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AHA 2003: Tackling LDL and HDL for atheroma regression

AHA 2003: Tackling LDL and HDL for atheroma regression. Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Steve Nissen MD Professor of Medicine Cleveland Clinic Foundation Cleveland, OH Scott Grundy MD

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AHA 2003: Tackling LDL and HDL for atheroma regression

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  1. AHA 2003: Tackling LDL and HDL for atheroma regression Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Steve Nissen MD Professor of Medicine Cleveland Clinic Foundation Cleveland, OH Scott Grundy MD Director, Center for Human Nutrition UT Southwestern Medical Center Dallas, TX

  2. Topics REVERSALEffects of atorvastatin vs pravastatin on atherosclerosis progression ApoA-1 Milano Effect of an HDL mimic on atherosclerosis progression

  3. REVERSing Atherosclerosis with Lipitor REVERSAL

  4. REVERSAL: Design • 654 patients randomized at 24 US centers, with indication for atherosclerotic disease, stenosis of >20%, and LDL levels between 125 and 210 mg/dL • Intensive atorvastatin (80 mg daily) vs moderate pravastatin (40 mg daily) therapy • Primary end point: percent change in coronary plaque volume, as measured by IVUS between baseline and 18 months

  5. REVERSAL: Results AHA 2003

  6. REVERSAL: Type of statin • Pravastatin: • 40 mg/day is the highest dose approved by the FDA • This was not the ideal dose to use to compare effects on the lipid profile • Why did you not compare two • different dosages ofatorvastatin? Fuster

  7. REVERSAL: Lowering LDL Question: Does lowering LDL below target levels have a measurable effect on atherosclerosis progression rate? Objective in REVERSAL: Group 1 with LDL around 100, group 2 with much lower LDL levels "It was really designed as an 'is-lower-better?' trial." Nissen

  8. REVERSAL: How low? ATP III guidelines:Levels of LDL should be below 100 TNT, SEARCH, IDEALAddress the issue of how low to go REVERSALFirst study to test this question "The results, in my opinion, look very promising." Grundy

  9. REVERSAL: Surprised • In the pravastatin group, 176 patients had LDL <100, with a mean LDL of 88 • They still showed highly significant progression • Different progression rates for every LDL level between groups • "We were very surprised by this outcome." Nissen

  10. REVERSAL: Cholesterol reduction p<0.0001 p<0.0001 AHA 2003

  11. Baseline LDL: 150 • Slightly higher than normal (135-140) • Average LDL reductions of 30% were right on target • "Those results were totally • predictable." Grundy

  12. REVERSAL: Adverse events AHA 2003

  13. REVERSAL: IVUS • Plaque volume measured by IVUS showed high person-to-person variability. • How accurate is this technique? Fuster • It's not so much the technique, but the biology of the disease • Incredibly dynamic • Patients with large increases, others with decreases in atheroma volume Nissen

  14. REVERSAL: End points AHA 2003

  15. REVERSAL: Impact Despite the significant results, the impact was very small, with only 18 months of follow-up Fuster Angiographic trials: Small plaque changes did correlate with changes in clinical end points IVUS: It is not known whether small changes can predict clinical events Grundy

  16. REVERSAL: Plaque changes • Perhaps other changes in the plaque • occurred, which IVUS was unable to • detect • Changes in plaque composition Fuster • Plaque composition cannot easily be measured by IVUS • The study showed a huge range of changes, with a 40% to 50% decrease in some patients • Nissen

  17. REVERSAL: Subgroups AHA 2003

  18. REVERSAL: Diabetics • Patients with diabetes 95 • Patients with metabolic 204 syndrome • Most important change in percentage of atheroma in diabetic patients • Multivariate analysis to understand the drivers of progression vs regression • Diabetics have more inherent underlying progression and need more aggressive treatment • Nissen

  19. REVERSAL: Pravastatin • "I was pretty surprised at how poorly the pravastatin group did." • Progression in patients in all 22 prespecified subgroups • More intensively treated patients had all the advantages Nissen

  20. REVERSAL: Waiting for definite answers • Dose of pravastatin never increased Fuster • Only about 3% additional LDL lowering with 80-mg pravastatin • "This was not an events trial." • We will know more when TNT, SEARCH, and IDEAL will come out • "REVERSAL tells us what we're likely to see." Nissen

  21. REVERSAL summary: Fuster • "Very good news." • We have a strategy that prevents progression, at least for 18 months • Minimal changes, but over a short time period • "I wonder if over a period of a few years this will be very significant." Fuster

  22. REVERSAL summary: Grundy Aggressive LDL lowering, well below 100 "My guess: the lower the better for LDL." Some questions remain unanswered, but an important first step NCEP will evaluate existing trials and issue an updated ATP III in the next six months At completion of all new trials there will be an ATP IV Grundy

  23. REVERSAL summary: Nissen • Progression rate • 3% difference between pravastatin and atorvastatin arms • "These are not small differences, they are actually large differences that over a period of years will translate into important differences in morbidity and mortality." Nissen

