Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering (IDEAL) Trial IDEAL Trial Presented at The American Heart Association Scientific Session 2005 Presented by Dr. Terje Pedersen

www. Clinical trial results.org IDEAL Trial: Background Several recent studies have evaluated a regimen of high-dose statin compared with a lower-dose, usual care statin regimen in the setting of stable or unstable acute coronary syndromes, including TNT, PROVE-IT TIMI-22 and A to Z. Several recent studies have evaluated a regimen of high-dose statin compared with a lower-dose, usual care statin regimen in the setting of stable or unstable acute coronary syndromes, including TNT, PROVE-IT TIMI-22 and A to Z. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT TIMI- 22) study of patients recently hospitalized with acute coronary syndromes, aggressive lipid lowering with 80 mg per day of atorvastatin provided more protection from death and cardiovascular events than 40 mg per day of pravastatin. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT TIMI- 22) study of patients recently hospitalized with acute coronary syndromes, aggressive lipid lowering with 80 mg per day of atorvastatin provided more protection from death and cardiovascular events than 40 mg per day of pravastatin. The Treating to New Targets (TNT) study demonstrated that aggressive lipid lowering with 80 mg per day of atorvastatin provided greater protection from major cardiovascular events than low-dose atorvastatin in stable CHD patients. The Treating to New Targets (TNT) study demonstrated that aggressive lipid lowering with 80 mg per day of atorvastatin provided greater protection from major cardiovascular events than low-dose atorvastatin in stable CHD patients. On the other hand, the Aggrastat to Zocor (A to Z) trial showed that treatment with high-dose simvastatin failed to show a significant reduction in the primary composite endpoint of cardiovascular death, MI readmission for ACS or stroke. On the other hand, the Aggrastat to Zocor (A to Z) trial showed that treatment with high-dose simvastatin failed to show a significant reduction in the primary composite endpoint of cardiovascular death, MI readmission for ACS or stroke. Presented at AHA 2005

www. Clinical trial results.org High-dose atorvastatin 80 mg/day If LDL was <40 mg/dL at 24 wks dose could be reduced to 40 mg/day n=4,439 High-dose atorvastatin 80 mg/day If LDL was <40 mg/dL at 24 wks dose could be reduced to 40 mg/day n=4,439 Primary Endpoint: Composite of major coronary event, defined as coronary death, hospitalization for non-fatal acute MI or resuscitated cardiac arrest. Secondary Endpoint: Major cardiovascular events, anyCHD event, hospitalization with a primary diagnosis of congestive heart failure, peripheral artery disease, any cardiovascular events and all-cause mortality. Primary Endpoint: Composite of major coronary event, defined as coronary death, hospitalization for non-fatal acute MI or resuscitated cardiac arrest. Secondary Endpoint: Major cardiovascular events, anyCHD event, hospitalization with a primary diagnosis of congestive heart failure, peripheral artery disease, any cardiovascular events and all-cause mortality. IDEAL Trial: Study Design Presented at AHA 2005 Standard-dose simvastatin 20 mg/day If cholesterol >190 mg/dL at 24 wks dose could be increased to 40 mg/day n=4,449 n=4,449 Standard-dose simvastatin 20 mg/day If cholesterol >190 mg/dL at 24 wks dose could be increased to 40 mg/day n=4,449 n=4,449 8,888 patients ≤80 years with definite history of myocardial infarction and qualified for stain therapy at time of recruitment Pts. on statin therapy at baseline: simvastatin (50%), atorvastatin (11%), pravastatin (10%); baseline LDL mg/dL; total cholesterol 196 mg/dL; median time from last MI 21 mos in atorvastatin group, 22 mos in simvastatin group 19% female, mean age 62 yrs, fasting blood samples were obtained at baseline, 12 weeks, 24 weeks, 1 year and each year thereafter, mean follow-up median of 4.8 years Randomized 8,888 patients ≤80 years with definite history of myocardial infarction and qualified for stain therapy at time of recruitment Pts. on statin therapy at baseline: simvastatin (50%), atorvastatin (11%), pravastatin (10%); baseline LDL mg/dL; total cholesterol 196 mg/dL; median time from last MI 21 mos in atorvastatin group, 22 mos in simvastatin group 19% female, mean age 62 yrs, fasting blood samples were obtained at baseline, 12 weeks, 24 weeks, 1 year and each year thereafter, mean follow-up median of 4.8 years Randomized

www. Clinical trial results.org IDEAL Trial: Primary Endpoint The primary composite endpoint of major coronary event occurred in 9.3% of the atorvastatin group and 10.4% of the simvastatin group. The primary composite endpoint of major coronary event occurred in 9.3% of the atorvastatin group and 10.4% of the simvastatin group. Primary Composite of major coronary event * (%) p = 0.07 Presented at AHA 2005 % * Major coronary event defined as coronary death, hospitalization for non-fatal acute MI or resuscitated cardiac arrest.

