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ESC 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

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ESC 2002

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  1. 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. Topics Acute coronary syndromes MAGIC OPTIMAAL RITA-3 BNP prognostics Off-pump surgery Stem cells

  3. 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. 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. 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. MAGIC: Rationale for the trial • 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. Cannon

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

  8. 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. OPTIMAAL: Results p=0.069 p=0.032 Lancet 360:752-760

  10. 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. OPTIMAAL: A Greek tragedy • 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

  12. OPTIMAAL: Misnamed • 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

  13. OPTIMAAL: Appropriate dosing • 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

  14. OPTIMAAL: ARBs • 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.” Weber

  15. 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. 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 benefitedfrom an early intervention strategy. Cannon

  17. 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. 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. RITA-3: Event rate p=0.001 14.5 p=0.58 9.6 7.6 8.3 ESC 2002

  20. RITA-3: Trial comparison ESC 2002

  21. 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. 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. RITA-3: Angina Lancet 360:743-751

  24. RITA-3: MI using standard definition Lancet 360:743-751

  25. 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. 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. 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. 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. 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. 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. 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. 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. BNP: Two patients Myocardial infarction EF = 35% Dilated cardiomyopathy EF = 35%

  34. BNP: Two patients • 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. Weber

  35. BNP: AMI • 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.” Cannon

  36. 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. 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. 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. Off-pump CABG: Suboptimal patency • 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.” Cannon

  40. 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. Off-pump CABG: Experience • 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.” Weber

  42. Stem cells: Mode of delivery SYLVAIN’s PIC

  43. Stem cells: Ventricular function *Percentage of hypokinetic, akinetic, or dyskinetic regions Strauer BE et al. Circulation 2002

  44. Stem cells: New cardiomyocytes Stromal-mesenchymalpathway Bone marrow Pluripotent cells Skeletal muscle, cardiomyocytes

  45. 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. Stem cells: A new hope • “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.” Cannon

  47. 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. 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. 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. 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

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