1. Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

2. Christopher P. Cannon, MD Senior Investigator, TIMI Study Group Cardiovascular Division Brigham and Women's Hospital Associate Professor of Medicine Harvard Medical School Boston, MA LDL or HDL: Which is More Important?

3. LDL or HDL: Which is More Important? Christopher Cannon, M.D. Senior Investigator, TIMI Study Group Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA

4. The Case for LDL

5. CHD Event Rates in Secondary Prevention and ACS Trials Updated from - O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6. y = 0.1629x · 4.6776 R² = 0.9029 p < 0.0001 LDL Cholesterol (mg/dl) CHD Events (%) PROVE-IT-PR PROVE-IT-AT CARE-S LIPID-S HPS-S 4S-S HPS-P CARE-P LIPID-P 4S-P 0 5 10 15 20 25 30 507090110130150170190210 TNT 80 TNT 10A2Z 80 A2Z 20 IDEAL S20/40 IDEAL A80

6. Cholesterol Trialist Collaboration Meta-Analysis of Dyslipidemia Trials Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78 Major Vascular Events 0.5 1.0 1.5 2.0 Reduction in LDL Cholesterol (mmol/L) Proportional Reduction in Event Rate (SE) TNT IDEAL 50% 40% 30% 20% 10% 0% -10%

7. High-dose betterHigh-dose worse Odds Reduction Event Rates No./Total (%) High DoseStd Dose -17% 147/2099 (7.0) 172/2063 (8.3) -15% 205/2265 (9.1) 235/2232 (10.5) -21% 334/4995 (6.7) 418/5006 (8.3) -12% 411/4439 (9.3) 463/4449 (10.4) -16% 1097/13798 (8.0) 1288/13750 (9.4) 0.65845111.51872 OR, 0.84 95% CI, 0.77-0.91 p=0.00003 Odds Ratio (95% CI) Meta-Analysis of Intensive Statin Therapy Coronary Death or MI Cannon CP, et al. PROVE IT-TIMI 22 A-to-Z TNT IDEAL Total

8. High-dose statin betterHigh-dose statin worse Odds Reduction Event Rates No./Total (%) High DoseStd Dose -16% 3972/13798 (28.8) 4445/13750 (32.3) -16% 1097/13798 (8.0) 1288/13750 (9.4) -12% 462/13798 (3.3) 520/13750 (3.8) +3% 340/13798 (2.5) 331/13750 (2.4) -6% 808/13798 (5.9) 857/13750 (6.2) -18% 316/13798 (2.3) 381/13750 (2.8) Coronary Death or Any Cardiovascular Event Coronary Death or MI Cardiovascular Death Non-Cardiovascular Death Total Mortality Stroke 0.512.5 OR 0.82 p=0.012 Odds Ratio (95% CI) Meta-Analysis of Intensive Statin Therapy Cannon CP, et al. OR, 0.94 P=0.20 OR, 1.03 p=0.73 OR, 0.88 p=.054 OR, 0.84 p=0.00003 OR, 0.84 p<0.000001 Cannon CP, et al. JACC 2006; 48: 438 - 445. slides available www.timi.org - TIMI Librarywww.timi.org

9. Odds ratio 0.5 1 3.0 Study (n) Treatment Achieved LDL (mg/dl) Odds ratio (95% CI) 0.74 (0.58,0.94) TNT (10,001) Atorvastatin 80 77 0.72 (0.52,0.98) A to Z (4497) Simvastatin 80 63 0.54 (0.34,0.85) PROVE-IT (4162) Atorvastatin 80 62 0.80 (0.61,1.05) IDEAL (8888) Atorvastatin 80 81 0.73 (0.63,0.84), p<0.001 Overall (95% CI) Intensive statin therapy better Moderate statin therapy better Atorvastatin 10 101 Simvastatin 20 77 Pravastatin 40 95 Simvastatin 20 104 Intensive Moderate Scirica BM, et al. AHA 2005 Meta-Analysis of Intensive Statin Therapy CHF

10. Meta-Analysis of Intensive Statin Therapy in ACS Any Cardiovascular Event HR (95% Cl) Hulten E, et al. Arch Intern Med. 2006;166:1814-1821 1.02 (0.95-1.09) 0.84 (0.72-1.02) 0.76 (0.70-0.84) 0.80 (0.76-0.84) 0.81 (0.77-0.87) 0.84 (0.76-0.94)

11. Month 4 LDL and Long-Term Risk of Death or Major CV Event *Adjusted for age, gender, DM, prior MI, baseline LDL Wiviott SD, et al. JACC. 2005 0.80 (0.59, 1.07) 0.67 (0.50, 0.92) 0.61 (0.40, 0.91) Hazard Ratio Lower BetterHigher Better Referent 012 <40 > 40 - 60 >60 - 80 >80 - 100 Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-1416.