www. Clinical trial results.org IDEAL Trial: Primary Endpoint cont. % Presented at AHA 2005 p=NS p=0.02 p=0.90 Among the components of the primary endpoint, there was no difference in CHD death or cardiac arrest with resuscitation, but nonfatal MI occurred less frequently in the atorvastatin group. Among the components of the primary endpoint, there was no difference in CHD death or cardiac arrest with resuscitation, but nonfatal MI occurred less frequently in the atorvastatin group.

www. Clinical trial results.org IDEAL Trial: Secondary Endpoints Major cardiovascular events, defined as any primary event plus stroke, occurred less often in the atorvastatin group. Major cardiovascular events, defined as any primary event plus stroke, occurred less often in the atorvastatin group. Any cardiovascular event, defined as major CV event plus hospitalization for CHF and peripheral artery disease, also occurred less often in the atorvastatin group.Any cardiovascular event, defined as major CV event plus hospitalization for CHF and peripheral artery disease, also occurred less often in the atorvastatin group. Major cardiovascular events and any cardiovascular event (%) Presented at AHA 2005 % p=0.02 p<0.001

www. Clinical trial results.org IDEAL Trial: Serious Adverse Events Presented at AHA 2005 There was no difference in the frequency of serious adverse events, but adverse event resulting in permanent drug discontinuation was more frequent in the atorvastatin group. Liver enzyme elevation occurred more frequently in the atorvastatin group as did myalgia. Liver enzyme elevation occurred more frequently in the atorvastatin group as did myalgia. % p=0.42 p<0.001 Serious adverse events and adverse event resulting in permanent study drug discontinuation (%)

www. Clinical trial results.org IDEAL Trial: Serious Adverse Events cont. Presented at AHA 2005 Liver enzyme elevation occurred more frequently in the atorvastatin group as did myalgia.Liver enzyme elevation occurred more frequently in the atorvastatin group as did myalgia. % p<0.001 ALT >3x upper limit of normal p<0.001 Liver enzyme elevation and myalgia (%)

www. Clinical trial results.org IDEAL Trial: Summary Among patients with a previous myocardial infarction, treatment with high-dose atorvastatin was associated with a directional but non- significant reduction in the primary composite endpoint of major coronary events compared with standard dose simvastatin at five year follow-up. The present trial further extends the evaluation of aggressive lipid- lowering to the setting of post-myocardial infarction patients. The present trial further extends the evaluation of aggressive lipid- lowering to the setting of post-myocardial infarction patients. While there was a reduction in the secondary endpoint of recurrent MI, adverse events and liver enzyme elevations were more frequent in the high-dose atorvastatin group, highlighting the need for careful monitoring of patients on this regimen. While there was a reduction in the secondary endpoint of recurrent MI, adverse events and liver enzyme elevations were more frequent in the high-dose atorvastatin group, highlighting the need for careful monitoring of patients on this regimen. Among patients with a previous myocardial infarction, treatment with high-dose atorvastatin was associated with a directional but non- significant reduction in the primary composite endpoint of major coronary events compared with standard dose simvastatin at five year follow-up. The present trial further extends the evaluation of aggressive lipid- lowering to the setting of post-myocardial infarction patients. The present trial further extends the evaluation of aggressive lipid- lowering to the setting of post-myocardial infarction patients. While there was a reduction in the secondary endpoint of recurrent MI, adverse events and liver enzyme elevations were more frequent in the high-dose atorvastatin group, highlighting the need for careful monitoring of patients on this regimen. While there was a reduction in the secondary endpoint of recurrent MI, adverse events and liver enzyme elevations were more frequent in the high-dose atorvastatin group, highlighting the need for careful monitoring of patients on this regimen. Presented at AHA 2005