The Heart Protection Study included 20,536 persons aged 40-80 years (5806 persons aged 70-80 years at study entry and 75-85 years at follow-up) with a serum total cholesterol of 135 mg/dL or higher and prior myocardial infarction (MI) (8510 persons), other CHD (4876 persons), or no CHD (7150 persons).⁴ Of the 7150 persons without CHD, 1820 had cerebrovascular disease, 2701 had peripheral arterial disease, and 3982 had diabetes. Although treated hypertension was present in 8457 persons, only 237 persons were included on the basis of hypertension alone. Persons were randomized to simvastatin 40 mg daily or to placebo. Mean follow-up was 5 years.

Compared with placebo, simvastatin caused significant decreases in all-cause mortality by 13%, in any vascular death by 17%, in major coronary events by 27%, in any stroke by 25%, in coronary or noncoronary revascularization by 24%, and in any major vascular event by 24%.4 In the 3500 persons with an initial serum LDL- cholesterol of lower than 100 mg/dL, reducing the serum LDL cholesterol from 97 mg/dL to 65 mg/dL by simvastatin caused a similar decrease in risk as did treatment of patients with higher serum LDL-cholesterol levels.⁴ Simvastatin significantly decreased all-cause mortality, vascular death, major coronary events, coronary or noncoronary revascularization, and any major vascular event regardless of initial levels of serum lipids, age, or gender.⁴ On the basis of these data, the Heart Protection Study Investigators recommended treating patients at high risk for vascular events with statins, regardless of the initial levels of serum lipids, age, or sex.⁴

At 3-year follow-up of 1410 persons, mean age 81 years, with prior MI and a serum LDL cholesterol of 125 mg/dL or higher, decreasing the serum LDL-cholesterol by statins to lower than 90 mg/dL was associated with a 20% incidence of new coronary events, whereas decreasing the serum LDL cholesterol to 90-99 mg/dL was associated with a 48% incidence of new coronary events.⁵ Statins significantly reduced the incidence of new coronary events in persons 60-70 years of age, in persons 70-80 years of age, in persons 80-90 years of age, and in persons 90-100 years of age.⁵ The incidence of new stroke was 7% if the serum LDL-cholesterol was decreased to lower than 90 mg/dL and 16% if the serum LDL cholesterol was decreased to 90-99 mg/dL.⁶ Statins significantly reduced new stroke in persons up to age 90 years but not in persons older than 90 years.⁶

In the Lipid Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes trial, 10,305 persons (6570 older than 60 years) with hypertension and at least 3 other cardiovascular risk factors with no history of CHD and a mean serum LDL cholesterol of 133 mg/dL were randomized to atorvastatin 10 mg daily or to placebo.¹¹ At 3.3-year follow-up, the serum LDL cholesterol was 90 mg/dL in persons treated with atorvastatin. At 3.3-year follow-up, atorvastatin significantly decreased the incidence of fatal CHD and nonfatal MI by 34% in persons aged 60 years and younger and by 36% in persons older than 60 years.¹¹ Atorvastatin significantly decreased fatal and nonfatal stroke by 27%.¹¹

In the Reversal of Atherosclerosis With Aggressive Lipid Lowering (REVERSAL) study, intravascular ultrasound was used to measure progression of atherosclerosis in 502 patients, mean age 57 years (up to age 75), with CHD randomized to pravastatin 40 mg daily or atorvastatin 80 mg daily.¹⁵ The serum LDL cholesterol was decreased to 110 mg/dL in the pravastatin group and to 79 mg/dL in the atorvastatin group. At 18-month follow-up, compared with baseline values, patients treated with atorvastatin had no change in atheroma burden, whereas patients treated with pravastatin had progression of coronary atherosclerosis.¹⁵

In 4162 patients, mean age 58 ± 11 years, hospitalized for an acute coronary syndrome (29% with unstable angina and 71% with an acute MI), the median serum LDL cholesterol was 95 mg/dL in patients randomized to pravastatin 40 mg daily versus 62 mg/dL in patients randomized to atorvastatin 80 mg daily.16 At 2-year follow-up, the primary end point of death from any cause, MI, documented unstable angina requiring rehospitalization, coronary revascularization (performed at least 30 days after randomization), and stroke was 26.3% in the pravastatin group versus 22.4% in the atorvastatin group, a 16% reduction in favor of atorvastatin (p = 0.005).¹⁶

These data favor modification of the NCEP III guidelines in elderly and younger persons. Elderly or younger persons at high risk for cardiovascular events should be treated with a statin, regardless of initial serum lipid levels. In addition, the serum LDL-cholesterol goal should be lower than 70 mg/dL, not lower than 100 mg/dL. The most potent statins for achieving these serum LDL-cholesterol goals are atorvastatin and rosuvastatin.^17,18 If another drug is needed to reach a serum LDL-cholesterol goal of lower than 70 mg/dL, the cholesterol absorption inhibitor ezetimibe should be administered in addition to a statin.¹⁸ Persons with 2 or more risk factors and a 10-year risk for CAD of 10% to 20% should have their serum LDL cholesterol reduced to lower than 100 mg/dL.

Since this editorial was submitted for publication, the Coordinating Committee of the National Cholesterol Education Program published new guidelines which were endorsed by the National Heart, Lung, and Blood Institute, the American College of Cardiology, and the American Heart Association.¹⁹ These guidelines state that in very high-risk persons, a serum LDL- cholesterol goal of lower than 70 mg/dL is a reasonable clinical strategy on the basis of the available data. When a high-risk patient has high serum triglycerides or low high-density lipoprotein cholesterol, consideration can be given to combining a fibrate or nicotinic acid with an LDL-cholesterol-lowering drug. For moderately high-risk persons (2 or more risk factors and a 10-year risk for CAD of 10% to 20%), a serum LDL-cholesterol goal of lower than 100 mg/dL is a therapeutic option on the basis of recent data. When LDL-cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the intensity of therapy should be sufficient to achieve at least a 30% to 40% reduction in serum LDL-cholesterol levels. Recent data also confirm that older persons benefit from therapeutic lowering of serum LDL cholesterol. Finally, any person at high risk or moderately high risk for CAD who has lifestyle-related risk factors is a candidate for therapeutic lifestyle changes regardless of the serum LDL-cholesterol level. I strongly support these recommendations.