Impact of Triglyceride Levels Beyond Low-Density Lipoprotein Cholesterol After Acute Coronary Syndrome in the PROVE IT-TIMI 22 Trial Michael Miller MD, FACC, Christopher P. Cannon MD FACC, Sabina A. Murphy MPH, Jie Qin MS, Kausik K. Ray MD, Eugene Braunwald MD, MACC for the PROVE IT-TIMI 22 Investigators Miller et al. J Am Coll Cardiol 2008;51:1724-30 Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.

Background and Objectives The PROVE IT-TIMI 22 trial demonstrated that LDL-C < 70 mg/dL was associated with greater CHD event reduction than LDL-C <100 mg/dL after ACS. We evaluated the impact of TG in the PROVE IT-TIMI 22 trial, reasoning that if high LDL-C and TG increases CHD risk more than isolated high LDL-C, then the combination of low on-treatment LDL-C and TG would be associated with reduced CHD risk compared to low LDL-C (< 70 mg/dL) alone. Miller et al. J Am Coll Cardiol 2008;51:1724-30 Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply

Methods Study Population: Blood Sampling: Composite Endpoint: 4,162 patients in The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial Blood Sampling: Plasma samples for lipids, lipoproteins, HS-CRP at baseline, 30 d, and 4, 8, 16, 24 months Composite Endpoint: Death, myocardial infarction (MI) or recurrent ACS between 30 d and 2 yr follow-up Miller et al. J Am Coll Cardiol 2008;51:1724-30 Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.

Methods (2) Statistical Analysis Kaplan-Meier event rates after censoring events within 30 days of initial ACS event. Cox proportional hazards model: Age, gender, DM, HTN, obesity (BMI > 30 kg/m2), cigarette smoking (active), low HDL-C to estimate effect of on-treatment LDL-C (70 mg/dL) and TG (150 mg/dL) within 30 days or 4 months of initial ACS event. CRP (2 mg/L) included to assess triple goal attainment Miller et al. J Am Coll Cardiol 2008;51:1724-30 Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.

Results Kaplan-Meier Estimates Based on LDL-C < 70 mg/dL or TG < 150 mg/dL Between 30 days and 2 yr Follow-Up 0.00 0.05 0.10 0.15 0.20 150 330 510 700 Days After Month 1 Visit TG < 150 TG ≥ 150 HR: 0.73 (0.62, 0.87) P < 0.001 Days After Month 1 Visit LDL < 70 LDL ≥ 70 HR: 0.81 (0.68, 0.96) P = 0.015 Kaplan-Meier estimates of death, MI and recurrent ACS between 30 days and 2 years of follow-up based on a) achieved LDL-C < 70 mg/dL and b) TG < 150 mg/dL. Miller et al. J Am Coll Cardiol 2008;51:1724-30 Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply. 5

Rate of Death, MI or Recurrent ACS after 30 days Results TG < 150 TG ≥ 150 LDL-C < 70 LDL-C ≥ 70 Rate of Death, MI or Recurrent ACS after 30 days Hazard of Death, MI & Recurrent ACS with on-treatment LDL-C (70 mg/dL) & TG (150 mg/dL) Ref 17.9% P = 0.180 P = 0.192 15.0% 16.5% P = 0.017 HR: 0.85 (0.67-1.08) 11.7% HR: 0.72 (0.54-0.94) HR: 0.84 (0.65-1.09) Adjusted for age, sex, smoking, DM, HTN, obesity, HDL, PVD, prior ACS, prior statin use and treatment effect Miller et al. J Am Coll Cardiol 2008;51:1724-30 Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply. 6

Results Proportion of Pravastatin (40 mg) and Atorvastatin (80 mg) Treated Patients Attaining LDL-C < 70, CRP < 2 & TG < 150 at 30 days * P < 0.0001 between the treatment groups 35%* 6.6% Proportion of on-treatment Percentage of TG reduction (mean and median) and proportion of Atorvastatin and Pravastatin treated patients attaining LDL-C < 70 mg/dL or TG < 150 mg/dL, the dual goals of LDL-C <70 mg/dL and TG <150 mg/dL or the triple goal of LDL-C<70 mg/dL, CRP < 2 mg/L and TG < 150 mg/dL at 30 days or 4 months after ACS. At 30 days Atorvastatin 34.5%, Pravastatin 6.6% Miller et al. J Am Coll Cardiol 2008;51:1724-30 Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.

Results Hazard of death, MI and recurrent ACS with number of goals achieved based on LDL-C < 70, CRP < 2 & TG < 150 mg/dL at 30 d 35%* 6.6% Percentage of TG reduction (mean and median) and proportion of Atorvastatin and Pravastatin treated patients attaining LDL-C < 70 mg/dL or TG < 150 mg/dL, the dual goals of LDL-C <70 mg/dL and TG <150 mg/dL or the triple goal of LDL-C<70 mg/dL, CRP < 2 mg/L and TG < 150 mg/dL at 30 days or 4 months after ACS. At 30 days Atorvastatin 34.5%, Pravastatin 6.6% Adjusted for age, sex, smoking, DM, HTN, obesity, HDL, PVD, prior ACS, prior statin use and treatment effect Miller et al. J Am Coll Cardiol 2008;51:1724-30 Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.

Conclusions On-treatment TG < 150 mg/dL was associated with a lower risk of recurrent CHD events independently of the level of LDL-C. Therefore, these data lend support to the concept that achieving both a low LDL-C and low TG may be important therapeutic parameters following ACS Miller et al. J Am Coll Cardiol 2008;51:1724-30 Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.