12. Screening P < 0.0001* P < 0.01* P < 0.0001* P < 0.05* *P-value for trend across LDL-C Major CV Events Across Quintiles of Achieved LDL LaRosa JC. AHA. 2005 % patients

13. Nissen et al JAMA 2004

14. Recent Coronary IVUS Progression Trials -1.2 -0.6 0 0.6 1.2 1.8 5060708090100110120 Median Change In Percent Atheroma Volume (%) Mean Low-Density Lipoprotein Cholesterol (mg/dL) REVERSAL pravastatin REVERSAL atorvastatin CAMELOT placebo A-Plus placebo ACTIVATE placebo Relationship between LDL-C and Progression Rate ASTEROID rosuvastatin r 2 = 0.95 p<0.001 Nissen S. JAMA 2006

15. The Statin Decade: For LDL: “Lower is Better” R² = 0.9029 p < 0.0001 LDL Cholesterol (mg/dl) CHD Events (%) Adapted and Updated from O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6. 30 50 70 90 110 130 150 170 190 210 4S CARE LIPID HPS PROVE IT –TIMI 22 IMPROVE IT 66 52 TNT

16. Lipid Management Goal LDL-C should be less than 100 mg/dL Further reduction to LDL-C to < 70 mg/dL is reasonable *Non-HDL-C = total cholesterol minus HDL-C If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL*

17. Subgroups: Reduction in All-Cause Mortality or Major CV Events All p interaction = NS except as noted Age > 65 Age < 65 Male Female 0.50.751.01.251.5 Diabetes No Diabetes 2 Year Events Atorva 80 Prava40 23.0%26.2% 20.3%27.0% 28.8%34.6% 21.0%24.6% 28.1%29.5% 20.1%25.0% 27.5%28.9% 20.6%25.5% 21.7% 26.7% 23.1% 26.0% 20.1% 28.2% 23.5% 25.6% Prior Statin No Prior Statin Atorvastatin 80 mg BetterPravastatin 40 mg Better LDL-C < 125 LDL-C > 125 HDL-C < 40 HDL-C > 40 % of Pts 7822 1882 30 70 25 75 44 56 27 73

18. The Case for HDL

20. Frequency of Low HDL-C in Men With Premature CHD Risk factor Controls Cases (n = 601) (n = 321) Cigarette smoking 29% 67%* HDL-C  35 mg/dL 19% 57%* Hypertension 21% 41%* LDL-C  160 mg/dL 26% 34%* Diabetes mellitus 1% 12%* *Significantly different from controls (P < 0.001) Genest JJ et al. Am J Cardiol 1991;67:1185–1189

21. Low HDL-C is a Risk Factor for CHD Even When LDL-C Levels are Well Controlled LDL (mg/dL) HDL (mg/dL) Risk of CHD After 4 Yrs Am J Med 1977;62:707-714

22. Low HDL-C is a Predictor of Coronary Events in Statin Treated Patients Adapted from Ballantyne CM et al. Circulation 1999;99:736-743. Coronary Events (%)  1.1 42 < 0.9 35  1.35 52  0.99 38  1.0 39  1.0 39  1.26 44  0.75 33 mmol/Lmg/dl 0 5 10 15 20 25 30 35 4SLIPIDCAREHPS HDL-C (mg/dl) StatinPlacebo

23. On treatment HDL-C (mg/dL) Barter et al. ACC 2006. Abstract 914-203. Major Cardiovascular Events % Mean LDL-C 73 mg/dL Mean LDL-C 99 mg/dL “On-treatment” HDL-C Predicts Cardiovascular Events: TNT

