1. IDEAL: Incremental Decrease In End Points Through Aggressive Lipid Lowering The IDEAL Steering Committee And Investigators

2. Background

3. 2 CVD: A Major Global Health Issue CHD and stroke are two major components of CVD 16.7 million worldwide die each year from CVD CVD affects 34.2% of US population Elevated plasma lipids are one of the most prevalent risk factors for CVD American Heart Association. Heart Disease and Stroke Statistics - 2005 Update. Available at: http://www.americanheart.org/downloadable/heart/1105390918119HDSStats2005Update.pdf. Accessed 11/9/05. World Health Organization. The Atlas of Heart Disease and Stroke. Available at: http://www.who.int/cardiovascular_diseases/resources/atlas/en/. Accessed 11/3/05.

4. 3 Although CVD-Related Deaths Remain High, the CVD-Related Death Rate Is Decreasing NCEP ATP I NCEP ATP II 1st Statin Introduced Year US 1979-2002 0 200 400 600 800 1000 1200 197919801981198219831984198519861987198819891990199119921993199419951996199719981999200020012002 Annual CVD Deaths x1000 (bar) 0 100 200 300 400 500 600 CVD Deaths/100,000 Population (line) There are nearly 1 million CVD-related deaths each year NCEP ATP III Adapted from National Institutes of Health. Morbidity & Mortality: 2004 Chart Book on Cardiovascular, Lung, and Blood Diseases. Available at: http://www.nhlbi.nih.gov/resources/docs/04_chtbk.pdf. Accessed 11/9/05; Mevacor approval history. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed December 8, 2005; Expert Panel. Arch Intern Med. 1988;148:36–69; Expert Panel. JAMA. 1993;269:3015–3023; Expert Panel. JAMA. 2001;285:2486-2497.

5. 4 Global Economic Impact of CVD Global CVD = leading cause of mortality and disability European Union Costs = €168.9 billion for CVD in 2003, of which €45.0 billion was for treating CHD United States CVD = single greatest economic burden on health care system Costs = $393.5 billion for CVD in 2005 –Total costs for all cancers = $190 billion in 2004 American Heart Association. Heart Disease and Stroke Statistics - 2005 Update. Available at: http://www.americanheart.org/downloadable/heart/1105390918119HDSStats2005Update.pdf. Accessed 11/9/05; British Heart Foundation. Total Costs of CVD in Europe. Available at: http://www.heartstats.org/topic.asp?id=4545. Accessed 11/3/05; Bonow RO et al. Circulation. 2002;106:1602-1605.

6. 5 Elevated Cholesterol Levels Associated With High Risk of CHD Adapted from Martin MJ et al. Lancet. 1986;2:933-936, with permission. Reproduced from Castelli WP. Am J Med. 1984;76:4-12, with permission. Framingham Study (N=5209) Multiple Risk Factor Intervention Trial (MRFIT) (N=361,662) Multiple Risk Factor Intervention Trial (MRFIT) (N=361,662) Each 1% Increase in Total Cholesterol Level Associated With a 2% Increase in CHD Risk Total Cholesterol (mg/dL) 204205-234235-264265-294295 0 25 50 75 100 125 150 6-Year CHD Incidence Per 1000 Men Each 1% Reduction in Total Cholesterol Level Resulted in a 2% Decrease in CHD Risk Age-Adjusted 6-Year CHD Mortality Per 1000 Men Total Cholesterol (mg/dL) 0 2 4 6 8 10 12 14 16 18 160200260300140180220240280320

7. 6 Evolution of Guidelines Driven By Clinical Evidence NCEP ATP III 2001 NCEP Report 2004 NCEP ATP I 1988 NCEP ATP II 1994 Outcomes Trials Early Data Angiographic Trials Meta-Analyses Recent Data HPS 2002 ALLHAT 2002 PROSPER 2002 ASCOT-LLA 2003 PROVE IT 2004 CARDS 2004 Third Joint European 2003 Second Joint European 1998 First Joint European 1994 Framingham 1981 Atherosclerosis Study Group 1984 LRC-CPPT 1984 MRFIT 1986 Coronary Drug Project 1986 Helsinki Heart Study 1987 CLAS 1987 FATS 1990 POSCH 1990 Lifestyle Heart Trial 1990 STARS 1992 Holme 1990 Rossouw 1991 4S 1994 WOSCOPS 1995 CARE 1996 LIPID 1998 AFCAPS/TexCAPS 1998 VA-HIT 1999 1980s1990s2000s TNT 2005 IDEAL 2005

