1. Aggressive Therapy for Hypercholesterolemia: Data, Strategy and Outcomes Timothy A. Denton, M.D. High Desert Heart Institute Victorville, CA

4. Can you identify these?

5. VLDL B100 CI CII CIII E IDL B100 E LDL B100 Chylomicrons B100 CI CII CIII E AI AII AIV B48 Remnants B48 E HDL2 AI AII AI AII HDL3 HDL1 AI AII

6. Standard Approach to LDL Management Event Diet Exercise DietDrugs 6 months

7. A Probabilistic Equation P(success | overall population) = P(success | ideal population) * P(compliance | overall population)

8. 1 - Diet 2 - Exercise 3 - Drugs 4 - Partial ileal bypass 5 - Portacaval shunting 6 - Apheresis adsorption column (LDL apheresis) plasma exchange double membrane dextran sulfate precipitation immunoabsorption 7 - Liver transplantation Methods for Modifying Cholesterol Levels

9. Diet

10. Ornish D, et al. Lancet 1990;336:129 Lifestyle Heart Trial

11. Ornish D, et al. Lancet 1990;336:129 Lifestyle Heart Trial

12. Ornish D, et al. Lancet 1990;336:129 Lifestyle Heart Trial Intervention group LDL after 1 year Mean = 93 mg/dl + 43 mg/dl NCEP Goal 55.3% 44.7%

13. Biosphere

14. Biosphere 2 “Isolated, confined environment”, 2 years 8 subjects Green and yellow vegetables Animal products of 1 egg, 112 g of meat, 500 cc of goat milk per WEEK All had consistent weight loss for 2 years Blood samples q 1-2 months Verdery, et al. Arch Intern Med 1998;158:900 Biosphere2 Dietary Restriction

15. Verdery, et al. Arch Intern Med 1998;158:900 Biosphere2 Dietary Restriction

16. Mean = 58 + 7 mg/dl LDL after 2 years NCEP Goal Verdery, et al. Arch Intern Med 1998;158:900 Biosphere2 Dietary Restriction 100% 0%

17. Dietary “Success”

18. Exercise

19. Effect of Fitness on Survival Blair JAMA 1989;262:2395

20. Effect of Fitness on Survival Blair JAMA 1989;262:2395

21. Sesso et al. Circ 2000;102:975-980 Harvard Alumni Health Study 4.2 kJ = 1 kcal 500 Cal 500-1000 Cal1000-2000 Cal2000-3000 Cal >3000 Cal

22. Effect of Exercise on Lipids Kokkinos Arch Int Med 1995:155:415  2906 men  age 30-64 years  exercise treadmill test to exhaustion  classified into 6 groups based on average miles run per week

23. Effect of Exercise on Lipids Kokkinos Arch Int Med 1995:155:415

24. Mean = 121 + 29 mg/dl NCEP Goal Verdery, et al. Arch Intern Med 1998;158:900 Running 21-60 Miles per Week 22.9% 77.1%

25. Cholesterol-Lowering Drugs

26. Cholesterol Modifying Agents

27. Achievement of NCEP Goal Brown, JACC 1998; 32:665 atorva = atorvastatin (Lipitor) simva = simvastatin (Zocor) lova = lovastatin (Mevacor) fluva = fluvastatin (Lescol) colest = colestipol (Colestid)

28. Achievement of NCEP Goal Brown, JACC 1998; 32:665 P=NS

29. Statins Jones et al. Am J Cardiol2003;92:152 Prava Simva Atorv Rosuva

30. Lancet 1994;344:1383 4S Survival Curves

31. MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) 122 centers -- Europe, North America, South Africa, Australasia adults with chest pain x15 min exclusion coronary revascularization planned cholesterol >270 mg% Q-wave MI 3 months CABG, 6 months PTCA, 4 weeks MI LBBB, CHF III, other drugs, DM, preg Schwartz JAMA 2001;285:1711

32. MIRACL P=0.048 Schwartz JAMA 2001;285:1711 Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Ischemic events

33. MIRACL P=0.02 Schwartz JAMA 2001;285:1711 Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering CVA

34. Pitt, B. et al. N Engl J Med 1999;341:70-76 Cumulative Incidence of First Ischemic Events 341 pts CCS 0,I PTCA vs MedRx

35. REVERSAL P=0.02 Nissen JAMA 2004;291:1071 Reversal of Atherosclerosis with Aggressive Lipid Lowering DB Random atorv v. prava (79 v. 110) IV US Atheroma vol

36. ASCOTT-LLA P=0.0005 Nissen JAMA 2004;291:1071 Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm 19,342 HTN + 3 RF Tchol < 250 Atorva v placebo trial stopped 3.3 yrs P=0.024 P=0.0005 P=0.16

37. ACCESS Smith Phamacoeconomics 2003;21:13 Atorvastatin Comparative Cholesterol Efficacy and Safety Study 3,387 54 weeks Atorva, fluva, lova, prava, simva titrate to LDL < 100 Drug Total Cost to Goal Atorva683.37 fluva+211.35 lova+607.96 Prava+424.60 simva+95.74

38. Baycol (cerivastatin) 12/1/2000 -- FDA approves 0.8 mg 3/30/2001 -- FDA warning about metabolism 8/1/01 -- 31 US deaths, 19 lone drug, 12 in combination 8/8/2001 -- Bayer removes Baycol from US Market

39. When should we START therapy?

40. CHAMP Fonarow, AJC 2001;87:819 (Cardiac Hospitalization Atherosclerosis Management Program) UCLA Observational / Interventional AHA Guidelines Standard orders, education, DC planning Phone follow-up

41. CHAMP Fonarow, AJC 2001;87:819

42. CHAMP

43. When should we START therapy? AS SOON AS POSSIBLE!!!!

44. But my hospitalized patient’s LDL is at goal.

45. Brugada, Cardiology 1996;87:194 Original paper reports total cholesterol Converted to LDL by assuming LDL = 0.67 * total cholesterol

46. But my hospitalized patient’s LDL is at goal. Not for long…

47. Aggressive Approach to LDL Management Event Drug therapy Diet Exercise X

48. The Guidelines

49. How often do we provide these therapies?

50. State Standings Jencks et al. JAMA 2000;284:1670 Ranked by CV indicators, mammog, immune, etc

51. Effects of Various Cardiac Therapies

54. The End