TNT: Study Design Treating to New Targets 2 5 years 10,001 Patients Clinically evident CHD LDL-C 130  250 mg/dL following up to 8-week washout and 8-week open-label run-in with atorvastatin 10 mg Patient Population Time to first occurrence of a major cardiovascular event (CHD death, nonfatal non–procedure- related MI, resuscitated cardiac arrest, fatal or nonfatal stroke) Primary End Point Atorvastatin 10 mg LDL-C target: 100 mg/dL Atorvastatin 10 mg LDL-C target: 100 mg/dL LaRosa JC et al. N Engl J Med. 2005;352: Atorvastatin 80 mg LDL-C target: 75 mg/dL Atorvastatin 80 mg LDL-C target: 75 mg/dL

TNT Primary Efficacy Outcome Measure: Major Cardiovascular Events* 3 *CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. LaRosa JC et al. N Engl J Med. 2005;352: HR = 0.78 (95% CI, 0.69–0.89) P <.001 Cumulative Incidence of Major Cardiovascular Events, % Atorvastatin 10 mg (n = 5006) LDL-C 101 mg/dL (2.6 mmol/L) Relative risk reduction = 22% Time, years Atorvastatin 80 mg (n = 4995) LDL-C 77 mg/dL (2.0 mmol/L)

TNT: Primary and Secondary Efficacy Outcomes 4 HR P Value <.001 Major CV event CHD death Nonfatal non–procedure-related MI Resuscitated cardiac arrest Fatal/nonfatal stroke Major coronary event* Cerebrovascular event Peripheral arterial disease Hospitalization for CHF All-cause mortality Any coronary event Any cardiovascular event Primary Efficacy Measure Secondary Efficacy Measures Atorvastatin 80 mg Better Atorvastatin 10 mg Better *CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest. LaRosa JC et al. N Engl J Med. 2005;352:

TNT: Time to First Fatal or Nonfatal Stroke 5 LaRosa JC et al. N Engl J Med. 2005;352: Time (years) HR = 0.75 (95% CI ) P=0.02 Relative RR = 25% Atorvastatin 10 mg Atorvastatin 80 mg Proportion of patients experiencing events

TNT: Safety Profile Persistent = 2 consecutive measurements. LaRosa JC et al. N Engl J Med. 2005;352: Atorvastatin 80 mg (n=4,995) Atorvastatin 10 mg (n=5,006) P<0.001 P =0.72 P<0.001 (n=406)(n=289)(n=241)(n=234) (n=9) (n=60) Treatment-Related Adverse Events Treatment-Related Myalgia Elevated Liver Enzymes* % of Patients 6

IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering): Study Design years Open label with blinded end-point evaluation 8888 Patients Previous hospitalization with definite acute MI or a history of definite MI Eligibility for statin therapy according to respective national guidelines at discharge Patient Population Time to occurrence of a major cardiovascular event (CHD death, nonfatal acute MI, resuscitated cardiac arrest) Primary End Point Atorvastatin 80 mg Pedersen TR et al. JAMA. 2005;294: Simvastatin 20 mg; titration to 40 mg for TC >190 mg/dL

IDEAL: Primary and Secondary End Points 8 The primary end point of IDEAL (a composite of CHD death, nonfatal MI, and resuscitated cardiac arrest) did not reach statistical significance (HR = 0.89; 95% CI, ; P = 0.07). Pedersen TR et al. JAMA. 2005;294: Years Since Randomization Cumulative Hazard, % HR = 0.89 (95% CI, 0.76–1.01) P =.07 11% RRR Simvastatin Atorvastatin Years Since Randomization Cumulative Hazard, % HR = 0.87 (95% CI, 0.78–0.98) P =.02 13% RRR Simvastatin Atorvastatin Years Since Randomization Cumulative Hazard, % HR = 0.84 (95% CI, 0.76–0.91) P < % RRR Simvastatin Atorvastatin Years Since Randomization Cumulative Hazard, % HR = 0.84 (95% CI, 0.78–0.91) P < % RRR Simvastatin Atorvastatin Any coronary event – secondary end pointAny CV event – secondary end point Major CV events – secondary end pointMajor coronary events – primary end point