8. 7 Current Lipid Treatment Guidelines The Primary Focus of Treatment Guidelines Is to Reduce LDL-C Expert Panel. JAMA. 2001;285:2486-2497; Grundy SM et al. Circulation. 2004;110:227-239; De Backer G et al. Eur Heart J. 2003;24:1601-1610. NCEP Guidelines Low risk: LDL-C <160 mg/dLLow risk: LDL-C <160 mg/dL Moderate risk: LDL-C <130 mg/dL for individuals with  2 risk factorsModerate risk: LDL-C <130 mg/dL for individuals with  2 risk factors High risk: LDL-C <100 mg/dL for individuals with CHD or CHD equivalentsHigh risk: LDL-C <100 mg/dL for individuals with CHD or CHD equivalents Very high risk (optional): LDL-C <70 mg/dL for high-risk individuals (eg, those with CHD and diabetes)Very high risk (optional): LDL-C <70 mg/dL for high-risk individuals (eg, those with CHD and diabetes) European Guidelines LDL-C <100 mg/dL for at-risk individualsLDL-C <100 mg/dL for at-risk individuals <100 mg/dL for high-risk individuals (eg, those with diabetes)<100 mg/dL for high-risk individuals (eg, those with diabetes) Triglycerides: secondary target for loweringTriglycerides: secondary target for lowering HDL-C: secondary target for raisingHDL-C: secondary target for raising

9. 8 4S to IDEAL 11 Years of Landmark Statin Trials Second Wave of Trials Focus on other high-risk groupsFocus on other high-risk groups – ACS, elderly, DM, HTN Comparisons beyond placeboComparisons beyond placebo – vs usual care (ALLIANCE, ALL-HAT) – vs usual care (ALLIANCE, ALL-HAT) – active comparator (PROVE IT, A to Z) – active comparator (PROVE IT, A to Z) Early Trials Proved Relative Risk Reduction in Morbidity and Mortality vs Placebo 19944S 1995WOSCOPS 1996CARE 1998AFCAPS/TexCAPS LIPID 2001MIRACL 2002HPS PROSPER ALL-HAT LLT 2003ASCOT-LLA 2004PROVE IT ALLIANCE CARDS A to Z 2005TNT IDEAL Intensity of Statin Treatment in Stable CHD Patients Receiving Contemporary Therapy

10. 9 4S Proved 2º Prevention With Statins Could Lower Mortality and CV Events * Defined as coronary death, nonfatal definite or probable MI, silent MI, or resuscitated cardiac arrest. Reproduced from Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389, with permission. Simvastatin Placebo Proportion Alive Years Since Randomization 30% RRR P=.0003 0.80 0.85 0.90 0.95 1.00 Proportion Without Major Coronary Event Years Since Randomization 0.50 0.60 0.70 0.80 0.90 1.00 01234560123456 Simvastatin Placebo 34% RRR P=.00001 Primary End Point: Total Mortality Secondary End Point: Major Coronary Events*

11. 10 4S Left Important Questions To Be Answered By Subsequent Trials In Secondary Prevention 1994 MIRACL MIRACL PROVE IT PROVE IT A to Z A to Z Benefit of Early Start in ACS Patients (excluded in 4S) IDEAL IDEAL Evolving Standard Therapy HPS HPS TNT TNT Finding the Optimal LDL-C Target CARE CARE LIPID LIPID Confirmation of 4S Findings 1995–2005

12. 11 50 70 90 110 130 150 170 190 4SLIPIDCAREHPS Usual-Dose Statin Therapy Established As Standard for CHD Patients Regardless of Baseline LDL-C LDL-C Level at Beginning and End of Therapy (mg/dL) Simvastatin 20 mg Pravastatin 40 mg Simvastatin 40 mg *End points cited (not primary end points): 4S and TNT=CHD death, nonfatal MI, and cardiac resuscitation; LIPID, CARE, and HPS=CHD death and nonfatal MI. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357; Sacks FM et al. N Engl J Med. 1996;335:1001- 1009; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22. Statin vs Placebo Relative Risk Reduction* 34% 24% 27% Event Rate* On Statin 19.0%12.3%10.2%8.7%

