Updated Guidelines for Cholesterol Management

During the past decade, there has been tremendous progress in identifying novel risk factors and precisely delineating the role of traditional risk factors associated with coronary heart disease (CHD), with substantial research advances related to the role of lipoproteins and lipid metabolism. Observational studies have established the relationship of serum cholesterol and other lipoproteins with CHD in specific subgroups.^{1 - 3} Clinical trials have demonstrated convincing benefits of cholesterol lowering for reducing death and myocardial infarction among patients with CHD^{4 - 5} as well as beneficial effects of cholesterol lowering for decreasing the incidence of cardiac events in patients without established coronary disease.^{6 - 7} Accurately synthesizing and appropriately applying this rapidly accumulating evidence into clinical practice is essential for reducing the morbidity and mortality associated with coronary disease.

Thus, the Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel (Adult Treatment Panel III [ATP III])⁸ published in this issue of THE JOURNAL is most welcome. The NCEP expert panel, a multidisciplinary group that includes leading clinicians and researchers, provides a detailed summary of updated clinical guidelines for the detection, evaluation, and management of high blood cholesterol in adults. The Executive Summary is based on the comprehensive ATP III document,⁹ a more than 200-page detailed report that includes numerous tables and over 800 references, and in which the NCEP panel thoroughly evaluates current scientific information on cholesterol, applies a rigorous evidence-based framework, and carefully outlines the clinical and scientific rationale for the guidelines and recommendations.

The marked increase in new information on lipoproteins that has become available since publication of Adult Treatment Panel II in 1993¹⁰ has resulted in many new and important features in ATP III. Although the authors summarize some of the new features of the updated guidelines (in their Table 1), several aspects of the ATP III Report deserve special mention.

First, among patients without clinical coronary disease, emphasis is placed on prospectively estimating absolute risk. Most clinical research literature reports relative risks with statements such as, "Patients with finding X were Y times more likely to have an event than patients without finding X." Although this information is helpful, it is an important step away from actual clinical practice. Real physicians caring for real patients care about real, that is, absolute, risk. The important clinical question is, "What is this patient's actual likelihood for developing disease?"

In ATP III, patients with an absolute 10-year risk of >20% for developing clinical coronary disease are considered candidates for very aggressive therapy. This includes a low-density lipoprotein (LDL) cholesterol treatment goal of <100 mg/dL and a recommendation to initiate drug therapy at an LDL level of >130 mg/dL. Patients with diabetes are also considered candidates for aggressive therapy, whether or not clinical coronary disease is present, because their absolute risk for major events is also very high. For patients with an estimated absolute risk of 10%-20%, somewhat less aggressive therapy is recommended, although the guidelines do suggest pharmacotherapy if needed to keep LDL levels <130 mg/dL.

To calculate absolute risk for developing new coronary disease, the ATP III Report presents a modification of the Framingham Risk Prediction Score. The scheme presented is slightly, but importantly, different from a previously published version¹¹ in that it does not include diabetes, because diabetes is now considered a CHD equivalent rather than a risk factor. The scheme takes into account important interactions of age with smoking, age with total cholesterol, and systolic blood pressure with treatment. Despite the sophistication of the sex-specific models, these risk prediction–scoring instruments should be easy to incorporate into clinical practice.

A second important feature of the ATP III Executive Summary is the inclusion of lipid abnormalities that go beyond elevated LDL cholesterol. The metabolic syndrome is a recently recognized constellation of findings thought to arise from insulin resistance and includes hypertension, abdominal obesity, hyperglycemia, elevated triglyceride levels, and low levels of high-density lipoprotein (HDL) cholesterol.^{12 - 13} Specific recommendations for treatment include weight control, physical activity, and a seemingly paradoxical dietary recommendation of greater fat intake, primarily as unsaturated fat. Other non–LDL-related recommendations in ATP III include raising the cutoff level for defining abnormally low HDL, incorporating triglyceride levels into treatment strategies when they exceed 200 mg/dL, and recognizing that in some patient populations treatment specifically designed to increase HDL levels is appropriate.¹⁴

A third important component of the Executive Summary is the set of recommendations specifically targeted toward women and older adults. Although women tend to manifest coronary disease 10 to 15 years later than men, it is highly underappreciated that CHD is the leading cause of death among women in the United States.¹⁵ Much of the literature on prevention of heart disease in women has focused on hormone replacement therapy, which thus far has yielded disappointing results in rigorous clinical trials.¹⁶ In contrast, at least for secondary prevention, statin therapy has been shown to be effective in women.^{7 ,17} The NCEP panel appropriately recommends that men and women be treated similarly. The sex-specific Framingham Prediction Scores should help clinicians appropriately assess and treat women with or at risk for CHD.

Although the prognostic importance of hypercholesterolemia in older adults has been questioned,¹⁸ data from major clinical trials have shown that older adults do benefit from lipid-lowering therapy.¹⁷ The Executive Summary recommends that older persons also receive aggressive drug therapy and make lifestyle modifications, with careful attention to individual circumstances. Furthermore, the Framingham Prediction Scores incorporate age both as a predictor in and of itself and as a modifying factor of increasing levels of total cholesterol. For example, among women aged 40 to 49 years, a cholesterol level of 200-239 mg/dL adds 6 points to the prediction score, whereas among women aged 60 to 69 years only 2 points are added.

Finally, the Executive Summary recognizes the importance of support for implementation of cholesterol treatment in routine clinical practice. The best guidelines are useless if patients are not given the opportunity to benefit from them. Despite the publication of cholesterol-related guidelines¹⁰ and major clinical trials,^{4 - 5} actual use of cholesterol-lowering measures remains disappointingly low.¹⁹ Two specific recommendations from the Executive Summary may help deal with this serious problem. First, among high-risk patients with a baseline LDL level >130 mg/dL and among patients hospitalized for major coronary events, the NCEP guidelines recommend immediate initiation of drug therapy as opposed to after a trial of dietary therapy. The reality is that if patients do not start cholesterol-lowering drugs earlier, they are less likely to be prescribed them later.²⁰ Second, the Executive Summary presents a series of interventions designed to improve adherence, including programs that have been shown to be effective, such as lipid clinics and case management by nurses.²¹

The "cholesterol hypothesis" is no longer a hypothesis. There is no doubt that abnormal cholesterol levels cause major morbidity and mortality and that aggressive treatment saves lives. Careful management of lipid disorders in adults with or at risk for CHD is an essential component of quality cardiovascular care. High-quality lipid management is at least as important, if not more important, than myocardial revascularization, which is often considered a more valuable aspect of cardiac care by many patients and physicians.²² We encourage physicians and health care organizations to widely disseminate and rapidly implement the ATP III guidelines and to audit themselves aggressively to ensure that their patients are receiving the lifesaving benefits of lipid-lowering therapy.