  24. Effect of recombinant ApoA-1 Milanoon atherosclerosis in ACS patients

  25. ApoA-1 Milano: Background Pilot trial of recombinant apolipoprotein A-1 Milano on atherosclerosis in patients with acute coronary syndromes • Little has been done to prove that raising HDL reduces CAD risk • People in a small Italian village, with low HDL and low CAD rates, carry ApoA-1 variant: ApoA-1 Milano • Esperion Therapeutics developed agent ETC-216

  26. ApoA-1 Milano: Design • 57 patients with ACS randomized to two doses of ETC-216 (15 mg/kg or 45 mg/kg) or placebo • IVUS to assess changes in atheroma within two weeks of ACS diagnosis and after five weeks of ApoA-1 Milano treatment

  27. ApoA-1 Milano: Results AHA 2003

  28. ApoA-1 Milano: Conclusions • Some regression of atherosclerosis after five weeks of ETC-216 infusion • "Very fascinating" • HDL may halt the progression of atherosclerotic disease by helping the artery to get rid of the excess oxidized LDL Fuster

  29. ApoA-1 Milano: The HDL question • REVERSAL"Putting icing on a cake that we already have." • "This work is pioneering, because it will get into the HDL question." • HDL known to be associated with CAD • Prevention of atherosclerosis by affecting HDL has been questioned Grundy

  30. ApoA-1 Milano: End points Different calculations of the primary end point in the two trials

  31. ApoA-1 Milano: Drastic changes • "Effectively, we saw the elimination of a couple of years' worth of progression." • "We were just shocked when the statisticians delivered the data." • Large changes in big fatty plaques Nissen

  32. ApoA-1 Milano: Mechanism • HDL may halt the progression of atherosclerotic disease • ApoA-1 Milano: • Elimination of excess of oxidized LDL by macrophages • Elimination of macrophages Disappearance of the macrophage after four weeks Injection of human HDL into rabbits Fuster

  33. ApoA-1 Milano: Effects of HDL • Many mechanisms for HDL • Reversal of cholesterol transport • Anti-inflammatory agent • Interference with atherogenic lipoproteins • Study does not differentiate between these mechanisms Grundy

  34. ApoA-1 Milano: Effects of HDL • Why was the HDL low in the Italian village population? • How does ApoA-1 Milano work? • Cleared more rapidly from the circulation • Lower production rate • Less ApoA-1 getting out Grundy

  35. ApoA-1 Milano: Combination • Catabolism is certainly higher • Would we have seen the same with wild-type ApoA-1? • Animal experiments with ApoA-1 Milano by PK Shah • Nothing worked as well as the combination of ApoA-1 Milano and phospholipid Nissen

  36. ApoA-1 Milano: Statins and raising HDL • REVERSAL • Basic mechanisms of progression/regression with statin therapy • Effect on inflammatory processes with CRP • ApoA-1 Milano • Therapeutically raising HDL • Even with few patients, images show that you've accomplished something Fuster

  37. ApoA-1 Milano: Clinical trials • What could be a feasible strategy in a clinical study to raise HDL? • Early intervention in ACS patients might show immediate benefit in terms of reducing recurrent events • Takes a while for the statins to take hold Grundy

  38. ApoA-1 Milano: Type of agent • What type of agent to use in clinical trials? • ApoA-1 derivative that could be produced in large amounts • Right now such an agent cannot be extracted from humans Grundy

  39. ApoA-1 Milano: The future • The manufacturing process of ApoA-1 Milano has come a long way • "We can make enough of this to do large-scale clinical trials." • 5000-patient post-MI ACS study looking at morbidity and mortality under discussion • Phase 3 trial with the CETP inhibitor torcetrapib launched Nissen

  40. ApoA-1 Milano: Added to statin therapy The agent would have to be given on top of a statin Grundy REVERSALWe can do active-controlled trials with positive results "If one statin can produce greater benefits than another statin, a statin plus agent x has a very good chance of beating a statin alone." Nissen

  41. Final word: Fuster • REVERSAL • Lowering lipids as much as possible, even below normal, is important • Anti-inflammatory/antithrombotic aspects of statins • ApoA1-Milano • HDL as a defense mechanism • Increasing the activity of LDL Fuster

  42. Final word: Grundy • Statins can reduce CAD risk by one third, which leaves two thirds of people going to get into trouble • "These two studies are telling us that we may be able to shut down the plaques." • Reducing the frequency of syndromes, by further lowering LDL and activating the HDL system Grundy

  43. Final word: Nissen A future of intensive LDL reduction, along with activation of the HDL pathways If we hit LDL and HDL hard, we can get beyond an event reduction of 30% to 35% Next phase: using agents together will result in a 50% to 70% mortality reduction "We will treat this disorder with a cocktail of drugs, much like they treat tuberculosis or HIV." Nissen

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