

15. Heartbeat – Sep 2002 ESC 2002 RITA-3: Trial design Randomized Intervention Trial of unstable Angina (RITA-3) PI: Keith AA Fox 1810 patients with non-ST-elevation Ml or unstable angina. Randomized to conservative or interventional approach. Primary end points: death, MI, and refractory angina at 4 months and death and MI at 1 year.

16. Heartbeat – Sep 2002 ESC 2002 RITA-3: Defining risk Troponin is the most potent: high vs low risk (FRISC II). ST-segment changes on the EKG also gives high vs low risk. TIMI risk score ranges from 0 to 7, defining low-, intermediate-, and high-risk groups. TACTICS-TIMI 18 and FRISC II both found intermediate to high risk benefited from an early intervention strategy. Cannon

17. Heartbeat – Sep 2002 ESC 2002 RITA-3: Heart failure as a risk factor Admission with heart failure is a very important predictor of death but a less important predictor of recurrent MI or recurrent ischemia. Markers of the burden of disease are more effective for predicting the broader impact of a therapy. Cannon

18. Heartbeat – Sep 2002 ESC 2002 RITA-3: Moderate risk? Patients in RITA-3 are called moderate risk but: 75% of the patients were troponin positive. Exclusion criteria included 2x normal CK elevation. The CK-negative/troponin-positive group is at highest risk of recurrent ischemic events.

19. Heartbeat – Sep 2002 ESC 2002 RITA-3: Event rate p=0.001 p=0.58 9.6 14.5 7.6 8.3

20. Heartbeat – Sep 2002 ESC 2002 RITA-3: Trial comparison

21. Heartbeat – Sep 2002 ESC 2002 RITA-3: More cath labs RITA-3 and TACTICS-TIMI used an early invasive approach, FRISC II a little later. “The hope is that this will really spur Canada and the European countries to start building some more cath labs and start talking with their health authorities to say this is way we can improve outcomes for a large group of patients.” Cannon

22. Heartbeat – Sep 2002 ESC 2002 RITA-3: So many patients We should see cath rates in the 80% to 85% range if we follow evidence-based medicine: Between 2/3 and 3/4 UA/NSTEMI patients are moderate to high risk. Three million estimated UA/NSTEMI patients in Europe and the US. Even in clinical trials, half the conservative therapy group goes on to cath eventually. Cannon

23. Heartbeat – Sep 2002 ESC 2002 RITA-3: Angina Lancet 360:743-751

24. Heartbeat – Sep 2002 ESC 2002 Lancet 360:743-751 RITA-3: MI using standard definition

25. Heartbeat – Sep 2002 ESC 2002 RITA-3: Inadequate resources “Even in this country we do have a great inadequacy of resources.” Most of the hospitals in Brooklyn do not have the resources to get quickly to a cath lab and to provide the appropriate intervention. “This is a big problem over here as well.” Weber

26. Heartbeat – Sep 2002 ESC 2002 RITA-3: Summary RITA-3 adds to the thinking that acute coronary syndromes fall more and more into the interventional arena. What will the economics of this mean to poorer countries? Fuster

27. Heartbeat – Sep 2002 ESC 2002 BNP prognostics: Trial design BNP as a prognostic for sudden death in HF PI: Rudolf Berger 452 ambulatory patients with LVEF ≤ 35%. Primary end point: sudden death over 3 years.

28. Heartbeat – Sep 2002 ESC 2002 BNP: Mortality results A log BNP ≥ 2.11 was the only independent predictor of sudden death This could discriminate who is a candidate for an ICD

29. Heartbeat – Sep 2002 ESC 2002 BNP: Prognostic tool The study is fascinating because this takes BNP from a diagnostic to a prognostic tool. Maybe we have to start monitoring BNP in our heart failure patients. Patients with so-called mild heart failure may be the people for whom this test would be particularly helpful. Weber

30. Heartbeat – Sep 2002 ESC 2002 BNP: Screening patients With a 20% total mortality rate, it’s hard to say how “mild” the heart failure really is. The predictive nature of BNP is really intriguing because we are all looking for ways to stratify patients for ICD. “I’d like to see this extended and confirmed.” Ferguson

31. Heartbeat – Sep 2002 ESC 2002 BNP: Questions about ICDs Patients with MI and low EF should receive ICDs, but we are still looking at ways to screen the patients who will most benefit. For cardiac failure not related to coronary artery disease, do we know if ICDs are even useful? Fuster

32. Heartbeat – Sep 2002 ESC 2002 BNP: We need risk stratification We need tools to pick out the patients who would most benefit from ICDs, because the costs could be prohibitive. Risk stratification is the right strategy, as it was with ACS. I’m hoping BNP can be measured in MADIT II and in upcoming trials. Cannon

33. Heartbeat – Sep 2002 ESC 2002 BNP: Two patients Myocardial infarction EF = 35% Dilated cardiomyopathy EF = 35%

34. Heartbeat – Sep 2002 ESC 2002 Monitor the cardiomyopathy patient, maybe measure BNP levels, look for an indication to use an ICD. I don’t think this particular information really speaks to patients with AMI. It’s not clear what the proper approach should be. BNP: Two patients Weber

35. Heartbeat – Sep 2002 ESC 2002 BNP will rise in the first 8 to 12 hours to a peak and then gradually descend with treatment. Maybe we need to treat patients differently, depending on how recent their MI. “[BNP] is now the new CRP for heart failure and I think we’ll have much more information in the next 6 to 12 months.” BNP: AMI Cannon

36. Heartbeat – Sep 2002 ESC 2002 BNP: Physiology matters “It brings us back to the issue that physiology matters.” The metabolic pathways underlying this process is important. “We just don’t quite understand enough about it to figure out exactly what’s going on yet.” Ferguson

37. Heartbeat – Sep 2002 ESC 2002 Off-pump CABG: Trial design Patency of Off-Pump CABG PI: Brompton group 103 patients. 54 off-pump, 49 conventional CABG. Primary end point: graft patency at 3- months.

