1. How Aggressive do we get on Lipids? Christopher Cannon, M.D. Senior Investigator, TIMI Study Group Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA

2. 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

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

4. 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

5. 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 95% CI, 0.71-0.96 p=0.012 Odds Ratio (95% CI) Meta-Analysis of Intensive Statin Therapy All Endpoints Cannon CP, et al. OR, 0.94 95% CI, 0.85-1.04 P=0.20 OR, 1.03 95% CI, 0.88-1.20 p=0.73 OR, 0.88 95% CI, 0.78-1.00 p=.054 OR, 0.84 95% CI, 0.77-0.91 p=0.00003 OR, 0.84 95% CI, 0.80-0.89 p<0.0001 Cannon CP, et al. JACC 2006; 48: 438 - 445.

6. 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

7. 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)

8. ACS Patients: Major Coronary Events MI + CHD Death + Resuscitated Cardiac Arrest Years Since Randomization Cumulative Hazard (%) 012345 0 4 8 12 16 20 HR =.66 (95% CI = 0.46, 0.95), P=.02 34% RRR Simvastatin Atorvastatin Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006

9. 20 40 30 0 10 030 months5 years Summary: 5 Years Of Follow-Up In IDEAL Is The Longest Period Of Follow-Up Of ACS Patients On Statin Therapy Cardiac Event (%) 50 60 Atorvastatin 80 mg Pravastatin 40 mg Simvastatin 20-40 mg 16% RRR P=0.005 PROVE IT MI or UA 18% RRR P=0.04 IDEAL All MI Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006

10. 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.

11. 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

12. 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

13. ASA + Standard Medical Therapy Simvastatin 40 mg* Vytorin 10/40 mg* Duration: Minimum 2 1/2 year follow-up (>2955 events) Primary Endpoint: CV Death, MI, Hospital Admission for UA, revascularization (> 30 days after randomization), or Stroke Study Design Double-blind Patients stabilized post Acute Coronary Syndrome < 10 days LDL < 125 mg/dL (or < 100 mg/dL if prior statin) N=10,000 Follow-Up Visit Day 30, Every 4 Months *uptitrated to 80mg if LDL>79

14. LDL > 70 mg/dL, CRP > 2 mg/L Clinical Relevance of Achieved LDL and Achieved CRP After Treatment with Statin Therapy Ridker PM. NEJM 2005;352:20-28

15. 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

16. Death/MI/UA post-month 4, by Month 4 Apo-B/Apo-A ratio Death/MI/UA post-month 4, by Month 4 Apo-B/Apo-A ratio Month 4 Apo-B/Apo-A Ratio Endpoint Probability 0.40.60.81.0 0.06 0.08 0.10 0.12 0.14 Combined

17. Month 4 Apo-B/Apo-A Ratio Endpoint Probability 0.40.60.8 1.0 0.06 0.08 0.10 0.12 0.14 CRP<2 CRP>=2 Ray AHA 05 The long term clinical risk of Apo B/AI can be further discriminated by achieved CRP levels

18. Median Achieved hsCRP hsCRP mg/dl 0 1 2 3 1 mo 4 mo 8 mo p = NS p < 0.001 Placebo  Simva 20 Simva 40  Simva 80 A to Z p < 0.001 hsCRP mg/dl 0 1 2 3 1 mo 4 mo 2 yrs p < 0.001 Prava 40 Atorva 80 PROVE IT

19. 051015202530 0 1 2 3 4 5 Pravastatin 40 mg Atorvastatin 80 mg Hazard ratio = 0.72 (CI 0.52,0.99) P=0.046 Days following randomization % of patients with death, MI or,rehospitalization for ACS Death, MI or ACS Rehospitalization (Early Phase) KK Ray et al. JACC Oct. 2005 (in press)

20. What Factors are Associated with Elevated CRP levels? Age (years)1.01<0.0001 Female on HRT vs Male2.4<0.0001 Female not on HRT vs Male1.5<0.0001 Current Smoker 1.5<0.0001 BMI >25 kg/m 2 1.4<0.0001 HDLC <50mg/dl 1.2 0.0001 LDL  70 mg/dl 1.2 0.0003 Glucose >110 mg/dl 1.2 0.0009 Clinical Event Pre-month 41.4 0.0027 Trig >150 mg/dl 1.1 0.003 Atorvastatin 80mg0.7 <0.0001

21. Achieved CRP on Statin Therapy vs. Number of Risk Factors Risk factors 1) BMI > 25 2) Current smoker 3) HDL <50 4) TG > 150 5) Glucose >110 6) BP > 130/85 7) LDL >70 P trend <0.0001 for each KK Ray et al. JACC 2005

22. Kaplan-Meier Estimates based on LDL-C < 70 mg/dL or TG < 150 mg/dL between 30 d and 2 yr follow-up Miller M AHA 2006

23. 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

25. Risk CategoryLDL-C GoalInitiate TLC Consider Drug Therapy Very High risk: ACS, or CHD w/ DM,mult CRF <70 mg/dL  70 mg/dL > 70 mg/dL High risk: CHD or CHD risk equivalents (10-year risk >20%) If LDL <100 mg/dl <100 mg/dL (optional goal: <70 mg/dL) Goal <70 mg/dl  100 mg/dL > 100 mg/dL (<100 mg/dL: consider drug Rx) Moderately high risk: 2+ risk factors (10-year risk 10% to 20%) <100 mg/dL  130 mg/dL > 130 mg/dL (100-129 mg/dL: consider drug Rx) Moderate risk: 2+ risk factors ( risk <10%) <130 mg/dL  130 mg/dL > 160 mg/dL Lower risk: 0-1 risk factor <160 mg/dL  160 mg/dL >190 mg/dL ATP III Update 2004: LDL-C Goals and Cutpoints for Therapy in Different Risk Categories Adapted from Grundy, S. et al., Circulation 2004;110:227-39.

26. Vytorin (Ezetimibe + Simvastatin) Greater LDL Reduction at Each Dose Simva 80 mg (n=67) Ezetimibe + Simva 80 mg (n=65) Simva 40 mg (n=65) Ezetimibe + Simva 40 mg (n=73) Simva 20 mg (n=61) Ezetimibe + Simva 20 mg (n=69) Simva 10 mg (n=70) Ezetimibe + Simva 10 mg (n=67) Mean % Change in LDL-C From Untreated Baseline simvastatinVytorin (ezetimibe +simvastatin) P  0.01 for Vytorin vs. simvastatin for each comparison Source: Vytorin package insert

27. Vytorin Reduces CRP More than Simvastatin at Each Dose 10 mg20 mg40 mg80 mg Sager PT, Atherosclerosis 2005;179:361-7 * p < 0.01 # p = 0.03 872 patients with LDL 145-250 enrolled in 2 RCTs

28. Conclusions: Early Benefit of Intensive Statin Therapy PROVE IT-TIMI 22 l Lower is better – LDL – CRP – Triglycerides l “Dual goal” and “triple goal” with statins Lower LDL and CRP and Trig, and probably HDL l Dual and triple therapy is frequently needed to achieve dual and triple goals (and probably) higher is better for HDL