Cardiovascular Drugs and Therapy 18 387–389 2004 C  2005 Springer Science + Business Media, Inc. Manufactured in The Netherlands REVIEW Lipid-Lowering Therapy in Patients with Average Cholesterol and High Cardiovascular Risk, Insights from the Heart Protection Study Amar M. Salam Department of Cardiology and Cardiovascular Surgery, Hamad Medical Corporation, Doha, Qatar Summary. Although the benefits of cholesterol-lowering with statins has been established for patients with high cholesterol levels as well as for patients with prior occlusive coronary heart disease, substantial uncertainty has existed about the long-term benefits of these agents in particular types of patient, including patients with moderate or low baseline cholesterol levels pre-treatment, women, the el- derly, and those with prior occlusive non-coronary vascular disease. The Heart Protection Study was designed to resolve these uncertainties and to provide substantially more safety information of statins. In this report the study is presented with the significance and practical implications of the re- sults briefly discussed. Key Words. coronary disease, cholesterol, lipid lowering, statins Introduction Since the introduction of HMG-CoA reductase in- hibitors in the late 1980s, several large-scale, ran- domised, placebo-controlled clinical trials have demon- strated the efficacy of these agents in reducing cholesterol and coronary heart disease (CHD) morbid- ity and mortality rates in both primary and secondary prevention. The Scandinavian Simvastatin Survival Study (4S) provided the first evidence that cholesterol- lowering therapy can reduce all-cause mortality in sub- jects with a history of angina pectoris or myocardial infarction (MI) [1]. This study of 4,444 men and women with total cholesterol levels of 212 to 310 mg/dl (5.5 to 8.0 mmol/L) initially used simvastatin at 20 mg/day and then titrated the drug to 10 or 40 mg/day. At five years, all-cause mortality was reduced by 30%, major coronary event rate by 34% and the coronary death rate by 42%. The dramatic results of the 4S study were extended in the West of Scotland Coronary Prevention Study (WOSCOPS), which was a primary-prevention trial of pravastatin 40 mg daily in 6,595 men with mean total cholesterol levels of 272 mg/dl (7.0 mmol/L) but without documented CHD [2]. After an average of 4.9 years of follow-up, all-cause mortality was non-significantly re- duced by 22% ( p = 0.051), but nonfatal MI or death from CHD was significantly reduced by 31% and the CHD death rate reduced by 28%. The need for coronary an- giography and revascularization was also significantly lower in the treated group. The Cholesterol and Re- current Events (CARE) trial was a secondary preven- tion trial of pravastatin 40 mg daily in 4,159 men and women who had an acute MI between 3 and 20 months before randomization and in whom the total cholesterol level was <240 mg/dl (6.2 mmol/L) with an LDL level of 115 to 174 mg/dl (3.0 to 4.5 mmol/L) [3]. The primary end point of fatal coronary event or nonfatal MI was reduced by 24%, and the need for coronary artery by- pass surgery was reduced by 26%. Finally, the CARE study also demonstrated that women experienced a ma- jor reduction in risk for coronary events and stroke, with benefit evident beginning at one year. Later on, The Air Force/Texas Coronary Atherosclerosis Pre- vention Study (AFCAPS/TexCAPS) [4] investigated 6,605 men and women without clinical evidence of CHD, with an average LDL level; 130 to 190 mg/dl (3.4 to 4.9 mmol/L) with below average HDL cholesterol level (<50 mg/dl), and who were treated with placebo or lo- vastatin titrated up to 40 mg daily to achieve an LDL level less than 110 mg/dl (2.9 mmol/L). After 4.8 years of follow-up, the incidence of first major acute coronary event was reduced by 37% in the treated group. The Long-term Intervention with Pravastatin in Ischemic Disease study (LIPID) [5] was a secondary prevention study to compare pravastatin 40 mg daily to placebo in 9,014 men and women with prior MI or unstable angina and total cholesterol levels between 155 and 271 mg/dl (4 to 7 mmol/L). After a mean follow-up of 6.1 years, all-cause mortality was reduced by 22%, mortality due to CHD by 24%, and stroke by 19%. Such results established the efficacy (i.e. reduction in coronary disease events) of cholesterol-lowering in some circumstances, and the tolerability of long-term daily statin therapy, but doubts have remained about how widely statins should be prescribed. The Heart Protection Study (HPS) [6] was designed to address Address for correspondence: Amar Mohammad Salam, MB, BS, MRCP (UK), Senior Specialist, Department of Cardiology and Cardiovascular Surgery, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar. Tel.: (+974) 4392642; Fax: (+974) 4392454; E-mail: amaramin@yahoo.com 387