Heart Protection Study (HPS)

Through the 1990s, most clinicians treated lipid-lowering as a matter of reaching a target LDL number. If a patient's LDL looked acceptable, the reasoning went, adding a statin offered little. The MRC/BHF Heart Protection Study was designed specifically to test that assumption, enrolling 20,536 adults whose cardiovascular risk was high for reasons beyond their cholesterol levels: prior heart disease, peripheral arterial disease, diabetes, or treated hypertension.

Between 1994 and 1997, 69 hospital clinics across the United Kingdom randomized participants to 40 mg simvastatin daily or matching placebo, and followed them for an average of five years. The primary results, published in the Lancet in July 2002, showed a 24% reduction in major vascular events in the statin group, encompassing coronary deaths, non-fatal myocardial infarction, stroke, and coronary or peripheral revascularization. All-cause mortality fell by 13% in the simvastatin arm.

The subgroup that drew the most attention had baseline LDL below 3.0 mmol/L (116 mg/dL). That group gained roughly the same relative benefit as those starting above the threshold, so the result did not depend on the entry cholesterol. The investigators put the gain in absolute terms: five years of simvastatin would prevent a major vascular event in about 70 to 100 of every 1,000 such patients, and the size of that benefit depended chiefly on their overall risk.

Clinicians had routinely withheld statins from diabetic patients without overt coronary disease, from stroke survivors, and from those with peripheral arterial disease on the grounds that LDL was not clearly elevated. HPS enrolled all three groups in meaningful numbers and showed consistent benefit across each. The trial enrolled 5,082 women, and women and patients over 70 showed the same proportional reduction in events; earlier statin trials had enrolled both groups sparsely.

Guideline committees in the United Kingdom, Europe and North America began to base statin eligibility on total cardiovascular risk as well as lipid levels. In 2004 the US National Cholesterol Education Program revised its guidelines in light of five statin trials published since 2001, HPS among them. It made an LDL goal below 70 mg/dL an option for patients at very high risk, including those whose LDL was already below 100 mg/dL.