13. 12 TNT Reached Lower LDL-C Levels With Intensive Therapy Relative Risk Reduction* 34% 24% 27%NA20% Event Rate* On Statin 19.0%12.3%10.2%8.7% Intensive vs Usual-Dose Lipid Lowering LDL-C Level at Beginning and End of Therapy (mg/dL) Simvastatin 20 mg Pravastatin 40 mg Simvastatin 40 mg *End points cited (not primary end points): 4S and TNT=CHD death, nonfatal MI, and cardiac resuscitation; LIPID, CARE, and HPS=CHD death and nonfatal MI. Atorvastatin is not indicated for secondary prevention of CHD. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357; Sacks FM et al. N Engl J Med. 1996;335: 1001-1009; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22; LaRosa JC et al. N Engl J Med. 2005;352:1425-1435. Statin vs Placebo 8.3%6.7% Atorvastatin 10 mg Atorvastatin 80 mg

14. 13 TNT Primary End Point: Time to First Major CV Event* 0123456 Time (years) HR = 0.78, P<.001 *CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. Atorvastatin is not indicated for secondary prevention of CHD. Reproduced from LaRosa JC et al. N Engl J Med. 2005;352:1425-1435, with permission. 0 5 10 15 Atorvastatin 10 mg Atorvastatin 80 mg Major CV Event (%) 22% RRR

15. 14 HPS HPS TNT TNT Finding the Optimal LDL-C Target CARE CARE LIPID LIPID Confirmation of 4S Findings MIRACL MIRACL PROVE IT PROVE IT A to Z A to Z Benefit of Early Start in ACS Patients (excluded in 4S) IDEAL IDEAL Evolving Standard Therapy 1994 1995–2005 4S Left Important Questions to Be Answered by Subsequent Trials In Secondary Prevention

16. 15 Study StudyIntervention Treatment Initiated Within N Follow- Up Risk Reduction (%) In 1º End Point P Value FLORIDA Fluva 80 mg vs placebo 8 days5401 year8NS PACTPrava 20/40 mg vs placebo 24 hours340830 days6.4NS A to Z Simva 40/80 mg vs placebo/simva 20 mg 5 days to 4 months 44972 years11NS MIRACL Atorva 80 mg vs placebo 24–96 hours308616 weeks16.048 PROVE ITAtorva 80 mg vs prava 40 mg 10 days4162 4 months 2 years 19 16.03.005 Of The 5 Major ACS Trials, Only MIRACL and PROVE IT Showed a Significant Benefit in Patients With ACS Atorvastatin is not indicated for secondary prevention of CHD. Liem AH et al. Eur Heart J. 2002;23:1931-1937; Thompson PL et al. Am Heart J. 2004;148:e2; de Lemos JA et al. JAMA. 2004;292:1307-1316; Schwartz GG et al. JAMA. 2001;285:1711-1718; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; Ray KK et al. Am J Cardiol. 2005;46:1405-1410.

17. 16 PROVE IT Primary End Point* All-Cause Mortality or Major CV Event *Death from any cause, MI, unstable angina, revascularization, or stroke. Atorvastatin is not indicated for secondary prevention of CHD. Reproduced from Cannon CP et al. N Engl J Med. 2004;350:1495-1504, with permission. Pravastatin 40 mg Atorvastatin 80 mg 30 0 5 10 15 20 25 36912151821242730 Months Of Follow-Up 0 HR =.84, P=.005 Death or Major CV Event (%) 16% RRR

18. 17 1994 1995–2005 HPS HPS TNT TNT Finding the Optimal LDL-C Target CARE CARE LIPID LIPID Confirmation of 4S Findings MIRACL MIRACL PROVE IT PROVE IT A to Z A to Z Benefit of Early Start in ACS Patients (excluded in 4S) IDEAL IDEAL Evolving Standard Therapy 4S Left Important Questions to Be Answered By Subsequent Trials in Secondary Prevention