Effects of Atorvastatin 80 mg/d vs Simvastatin 20 to 40 mg/d on Any CV Event 9 *Adjusted for sex and age at baseline. Tikkanen MJ et al. J Am Coll Cardiol. 2009;54: st 2nd 3rd 4th 5th (0.77 – 0.90) (0.67 – 0.86) (0.67 – 0.99) (0.57 – 1.01) (0.48 – 1.09) < Atorvastatin better Simvastatin better EventsHR (95% CI)* Relative Risk Reduction (%) P Value Subjects With Event

MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering): Study Design weeks double-blind 3086 Patients Non-Q-wave MI or unstable angina Randomized 24–96 hours from admission Patient Population Time to ischemic events (CHD death, nonfatal MI, documented angina requiring hospitalization) Primary End Point Atorvastatin 80 mg Schwartz GG et al. JAMA. 2001;285: Placebo

MIRACL: Primary Efficacy Measure— Time to First Event* 11 *Death (any cause), nonfatal MI, resuscitated cardiac arrest, worsening angina with new objective evidence and urgent rehospitalization. Schwartz GG et al. JAMA. 2001;285: Time Since Randomization, weeks RR = 0.84 P = % CI, 0.701–0.999 Atorvastatin 80 mg (n = 1538) LDL-C 72 mg/dL (1.9 mmol/L) Placebo (n = 1548) LDL-C 135 mg/dL (3.5 mmol/L) % 14.8% Cumulative Incidence, % 16% RRR

MIRACL: Stroke Placebo (n=1548)Atorvastatin (n=1538) Total strokes2513 Fatal stroke23 Nonfatal stroke2310 Type of stroke Hemorrhagic30 Embolic10 Thrombotic/embolic1910 Indeterminate23 Number patients experiencing a stroke (P=0.04) (%) 24 (1.6)12 (0.8) Fatal stroke2 (0.1)3 (0.2) Nonfatal stroke (P=0.02)22 (1.4)9 (0.6) 12 Water DD et al. Circulation. 2002;106:

PROVE IT-TIMI (Pravastatin or Atorvastatin Evaluation and Infection Therapy– Thrombolysis in Myocardial Infarction) 22: Study Design 13 Double-blind 925 primary end points 4162 Patients Hospitalized for an acute coronary syndrome in the preceding 10 days TC ≤240 mg/dL (6.2 mmol/L) or TC ≤200 mg/dL (5.2 mmol/L) if receiving lipid-lowering therapy Patient Population Time to first occurrence of a major cardiovascular event (death from any cause, MI, unstable angina, revascularization, stroke Primary End Point Atorvastatin 80 mg Cannon CP et al. N Engl J Med. 2004;350: Pravastatin 40 mg

Months of Follow-up % RRR (P =.005) 26.3% 22.4% Death or Major CV Event, % –35% LDL reduction Pravastatin 40 mg (n = 1548) 95 mg/dL (2.5 mmol/L) Atorvastatin 80 mg (n = 2099) 62 mg/dL (1.6 mmol/L) Major CV event = MI, unstable angina requiring rehospitalization, revascularization, or stroke. Cannon CP et al. N Engl J Med. 2004;350: PROVE IT: Primary End Point (All-Cause Death or Major CV Events in All Randomized Subjects) 14

Adapted from Ray KK et al. J Am Coll Cardiol. 2005;46: *Death, MI, or rehospitalization with recurrent ACS. PROVE IT-TIMI 22: Intensive Therapy With Statins in Patients With ACS: Early and Long-term Benefits 15 Atorvastatin 80 mg Pravastatin 40 mg Month 6 to end of study RRR = 28% P = Months following randomization Composite triple end point* (%) n = 1752 n= 1812 Randomization to 30 days Days following randomization Composite triple end point* (%) RRR = 28% P =.046 n = 2063 n =

Safety of Atorvastatin 80 mg in Clinical Trials 16 *Consecutive measurements. † Newman C et al. Am J Cardiol. 2006;97:61-67; Cannon CP et al. N Engl J Med. 2004;350: ; LaRosa JC, et al. N Engl J Med. 2005;352: ; Pedersen TR et al; for the IDEAL Study Group. JAMA. 2005;294: ; Amarenco P et al. N Engl J Med. 2006;355:

Overview of Adverse Events for Atorvastatin 10 mg and 80 mg and Placebo 17 Newman C et al. Am J Cardiol. 2006;97:61-67.