Principal Findings:

Designed as a 2 x 2 factorial study to assess separately the effects of antioxidant vitamins and simvastatin in a high risk population.

With the vitamin cocktail employed, there was no benefit seen in terms of mortality: vitamin group 1443 (14.1%) vs 1388 (13.5%) placebo. No evidence found that the vitamins either reduced or increased the risk of a particular cause of death.

Additionally, no benefit was found from the vitamins in terms of major vascular outcomes: 2327 (22.7%) vs 2321 (22.6%).

Compliance over 6 years averaged 85% in the simvastatin group but 18% used non-study statin in the placebo group. Hence, three was an average difference in statin use between those allocated simvastatin and those allocated placebo of 67%.

This two-thirds difference for statin use produced an average reduction in LDL of nearly 1 mmol/L (40 mg/dL).

With a two-thirds compliance rate, simvastatin significantly reduced total mortality by 12% (12.9% vs 14.6%; p<0.001) and was even efficacious against vascular mortality with a 17% reduction rate (7.7% vs 9.2%; p<0.0002).

There was a nonsignificant but slightly favorable trend in reduction of nonvascular mortality, but no evidence of hazard on any particular nonvascular cause of death, including cancer.

Overall, patients experienced a 27% reduction in stroke risk (4.4% vs 6.0%; p<0.00001), most prominently in ischemic stroke, but no excess hemorrhagic stroke.

In terms of all major vascular events, researchers again found a significant 24% reduction in total CHD, total stroke, and revascularization (19.9% vs 25.4%; p<0.00001).

Over time the benefits of the statin therapy increase, suggesting that with more prolonged treatment than in such a 5-year trial, bigger absolute benefits would be expected.

All patient groups benefited from the simvastatin therapy, including patients with a previous MI (who were predominantly the elderly, women, and people with low LDL or total cholesterol for whom there was substantial uncertainty at the beginning), other coronary or vascular disease or diabetes.

This study is the largest study of cholesterol-lowering drug therapy in women (n=5,082) and provides direct evidence that women benefit from cholesterol-lowering therapy equally as men, and evidence of benefit in patients of ages over 75 at entry (n=5805).

HPS also substantially increases knowledge about diabetics; this trial included the largest number of diabetic patients ever randomized in a lipid-lowering trial. In diabetics with no history of CHD, there was a 28% reduction in major vascular events with simvastatin.

Looking at patients by baseline LDL cholesterol levels (split into 3 groups: <3.0 mmol/L; 3.0 to <3.5; and >3.5), there was a significant reduction in vascular events in all these groups, irrespective of their starting cholesterol level. Even in the lowest group, there was a 24% reduction in risk of major vascular events.

Simvastatin treatment was well tolerated, with only 0.8% of patients experiencing a liver enzyme elevation ALT 3x the upper limit of normal (compared with 0.6% of placebo-allocated patients) and only 0.09% experiencing muscle symptoms per creatinine kinase level (vs 0.05% placebo).

Investigators concluded that compliance with a regimen of 40 mg qd of simvastatin safely reduces the risk heart attack, stroke and revascularization by at least one-third in all study groups irrespective of starting cholesterol levels. In this population of high-risk patients, statin therapy prevented anywhere from 70 to 100 major vascular events per 1,000 treated for 5 years.

The researchers extrapolated that if an extra 10 million people were treated with a statin worldwide, there would be 50,000 lives saved annually and even larger numbers of nonfatal heart attacks and strokes prevented.