1. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 REVERSAL Effects of atorvastatin vs pravastatin on atherosclerosis progression ApoA-1 Milano Effect of an HDL mimic on atherosclerosis progression Topics

3. Heartbeat – Dec 2003 AHA 2003 REVERSing Atherosclerosis with Lipitor REVERSAL

4. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 OutcomePravastatin (n=249) Atorvastatin (n=253) p Final LDL level 11079<0.001 % change in atheroma volume +2.7 (progression) -0.4 (no change) 0.02 REVERSAL: Results AHA 2003

6. Heartbeat – Dec 2003 AHA 2003 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 of atorvastatin? Fuster

7. Heartbeat – Dec 2003 AHA 2003 REVERSAL: Lowering LDL Nissen 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."

8. Heartbeat – Dec 2003 AHA 2003 REVERSAL: How low? ATP III guidelines: Levels of LDL should be below 100 TNT, SEARCH, IDEAL Address the issue of how low to go REVERSAL First study to test this question "The results, in my opinion, look very promising." Grundy

9. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 REVERSAL: Cholesterol reduction p<0.0001

11. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 REVERSAL: Adverse events

13. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 End pointPravastatinAtorvastatinp % change in atheroma volume +2.7-0.40.2 Change in total atheroma volume +4.4-0.90.02 Change in % obstructive volume 1.60.20.0002 REVERSAL: End points AHA 2003

15. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 REVERSAL: Subgroups

18. Heartbeat – Dec 2003 AHA 2003 REVERSAL: Diabetics Patients with diabetes 95 Patients with metabolic204 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 REVERSAL summary: Nissen 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."

24. Heartbeat – Dec 2003 AHA 2003 Effect of recombinant ApoA-1 Milano on atherosclerosis in ACS patients

25. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 OutcomeCombined ETC- 216 groups Placebo Mean change in atheroma volume (%) -1.06+0.14 Mean change in total atheroma volume (mm 3 ) -14.1-2.9 Mean change in maximum atheroma thickness (mm) -0.042-0.008 ApoA-1 Milano: Results AHA 2003

28. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 ApoA-1 Milano: End points Different calculations of the primary end point in the two trials Agent% change in total atheroma volume Pravastatin+2.7 Atorvastatin-0.4 ApoA-1 Milano-4.2

31. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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 Fuster Injection of human HDL into rabbits Disappearance of the macrophage after four weeks

33. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 ApoA-1 Milano: Added to statin therapy The agent would have to be given on top of a statin Grundy REVERSAL We 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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. Heartbeat – Dec 2003 AHA 2003 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