ANAHEIM, CALIF—Results of the largest cholesterol-lowering study to date show that a broad range of patients, regardless of their baseline or posttreatment cholesterol levels, will benefit from treatment with a cholesterol-lowering drug. The researchers estimate that cholesterol lowering with statin treatment reduces the risk of heart attack and stroke by nearly one third and that, overall, the numbers of potential treatment candidates will expand by “tens, perhaps hundreds of millions worldwide.”

“This is a stunning result, with massive public health implications,” said lead author Rory Collins, MBBS, British Heart Foundation Professor of Medicine and Epidemiology and Co-Director of the Clinical Trial Service Unit at the University of Oxford. “We’ve found that cholesterol-lowering treatment can protect a far wider range of people than was previously thought, and that it can prevent strokes as well as heart attacks.”

The findings from the Medical Research Council/British Heart Foundation Heart Protection Study were presented at the American Heart Association’s 2001 Scientific Sessions.

The trial included 20,536 patients, ages 40 to 80, from 69 hospitals in the United Kingdom. The investigators targeted individuals at high risk of coronary heart disease but for whom their personal physicians felt there was no clear indication for lipid-lowering therapy. According to Dr. Collins, these criteria resulted in a good representation of patient groups in which the benefit of cholesterol lowering had been uncertain, including women (n = 5,082), patients older than 70 (n = 5,805), and patients with low-density lipoprotein (LDL) levels below 116 mg/dL (n = 6,793), as well as patients with a diagnosis of diabetes or noncoronary vascular disease, but without preexisting coronary heart disease.

The patients were randomized to receive 40 mg/d of simvastatin (n = 10,269) or placebo (n = 10,267), and were followed for an average of five and a half years. Using a factorial design, the researchers also assessed the effects of a regimen of antioxidant vitamins. Patients were randomized to a combination of 600 mg vitamin E, 250 mg vitamin C, and 20 mg beta carotene daily or placebo.

During the study, an average of about one–sixth of the patients allocated to statin therapy stopped tretment, and average of about one–sixth of those randomized to placebo started taking a statin, yielding an average difference in LDL between the groups of aobut 39mg/dL.

Dr. Collins reported that treatment with simvastatin resulted in a reduction of major vascular events from 2,606 (25.4%) in the placebo group to 2,042 (19.9%) in the treatment group, a highly significant relative risk reduction of 24%. Reductions were seen in each of the events making up this primary composite end point. Total coronary heart disease events were reduced from 1,234 (12.0%) in the placebo group to 914 (8.99%) on simvastatin treatment; revascularization was required in 926 in the simvastatin group compared to 1,185 in the placebo group; and total stroke was reduced from 613 (6.0%) with placebo to 456 (4.4%) with simvastatin, a significant 27% relative risk reduction.

Event-free survival curves showed separation between the groups by one year, which continued diverging to six years, suggesting that the absolute benefit may continue to increase further with even longer treatment. Positive gains were seen regardless of other preventive drugs already being used.

THE NEW ASPIRIN?

Dr. Collins compared his group’s findings with those regarding aspirin’s effects on heart attack and stroke. “Those findings changed medical practice, and we expect these to have the same effect,” he said. “In fact, statins are the new aspirin.”

Epidemiologic studies have shown that cholesterol levels are strongly associated with the risk of heart attack but not so strongly with the risk of stroke, Dr. Collins pointed out. “And yet, in this study we saw a reduction of at least a third in the risk of stroke with this regimen, despite the lack of a strong association in observational epidemiology,” he said.

THERAPEUTIC GAINS ARE WIDESPREAD

The researchers made several calculations to give some sense of the magnitude of their findings. They estimated that five years of statin treatment in these patients would typically prevent major vascular events in 100 of every 1,000 patients with previous myocardial infarction; 80 of every 1,000 patients with angina or other evidence of coronary heart disease; and 70 of every 1,000 patients with previous stroke, occlusive disease in leg or another artery, or diabetes.

Overall, the side-effect profile of this statin regimen was very good in this study, Dr. Collins noted. “I think the important thing is these drugs are incredibly well tolerated,” he said. A small number of withdrawals were seen in each group for elevations in liver or muscle enzymes during the study. No evidence was seen of any increase with simvastatin treatment of nonvascular causes of death, cancer, or hemorrhagic stroke.

A GLOBAL PERSPECTIVE

Dr. Collins believes the benefit of statins regarding stroke prevention are particularly significant for other countries. “If you look at China, for example, they don’t have a lot of heart attacks, but they have an awful lot of strokes,” he said. Lowering cholesterol in people living in China, despite the country’s relatively low cholesterol levels, could produce substantial reductions in the risk of stroke there. “Obviously, we’re extrapolating from Britain to China, but I think it’s an appropriate extrapolation to consider as a way of preventing disability and death in the developing world,” he said.

No evidence of either risk or benefit was seen with antioxidant vitamin supplementation, noted Dr. Collins. However, the study did provide strong evidence of safety, with no excess risk of hemorrhagic stroke or of cancers at any site. “This contradicts the apparent adverse trends in some previous smaller studies of vitamin E and beta carotene,” said Dr. Collins. He added that his group will continue to follow this cohort to see if some benefit may emerge over time.

NR