19. Study Rationale

20. 19 IDEAL Begins Where 4S Left Off Simvastatin 20 mg: Titrate to achieve TC 3.0-5.2 mmol/L Placebo 188 mg/dL (4.9 mmol/L) LDL-C 4444 Patients Simvastatin 20 mg: Titrate to 40 mg for TC <4.9 mmol/L Atorvastatin 80 mg ? LDL-C 8888 Patients The Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; Pedersen TR et al. Am J Cardiol. 2004;94:720-724. 125 mg/dL 122 mg/dL No prior statin (3.2 mmol/L) ~75% on statins (3.1 mmol/L) 4SIDEAL

21. 20 The Face Of CV Risk Has Changed Since 4S Coronary atherosclerosis is changing in its clinical manifestations There appear to be fewer nonfatal MIs and coronary deaths than in the past, at least according to projections from Framingham scoring ….Improved management of established CHD results in fewer deaths Other forms of atherosclerotic CV disease now predominate and probably represent the preferred end point for clinical trial Grundy SM. J Am Coll Cardiol. 2005;46:173-175.

22. 21 Plan For 5.5-Year Follow-Up 8888 Patients Randomized Open-Label Period With Blinded End Point Evaluations Atorvastatin 80 mg/day Simvastatin 20 mg/day (titrated to 40 mg/day at week 24*) Study Design *Simvastatin dose was increased to 40 mg/day at week 24 in patients whose plasma total cholesterol remained >5.0 mmol/L (190 mg/dL) or whose LDL cholesterol remained >3.0 mmol/L (115 mg/dL). Pedersen TR et al. Am J Cardiol. 2004;94:720-724. Patient Population Enrolled at 190 sites History of MI Eligible for statin therapy 9689 screened Primary Composite End Point Major coronary event Secondary Composite End Points Major CV event Any CHD event Any CV event

23. 22 Study Eligibility Pedersen TR et al. Am J Cardiol. 2004;94:720-724. Inclusion Criteria Men and women aged  80 years History of definite MI Qualified for statin therapy Selected Exclusion Criteria TG > 600 mg/dL (6.8 mmol/L) > Simva 20 mg/day or equivalent statin dose Rx with nonstatin lipid agents Usual statin contraindications

24. From 4S To IDEAL: Comparison of Features of 2º Prevention Trials

25. 24 IDEAL: Real-World Statin Trial Used Prospective Randomized Open Blinded End-point (PROBE) study design Only statin trial with no run-in/washout phase 76% of patients receiving statins at randomization Majority on concomitant aspirin or β-blockers –reflects improved standard of care for CHD patients since 4S Pedersen TR et al. JAMA. 2005;294:2437-2445.

26. 25 IDEAL: Enrolled Older Patients With History of MI *Age breakout provided for 60 years and above. **HPS included both primary and secondary prevention patients. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; The Scandinavian Simvastatin Survival Study group. Am J Cardiol. 1993;71:393-400; Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357; Sacks FM et al. N Engl J Med. 1996;335:1001-1009; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22; LaRosa JC et al. N Engl J Med. 2005;352:1425-1435; MBC/BHF Heart Protection Study Collaborative Group. Eur Heart J. 1999;20:725-741; Pedersen TR et al. Am J Cardiol. 2004;94:720-724; Pedersen TR et al. JAMA. 2005;294:2437-2445; Waters DD et al. Am J Cardiol. 2004;93:154-158. Study Study4S(N=4444)CARE(N=4159)LIPID(N=9014)HPS(N=20,536)TNT(N=10,001)IDEAL(N=8888) Men (%)8186837581 Age range (y) % >65 35-70 23 21-75 51* 31-75 39 40-80 46** 35-75 37  80 43 History of MI (%)79100644158100

27. 26 IDEAL: Baseline Characteristics Reflect Improvement in Care Since 4S Study 4S 1994 (N=4444)CARE1996(N=4159)LIPID1998(N=9014)HPS2002(N=20,536)TNT2005(N=10,001)IDEAL2005(N=8888) Concomitant medications (%) Aspirin3783 638879 β-blocker574147265575 Calcium antagonist314036–2619 Revascularization (%)85441–8640 LDL-C (mg/dL)18813915013298122 Statin use (%)000057~76 Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357; Sacks FM et al. N Engl J Med. 1996;335:1001-1009; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22; LaRosa JC et al. N Engl J Med. 2005;352:1425-1435; McGowan MP et al. Circulation. 2004;110:2333-2335; Pedersen TR et al. JAMA. 2005;294:2437-2445; Waters DD et al. Am J Cardiol. 2004;93:154-158. Simvastatin50% Atorvastatin11% Pravastatin10% Others4% Simvastatin50% Atorvastatin11% Pravastatin10% Others4%

