Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Trial

1. MEGA Trial Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Trial Presented at The American Heart Association Scientific Session 2005 Presented by Dr. Haruo Nakamura

2. MEGA Trial: Background • In Japan, the incidence of coronary disease is about one third lower than the US and Europe, where most of the statin trials have been conducted • The goal of this study was to examine whether the addition of a low-dose statin to a diet rich in omega-3 fatty acids could reduce the risk of CHD. Presented at AHA 2005

3. MEGA Trial 7,832 men age 40-70 years and postmenopausal women up to age 70 with total cholesterol 220-270 mg/dL Mean BMI 23.8 kg/m2, 21% Diabetics, 20% Current Smokers, baseline total cholesterol 242.6 mg/dL, LDL 157 mg/dL, HDL 57.5 mg/dL, triglycerides 127 mg/dL 32% Female, Mean Age 58 years, Mean Follow-Up 5.3 years Prospective. Randomized. Open-label. Diet Modification n=3,966 Diet Modification + Pravastatin 10-20 mg/day n=3,866 Primary Endpoints: Composite of coronary heart disease events, defined as cardiac and sudden death, fatal and nonfatal myocardial infarction (MI), angina and cardiac or vascular intervention. Secondary Endpoints: Stroke, CHD composite or cerebral infarction, any cardiovascular event, total mortality. Presented at AHA 2005

4. MEGA Trial: Cholesterol and Triglyceride Levels Total Cholesterol HDL Triglycerides LDL • Total cholesterol reduction was larger in the pravastatin group • LDL reduction was greater in the pravastatin group • HDL increase was greater in the pravastatin group • Triglyceride reduction was greater in the pravastatin group mg/dL Presented at AHA 2005

5. MEGA Trial: Primary Composite Endpoint Primary composite endpoint of coronary heart disease events p = 0.01 • The primary composite endpoint of coronary heart disease events occurred less frequently in the pravastatin plus diet group (3.3 vs 5.0 per 1000 patient years, hazard ratio [HR] 0.67, p=0.01). # per 1000 patient years Presented at AHA 2005

6. MEGA Trial: Secondary Endpoints • Total mortality was non-significantly lower in the pravastatin group (2.7 vs 3.8, HR 0.71, p=0.055) • MI occurred less often in the pravastatin group (0.9 vs 1.6, p=0.03) • No significant difference was observed in stroke (2.5 vs 3.0, p=0.33) or cerebral infarction plus TIA (2.0 vs 2.6, p=0.23) p=0.055 p=0.33 p=0.23 p=0.03 # per 1000 patient years Presented at AHA 2005

7. MEGA Trial: Secondary Endpoints cont. Composite of CHD event or cerebral infarction p = 0.005 • The composite of CHD event or cerebral infarction was lower in the pravastatin group (5.0 vs 7.1, p=0.005) # per 1000 patient years Presented at AHA 2005

8. MEGA Trial: Safety Data Frequency of cancer (per 1000 patient years) Frequency of elevated liver function abnormalities (%) % # per 1000 patient years • There was no difference in the frequency of cancer or elevated liver function abnormalities and no cases of rhabdomyolysis. Presented at AHA 2005

9. MEGA Trial: Summary • Among Japanese patients with hypercholesterolemia, treatment with pravastatin therapy in addition to diet modification was associated with a reduction in the primary composite endpoint of coronary heart disease events compared with diet modification alone at a mean 5.3 year follow-up. • Previous studies conducted in western populations have shown reductions in adverse coronary events associated with statin therapy use; however, the cardiac morbidity and mortality in Japan is much lower than in the U.S. and other western countries where statin therapy has been predominantly studied. • The present study demonstrated that even in this lower risk population, primary prevention with low-dose statin therapy can be effective in reducing cardiac events, with a modest reduction in lipid parameters. Presented at AHA 2005