38. Heartbeat – Sep 2002 ESC 2002 Off-pump CABG: Patency results Not a significant finding If the grafts are more occluded, are all the advantages of off- pump surgery irrelevant? Do we need to look deeper into what is happening with off- pump CABG? Fuster

39. Heartbeat – Sep 2002 ESC 2002 The most important thing is graft patency. “If it were me or my family member, I’d definitely go for the real thing.” “I suppose it’s a replay of the PCI story, that suboptimal stent deployment leads to suboptimal results.” Off-pump CABG: Suboptimal patency Cannon

40. Heartbeat – Sep 2002 ESC 2002 Off-pump CABG: Tweaking the technique We improved adjunctive therapy with PCI over time, we can do the same here. “I think that off-pump is here to stay. I think we may just need to tweak it and may need to do the larger-scale trials looking closely at patency but also making an effort to optimize the adjunctive therapy.” Ferguson

41. Heartbeat – Sep 2002 ESC 2002 Two or 3 patients made all the difference in this trial. These results must be very dependent on the skill and experience of the surgeons. We might see no difference between off-pump and on-pump patency in 5 or 6 years “But I suspect that in a handful of years we’re going to see much more shift to the off-pump method.” Off-pump CABG: Experience Weber

42. Heartbeat – Sep 2002 ESC 2002 Stem cells: Mode of delivery SYLVAIN’s PIC

43. Heartbeat – Sep 2002 ESC 2002 Strauer BE et al. Circulation 2002 Stem cells: Ventricular function Function parameter Before cell therapy 3-month follow-up p Infarct region as functional defect* (%) 30+1312+70.005 Infarct region as perfusion defect (cm 2 ) 174+99128+710.016 Stroke volume index (mL/m 2 ) 49+756+70.010 Infarction wall movement velocity (mm/s) 2.0+1.14.0+2.60.028 *Percentage of hypokinetic, akinetic, or dyskinetic regions

44. Heartbeat – Sep 2002 ESC 2002 Stem cells: New cardiomyocytes Bone marrow Pluripotent cells Stromal-mesenchymal pathway Skeletal muscle, cardiomyocytes

45. Heartbeat – Sep 2002 ESC 2002 Stem cells: Arrhythmia There are concerns about increased risk of arrhythmias with this technique. We need studies with more patients. “As we look at heart failure, as we look at acute myocardial infarction, I think [stem cell therapy] is an area that we’re going to be seeing an awful lot more from. ” Ferguson

46. Heartbeat – Sep 2002 ESC 2002 “The whole field of acute MI has revolved around the need for early salvage because you can’t get the heart cells back. But if in fact you can repair the heart then it’s just a wonderful new hope.” Stem cells: A new hope Cannon

47. Heartbeat – Sep 2002 ESC 2002 Summary: MAGIC Randomized MI patients to IV magnesium or placebo. Absolutely no effect on mortality at 30 days. “We have to forget about magnesium, at least for the next 25 years.” Fuster

48. Heartbeat – Sep 2002 ESC 2002 Summary: OPTIMAAL Losartan 50 mg once daily vs captopril 50 mg 3 times daily. Trend favored captopril, but questions remain because the dose of losartan was so low. “The issue is not closed.” Fuster

49. Heartbeat – Sep 2002 ESC 2002 Summary: RITA-3 NSTEMI/UA patients randomized to conservative or interventional approach. Intervention is much better than conservative therapy. “This really moves the field of acute coronary syndromes more and more toward the interventional area.” Fuster

50. Heartbeat – Sep 2002 ESC 2002 Summary: BNP BNP was a predictor of sudden death in patients with chronic cardiac failure. This opens the possibility of screening patients for ICD use. The data don’t translate into AMI patients, where BNP levels are highly variable. Fuster

51. Heartbeat – Sep 2002 ESC 2002 Summary: Off-pump surgery We all think off-pump surgery lets patients go home early and has fewer bleeding complications. Graft patency was better in the on-pump CABG patients. We need to follow this new technology closely. Fuster

52. Heartbeat – Sep 2002 ESC 2002 Summary: Stem cells Injection of pluripotent bone-marrow cells into myocardium post-MI. No inflammatory response, potential improvement in ventricular function, but a possible increase in arrhythmia. Fuster

53. Heartbeat – Sep 2002 ESC 2002 Patients in the original SOLVD trial got 8 to 9 months of increased life expectancy from aggressive ACE inhibitor treatment. It just emphasizes how the newer modalities we talked about today may be the ones that will make a real difference for people with heart failure. Final word: SOLVD Weber

54. Heartbeat – Sep 2002 ESC 2002 In the ACS arena, the invasive strategy has held up as the best management strategy. “Hopefully we’ll start to see a move toward more patients being referred appropriately for cardiac catheterization and probably a need for more cath labs.” Final word: Interventional strategy Cannon

55. Heartbeat – Sep 2002 ESC 2002 “The dose of a given drug is almost as important as the drug itself.” We need to make sure we are dosing appropriately in our practice. It’s not just enough to be on the right drug, the dose must be the right dose. Final word: Dose Cannon

56. Heartbeat – Sep 2002 ESC 2002 Final word: 3 lessons 1: We need clinical trials: more and more important at meetings. 2: If you do trials, you need to do them right: dosing, logistics, understand the biology. 3: Care moves forward: We have a responsibility to take the information and apply it to real-world practice. Ferguson

57. Heartbeat – Sep 2002 ESC 2002 ESC 2002: End 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