28. Baseline Characteristics

29. 28 Evaluation Groups 9689 Screened 801 Excluded* 8888 Randomized 4449 Assigned to Simvastatin 20 mg 4439 Assigned to Atorvastatin 80 mg 4427 Followed for End Points Through End of Study 3 Withdrew Consent, Vital Status Unknown † 2 Lost to Follow-Up ‡ 4407 Followed for End Points Through End of Study 10 Withdrew Consent, Vital Status Unknown † 4 Lost to Follow-Up ‡ *801 excluded: 416 met exclusion criteria, 246 unwilling to participate, 14 lost to follow-up, 125 other. † 13 patients (0.1%) withdrew consent prior to study close-out, vital status unknown; ‡ 6 patients (0.1%) lost to follow-up prior to study close-out. Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.

30. 29 Baseline Characteristics Atorvastatin (N=4439) Simvastatin (N=4449) Age, y61.861.6 Male81 CABG/PCI3940 Heart failure76 Smoker2021 Hypertension33 Diabetes12 % Of Patients Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.

31. 30 Baseline Characteristics CV History Atorvastatin (N=4439) Simvastatin (N=4449) Cardiovascular history More than 1 previous MI16.617.0 Months since last MI ≤ 211.111.4 Coronary angioplasty only19.919.7 Coronary bypass only16.516.8 Both angioplasty and bypass2.93.7 Cerebrovascular disease8.08.5 Peripheral vascular disease4.14.4 Congestive heart failure6.65.5 Atrial fibrillation or flutter7.87.6 % Of Patients Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.

32. 31 Concomitant CV Medications at Baseline Atorvastatin (N=4439) Simvastatin (N=4449) Aspirin7980 Warfarin13  -Blocker 7674 Calcium antagonists2019 ACE inhibitors2931 Angiotensin II blockers66 % Of Patients Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.

33. 32 Prerandomization Statin Use Atorvastatin (N=4439) Simvastatin (N=4449) Simvastatin50 Atorvastatin1112 Pravastatin910 Other statins45 Any statin75.175.8 % of Patients Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.

34. Statin Dose and Adherence

35. 34 Last Dose Prescribed at End of Study* *Values are number of subjects (%) with prescription data from routine clinic visit forms at last study visit. Pedersen TR et al. JAMA. 2005;294:2437-2445. Atorvastatin (N=4439) 13.2% 40 mg 86.8% 80 mg Simvastatin (N=4449) 76.7% 20 mg 23.3% 40 mg

36. 35 Adherence With Treatment Data on file. Pfizer Inc, New York, NY. Pedersen TR et al. JAMA. 2005;294:2437-2445. Adherence (%) 92% 86% Overall Adherence: Simvastatin95% Atorvastatin89%

37. Lipid Parameter Changes

38. 37 LDL-C by Statin Use at Baseline Simvastatin No Statin Percent Change at 1 Year: Simvastatin Atorvastatin No Statin: - 33%No Statin: - 47% 70 90 110 130 150 170 Randomization Years Weeks 1212345 2.0 2.5 3.0 3.5 4.0 LDL-C (mmol/L) LDL-C (mg/dL) 0 1.5 0 Data on file. Pfizer Inc, New York, NY. Atorvastatin On Statin On Statin: - 5%On Statin:- 27%

39. 38 Reductions in LDL-C by Treatment Group Pedersen TR et al. JAMA. 2005;294:2437-2445. Mean LDL-C at 1 Year = 102 mg/dL (2.6 mmol/L) Mean LDL-C During Treatment = 104 mg/dL (2.7 mmol/L) 0 70 80 90 100 110 120 130 Randomization1212345 LDL-C (mg/dL) Atorvastatin Simvastatin 0 1.8 2.0 2.3 2.6 2.8 3.1 3.4 LDL-C (mmol/L) Mean LDL-C at 1 Year = 79 mg/dL (2.0 mmol/L) Mean LDL-C During Treatment = 81 mg/dL (2.1 mmol/L) Years Weeks