24. Coronary Drug Project Long-term efficacy and safety of five lipid-influencing drugs –Niacin, clofibrate, dextrothyroxine, and two estrogen regimens 8,341 men (aged 30–64 y) with previous MI Initial study conducted between 1966 and 1975 (mean follow-up: 6.2 y) At end of study, 6,008 survivors followed for additional mean 8.8 y Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255

25. Coronary Drug Project Long-Term Mortality Benefit of Niacin in Post-MI Patients Niacin Placebo P = 0.0012 100 90 80 70 60 50 40 30 20 10 0 2 4 6 8 12 14 16 Years of follow-up Survival (%) Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255

26. Vascular Dz. Age >45 years Atherogenic Dyslipidemia (HDL 149; LDL<160) Simvastatin Simvastatin + niaspan 3-5 yr 3300 patients from 60 sites (U.S. and Canada CV Death NFMI Stroke ACS AIM-HIGH Study Overview LDL-C target <80 mg/dl both groups (may add ezetimibe if needed) Hypothesis -30% event rate with Simva -23% event rate with simva-nia - 50% relative reduction based on ~46% placebo rate 2 year enrollment

27. Clinical Trial Results. org Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis: Study Design  Primary Endpoint: Relationship between changes in LDL-C and HDL-C levels and atheroma burden.  Primary Endpoint: Relationship between changes in LDL-C and HDL-C levels and atheroma burden. REVERSAL n=502 REVERSAL n=502 1455 patients from 4 trials (REVERSAL, CAMELOT, ACTIVATE, ASTEROID) with CAD undergoing serial intravascular ultrasonography while receiving statin treatment. Post-hoc analysis of raw data from the four prospective, randomized trials. Follow-up at 18 or 24 months. Exclusion criteria: Target segment selected was required to have no greater than 50% lumen narrowing for a length of at least 30 mm and target vessel required to have not previously undergone percutaneous coronary intervention. 1455 patients from 4 trials (REVERSAL, CAMELOT, ACTIVATE, ASTEROID) with CAD undergoing serial intravascular ultrasonography while receiving statin treatment. Post-hoc analysis of raw data from the four prospective, randomized trials. Follow-up at 18 or 24 months. Exclusion criteria: Target segment selected was required to have no greater than 50% lumen narrowing for a length of at least 30 mm and target vessel required to have not previously undergone percutaneous coronary intervention. 18 or 24 mos. follow-up CAMELOT n=240 CAMELOT n=240 ACTIVATE n=364 ACTIVATE n=364 ASTEROID n=349 ASTEROID n=349 Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508.

28. Clinical Trial Results. org Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis: Study Design Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508.

29. The Case for HDL Many patients have low HDL Low HDL-C is a major predictor of CV events (even with low LDL-C) Niacin worked in large outcomes trial

30. Kaplan-Meier Estimates by TG Quintiles between 30 d and 2 yr follow-up Miller M AHA 2006

31. Triple Goal: Hazard of death, MI and recurrent ACS with number of goals achieved based on LDL-C (< 70 mg/dL), CRP (< 2 mg/L) & TG (< 150 mg/dL) Miller M AHA 2006

32. LDL > 70 mg/dL, CRP >2 mg/L Clinical Relevance of Achieved LDL and CRP Post Statin Therapy Treatment Ridker PM, et al. N Engl J Med. 2005;352:20-28.

33. CRP < 2 and LDL< 70 N = 659 CRP <2 and LDL ≥ 70 N = 1140 CRP ≥ 2 and LDL ≥ 70 N = 1244 CRP ≥ 2 and LDL < 70 N = 500 Figure 4 Cumulative probability of death or MI (%) Follow-up after Month 4 (days) Achieved CRP and LDL vs. Outcomes Morrow JACC 2006

34. % US CVD Patients Cardiomonitor: Trends in LDL Levels in Acute Coronary Syndrome Patients

35. Cardiomonitor 4,676 U.S. outpatients with CVD from 250 primary care physicians and 50 cardiologists

36. Conclusion In 2007: LDL > HDL In 2007: LDL > HDL But Both are important Both are important (as well as Trig, and BP, gluc…) (as well as Trig, and BP, gluc…) We need to do better on implementation We need to do better on implementation

37. Question&Answer

38. Thank You! Please make sure to hand in your evaluation and pick up a ClinicalTrialResults.org flash drive