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

www. Clinical trial results.org 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 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. 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. 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 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. 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

www. Clinical trial results.org Diet Modification n=3,966 Diet Modification n=3,966 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. 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. MEGA Trial Presented at AHA 2005 Diet Modification + Pravastatin mg/day n=3,866 Diet Modification + Pravastatin mg/day n=3,866 7,832 men age years and postmenopausal women up to age 70 with total cholesterol mg/dL Mean BMI 23.8 kg/m2, 21% Diabetics, 20% Current Smokers, baseline total cholesterol 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. 7,832 men age years and postmenopausal women up to age 70 with total cholesterol mg/dL Mean BMI 23.8 kg/m2, 21% Diabetics, 20% Current Smokers, baseline total cholesterol 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.

www. Clinical trial results.org MEGA Trial: Cholesterol and Triglyceride Levels Presented at AHA 2005 Total cholesterol reduction was larger in the pravastatin group Total cholesterol reduction was larger in the pravastatin group LDL reduction was greater in the pravastatin group HDL increase was greater in the pravastatin groupHDL increase was greater in the pravastatin group Triglyceride reduction was greater in the pravastatin groupTriglyceride reduction was greater in the pravastatin group Total Cholesterol LDL HDL Triglycerides mg/dL

www. Clinical trial results.org MEGA Trial: Primary Composite Endpoint 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). 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). Primary composite endpoint of coronary heart disease events p = 0.01 Presented at AHA 2005 # per 1000 patient years

www. Clinical trial results.org MEGA Trial: Secondary Endpoints Presented at AHA 2005 p=0.055 p=0.03 p=0.33 Total mortality was non-significantly lower in the pravastatin group (2.7 vs 3.8, HR 0.71, p=0.055)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)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)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) # per 1000 patient years p=0.23

www. Clinical trial results.org MEGA Trial: Secondary Endpoints cont. Presented at AHA 2005 The composite of CHD event or cerebral infarction was lower in the pravastatin group (5.0 vs 7.1, 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 Composite of CHD event or cerebral infarction p = 0.005

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

www. Clinical trial results.org 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. 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. 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. 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. 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. 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. 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. 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