40. 39 Reductions in TC by Treatment Group 0 160 180 200 Years 1212345 TC (mmol/L) TC (mg/dL) 0.0 4.1 4.7 5.2 Randomization 190 170 150 4.9 4.4 Atorvastatin Simvastatin Weeks Mean TC at 1 Year = 147 mg/dL (3.8 mmol/L) Mean TC at 1 Year = 176 mg/dL (4.6 mmol/L) Pedersen TR et al. JAMA. 2005;294:2437-2445. 3.9

41. 40 Reductions in HDL-C by Treatment Group 0 25 35 45 55 Years 1212345 HDL-C (mmol/L) HDL-C (mg/dL) 0.0 0.6 1.0 1.4 Randomization 50 40 30 20 1.2 0.8 Weeks Mean HDL-C at 1 Year = 46 mg/dL (1.19 mmol/L) Mean HDL-C at 1 Year = 47 mg/dL (1.22 mmol/L) Pedersen TR et al. JAMA. 2005;294:2437-2445. Atorvastatin Simvastatin

42. 41 Reductions In TG By Treatment Group 0 125 135 145 155 Years 1212345 TG (mmol/L) TG (mg/dL) 0.0 1.3 1.5 1.7 Randomization 150 140 130 110 1.6 1.4 Atorvastatin Simvastatin Weeks Mean TG at 1 Year = 116 mg/dL (1.31 mmol/L) Mean TG at 1 Year = 139 mg/dL (1.57 mmol/L) Pedersen TR et al. JAMA. 2005;294:2437-2445. 115 120 1.2

43. Efficacy Outcome Measures

44. 43 Composite End Point Definitions *PROVE IT primary end point = composite of death from any cause, MI, revascularization, hospitalization for unstable angina, or stroke. Pedersen TR et al. JAMA. 2005;294:2437-2445. Primary Composite End Point Major Coronary Event Composite of CHD death, nonfatal MI, resuscitated cardiac arrest Secondary Composite End Point Major CV Events Composite of major coronary event and stroke Any CHD Event Composite of major coronary event, revascularization, and hospitalization for unstable angina Any CV Event Composite of any CHD event, stroke, hospitalization for CHF, PAD TNT Primary End Point Similar to PROVE IT Primary End Point*

45. 44 Atorvastatin (N=4439) Simvastatin (N=4449)Hazard RatioP Value Major coronary event CHD death Nonfatal MI Resuscitated cardiac arrest 411 (9.3) 175 (3.9) 267 (6.0) 10 (0.2) 463 (10.4) 178 (4.0) 321 (7.2) 7 (0.2) 0.89 0.99 0.83 -.07.90.02 - Primary Composite End Point No. of Patients (%) Atorvastatin is not indicated for secondary prevention of CHD. Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.

46. 45 Post Hoc Analysis Of Primary End Point In a post hoc analysis, the primary end point was adjusted for baseline characteristics, including gender, age, statin use at randomization, duration since last MI, TC, HDL-C (Cox regression analysis) 13% reduction in major coronary events with atorvastatin 80 mg vs simvastatin 20 mg to 40 mg (hazard ratio = 0.87; P=.04) Atorvastatin is not indicated for secondary prevention of CHD. Pedersen TR et al. JAMA. 2005;294:2437-2445.

47. 46 Major Coronary Events* Years Since Randomization Major Coronary Events Cumulative Hazard (%) 012345 0 4 8 12 Simvastatin Atorvastatin HR = 0.89, P=.07 *CHD death, nonfatal MI, and resuscitated cardiac arrest. Atorvastatin is not indicated for secondary prevention of CHD. Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. 11% RRR

48. 47 Nonfatal MI Nonfatal MI Cumulative Hazard (%) Years Since Randomization 012345 0 2 4 6 8 10 HR = 0.83, P=.02 Simvastatin Atorvastatin Atorvastatin is not indicated for secondary prevention of CHD. Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. 17% RRR

