Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) TrialMEGA TrialPresented atThe American Heart AssociationScientific Session 2005Presented by Dr. Haruo Nakamura

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

Diet Modification n=3,966Primary 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 TrialPresented at AHA 2005Diet Modification + Pravastatin10-20 mg/dayn=3,8667,832 men age 40-70 years and postmenopausal women up to age 70 with total cholesterol 220-270 mg/dLMean 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/dL32% Female, Mean Age 58 years, Mean Follow-Up 5.3 yearsProspective. Randomized. Open-label.

MEGA Trial: Cholesterol and Triglyceride Levels Presented at AHA 2005 Total cholesterol reduction was larger in the pravastatin groupLDL reduction was greater in the pravastatin groupHDL increase was greater in the pravastatin groupTriglyceride reduction was greater in the pravastatin groupTotal CholesterolLDLHDLTriglyceridesmg/dL

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).Primary composite endpoint of coronary heart disease events p = 0.01Presented at AHA 2005# per 1000 patient years

MEGA Trial: Secondary EndpointsPresented at AHA 2005p=0.055p=0.03p=0.33Total 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)# per 1000 patient yearsp=0.23

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

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.%Frequency of cancer (per 1000 patient years)Frequency of elevated liver function abnormalities (%)

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