Statin Landmark Trials Across the Spectrum of Risk: Secondary CV Prevention

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.

TNT: Changes in LDL-C by Treatment Group 18 LaRosa JC et al. N Engl J Med. 2005;352: P <.001 Baseline Mean LDL-C level = 101 mg/dL (2.6 mmol/L) Mean LDL-C level = 77 mg/dL (2.0 mmol/L) FinalScreen Study Visits, months Mean LDL-C, mmol/L Mean LDL-C, mg/dL Atorvastatin 10 mg (n = 5006) Atorvastatin 80 mg (n = 4995)

2-Year Event Rates RRAtorva 80Prava 40 28%2.2%3.2% 30%1.1%1.4% 13%6.6%7.4% 18%8.3%10.0% 14%16.3%18.8% 29%3.8%5.1% 25%12.9%16.7% All-Cause Mortality Death or MI Death/MI/Urg. Revasc MI Revasc >30 d UA Req Hosp Atorvastatin 80 mg BetterPravastatin 40 mg Better CHD Death PROVE IT: Reductions in Major Cardiac End Points 19 Cannon CP et al. N Engl J Med. 2004;350:

Effect of Intensive Statin Therapy on Clinical OutcomesAmong Patients Undergoing Percutaneous Coronary Intervention for ACS: PCI-PROVE IT Substudy 20 Gibson CM et al. J Am Coll Cardiol. 2009;54: Post hoc analysis of 2868 patients who underwent PCI just prior to enrollment 25% 20% 15% 10% 5% 0% Primary End Point Time, days 30% Pravastatin Atorvastatin Hazard ratio % CI, 0.67–0.91 P < % 15% 10% 5% 0% Death, MI, RI, UA Time, days 25% Pravastatin Atorvastatin Hazard ratio % CI, 0.61–0.87 P <.001

Long-term Statin Treatment in IDEAL Maintained Benefit Over 5 Years 21 Cannon CP et al. N Engl J Med. 2004;350: ; Pedersen TR et al. Am J Cardiol. 2010;106: Longest Period of Follow-up of ACS Patients on Statin Therapy *Composite end point = death, nonfatal MI, hospitalization for UA, or coronary revascularization months5 years Composite End Point *, % Atorvastatin 80 mg Pravastatin 40 mg Simvastatin mg 18% RRR P = 0.04 PROVE IT (MI or UA) IDEAL (All MI) 16% RRR P = 0.005

MIRACL: Secondary End Points 22 Relative Risk Atorvastatin 12 (0.8) 254 (16.5) 91 (5.9) 40 (2.6) *P =.045. Placebo 24 (1.6) 250 (16.1) 106 (6.8) 43 (2.8) * Atorvastatin BetterPlacebo Better Stroke (fatal and nonfatal) Revascularization (CABG or PTCA) Worsening angina (without objective evidence of ischemia) Worsening congestive heart failure Schwartz GG et al. JAMA. 2001;285: No. of Events (%)

Association of Dyslipidemia and myocardial Infarction Risk: INTERHEART 23 AMI, acute myocardial infarction; Smk, smoking; DM, diabetes mellitus; HTN, hypertension; O, obesity; PS, psychosocial; RF, risk factors; OR; odds ratio. Yusuf S et al. Lancet. 2004;364: SmkDMHTNLipids1+2+3all4+O+PSAll RFs OR (99% CI) 3-fold increase in risk of acute MI Risk of AMI With Multiple Risk Factors

ASCOT CRP Analysis Post hoc subgroup (nested case control) analysis of ASCOT data – To assess baseline CRP and risk of CV events: 5.5 years follow-up, 485 patients with major CV events matched with 1367 controls from baseline population (ASCOT BPLA) – To assess the effect of statin treatment on CRP and risk of CV events: 5.5 years follow-up, 235 patients with major CV events matched with 777 controls from statin trial population (ASCOT LLA) Baseline CRP and risk of CV events – Inclusion of CRP in a Framingham risk model modestly improved the prediction of CV events beyond use of standard CV risk factors by a small amount On-statin-treatment CRP and risk of CV events – Levels of LDL-C were strongly associated with reductions in CV events – On-statin-treatment CRP levels were not predictive of CV outcomes – Atorvastatin 10 mg reduced median CRP by 27% 24 Late Breaking Clinical Trials. AHA Scientific Session Abstract downloaded from