49. 48 Secondary Composite End Points Atorvastatin is not indicated for secondary prevention of CHD. Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. Atorvastatin (N=4439) Simvastatin (N=4449) Hazard RatioP Value Major CV event Fatal or nonfatal stroke Any CHD event Revascularization Hospitalized unstable angina Any CV event Hospitalized nonfatal CHF Peripheral arterial disease 533 (12.0) 151 (3.4) 898 (20.2) 579 (13.0) 196 (4.4) 1176 (26.5) 99 (2.2) 127 (2.9) 608 (13.7) 174 (3.9) 1059 (23.8) 743 (16.7) 235 (5.3) 1370 (30.8) 123 (2.8) 167 (3.8) 0.87 0.84 0.77 0.83 0.84 0.81 0.76.02.20 <.001.06 <.001.11.02 No. of Patients (%)

50. 49 Composite End Points Atorvastatin is not indicated for secondary prevention of CHD. Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. Major Coronary Events Major CV Events Any CHD Event Any CV Event Simvastatin Atorvastatin Years Since Randomization Cumulative Hazard (%) 012345 0 4 8 12 16 HR = 0.89, P=.07 Years Since Randomization Cumulative Hazard (%) 012345 0 4 8 12 16 HR = 0.87, P=.02 Years Since Randomization Cumulative Hazard (%) 012345 0 10 20 30 40 HR = 0.84, P<.001 Years Since Randomization Cumulative Hazard (%) 012345 0 10 20 30 40 HR = 0.84, P<.001 Simvastatin Atorvastatin Simvastatin Atorvastatin Simvastatin Atorvastatin 11% RRR13% RRR16% RRR

51. 50 Major CV Events* Years Since Randomization Major CV Events Cumulative Hazard (%) 012345 0 4 8 12 16 HR = 0.87, P=.02 Simvastatin Atorvastatin *Major coronary event + stroke. Atorvastatin is not indicated for secondary prevention of CHD. Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. 13% RRR

52. 51 Any CHD Event* Years Since Randomization Any CHD Events Cumulative Hazard (%) 012345 0 10 20 30 40 HR = 0.84, P<.001 Simvastatin Atorvastatin *Any CHD event = major coronary event + revascularization + unstable angina. Atorvastatin is not indicated for secondary prevention of CHD. Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. 16% RRR

53. 52 Any CV Event* Years Since Randomization Any CV Events Cumulative Hazard (%) 012345 0 10 20 30 40 HR = 0.84, P<.001 Simvastatin Atorvastatin Any CHD + CHF + PAD. *Any CHD + CHF + PAD. Atorvastatin is not indicated for secondary prevention of CHD. Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. 16% RRR

54. 53 Selected Secondary End Points Nonfatal MI StrokeStroke RevascularizationRevascularizationPADPAD Atorvastatin is not indicated for secondary prevention of CHD. Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. Simvastatin Atorvastatin Years Since Randomization 012345 0 2 4 6 8 10 HR = 0.83, P=.02 Cumulative Hazard (%) 17% RRR Simvastatin Atorvastatin Years Since Randomization Cumulative Hazard (%) 012345 0 2 4 6 8 10 HR = 0.87, P=.20 13% RRR Simvastatin Atorvastatin Years Since Randomization 012345 0 4 8 12 16 20 HR = 0.77, P<.001 Cumulative Hazard (%) 23% RRR Simvastatin Atorvastatin Years Since Randomization Cumulative Hazard (%) 012345 0 2 4 6 8 10 HR = 0.76, P=.02 24% RRR

55. 54 Mortality *No significant differences in cancer mortality for any particular body system. Atorvastatin is not indicated for secondary prevention of CHD. Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. Atorvastatin (N=4439) Simvastatin (N=4449) Hazard RatioP Value All-cause mortality Cardiovascular mortality Noncardiovascular mortality Malignant disease* Suicide, violence, accident Other Unclassified 366 (8.2) 223 (5.0) 143 (3.2) 99 (2.2) 5 (0.1) 32 (0.7) 7 (0.2) 374 (8.4) 218 (4.9) 156 (3.5) 112 (2.5) 9 (0.2) 30 (0.7) 5 (0.1) 0.98 1.03 0.92 0.89 -.81.78.47.38 - No. of Patients (%)

56. Safety

57. 56 Investigator-Reported Adverse Events Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. Atorvastatin(N=4439)Simvastatin(N=4449) Any serious adverse event 2064 (46.5)2108 (47.4) Any adverse event resulting in permanent discontinuation with incidence  0.5% 426 (9.6)186 (4.2) Myalgia Myalgia Diarrhea Diarrhea Abdominal pain Abdominal pain Nausea Nausea 97 (2.2) 38 (0.9) 37 (0.8) 22 (0.5) 51 (1.1) 9 (0.2) 10 (0.2) 7 (0.1) Investigator-reported myopathy 6 (0.14)11 (0.25) Investigator-reported rhabdomyolysis 2 (0.05)3 (0.07)

58. 57 Protocol-Defined Clinically Important Lab Abnormalities Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. Atorvastatin(N=4439)Simvastatin(N=4449) AST >3  ULN at 2 consecutive measurements* 18 (0.4) 2 (0.0) ALT >3  ULN at 2 consecutive measurements* 43 (1.0)5 (0.1) Myopathy defined as CPK >10  ULN at 2 consecutive measurements* with muscle symptoms 00 *4 to10 days apart. Values are number of unique subjects (%).

59. Summary and Conclusions

60. 59 Summary Results from 4S showed that simvastatin 20 mg to 40 mg reduces CV morbidity and mortality Since 4S in 1994, clinical landscape has continued to evolve –lower LDL-C levels recommended by guidelines –statins are first-line therapy –increased use of other proven CV meds aspirin  -blockers In IDEAL, mean LDL-C levels were 81 mg/dL (2.1 mmol/L) with atorvastatin 80 mg compared with 104 mg/dL (2.7 mmol/L) with simvastatin 20 mg to 40 mg

61. 60 Implications of IDEAL Results High-dose Strategy vs Usual-Dose Strategy: Treating 1000 MI patients over 5 years Prevention of 68 patients having CVD events Atorvastatin is not indicated for secondary prevention of CHD. Pedersen TR et al. JAMA. 2005;294:2437-2445.

62. 61 IDEAL Results Are Consistent With TNT *Major CV event = CHD death, nonfatal MI, resuscitated cardiac arrest, fatal or nonfatal stroke. Atorvastatin is not indicated for secondary prevention of CHD. Reproduced from LaRosa JC et al. N Engl J Med. 2005;352:1425-1435, with permission. Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. Years Since Randomization Major CV Event Cumulative Hazard (%) 012345 0 4 8 12 16 HR = 0.87, P=.02 Simvastatin 20 mg to 40 mg Atorvastatin 80 mg HR = 0.78, P<.001 0 5 10 15 Atorvastatin 10 mg Atorvastatin 80 mg Major CV Event Cumulative Hazard (%) 0123456 Years Since Randomization IDEAL Secondary End Point* IDEAL Secondary End Point* TNT Primary End Point* TNT Primary End Point* 22% RRR 13% RRR

63. 62 IDEAL Results Are Consistent With PROVE IT Atorvastatin is not indicated for secondary prevention of CHD. Reproduced from Cannon CP et al. N Engl J Med. 2004;350:1495-1504, with permission. Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission. IDEAL Secondary End Point* PROVE IT Primary End Point** Years Since Randomization Any CHD Cumulative Hazard (%) 012345 0 10 20 30 40 HR = 0.84, P<.001 Simvastatin 20 mg to 40 mg Atorvastatin 80 mg 30 0 5 10 15 20 25 36912151821242730 Months Of Follow-Up 0 HR = 0.84, P=.005 Death Or Major CV Event (%) Pravastatin 40 mg Atorvastatin 80 mg 16% RRR *Any CHD event = composite of major coronary event, revascularization, or hospitalization for unstable angina. **Death from any cause, MI, revascularization, hospitalization for unstable angina, or stroke.

64. 63 Summary IDEAL showed incremental reductions in clinical end points can be achieved with atorvastatin 80 mg compared with simvastatin 20 mg to 40 mg without compromising safety  11% difference in major coronary events (P=.07)  17% difference in nonfatal MI (P=.02)  13% difference in major CV events (P=.02)  16% difference in any CHD event (P<.001)  16% difference in any CV event (P<.001) Reductions in CV events in IDEAL build upon results seen in TNT and PROVE IT Atorvastatin is not indicated for secondary prevention of CHD.