Department of Medicine Baylor College of Medicine Houston, Texas 77030
Address correspondence to: Robert A. Kreisberg, M.D., Dean and Vice President for Health Affairs, University of South Alabama, CSAB 170, Mobile, Alabama 36688-0002.
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Primary Prevention of Coronary Heart Disease |
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The pain, suffering, and cost of CHD is even more distressing because so many CHD events are preventable. Available clinical trial evidence confirms that CHD morbidity and mortality can be reduced by treating risk factors such as dyslipidemia; lipid-regulating therapy can reduce the relative risk for CHD events by 2535% (2). However, although CHD mortality rates are decreasing overall, many high-risk patients without known CHD do not receive appropriate treatment. In an analysis of data from the Atherosclerosis Risk in Communities (ARIC) study, using a retrospective surveillance system, CHD death decreased by 45% and recurrent MI decreased by 23% annually from 1987 to 1994, whereas first MI did not change (+0.1% in men, -0.2% in women) (3).
National Cholesterol Education Program (NCEP) treatment guidelines
The United States NCEP guidelines for the diagnosis and
treatment of hypercholesterolemia stratify individuals on the basis of
risk categories (4). At highest risk for a CHD event are individuals
with known CHD or other atherosclerotic vascular disease; for
individuals without known CHD, the guidelines further categorize risk
according to the number of CHD risk factors present. Positive risk
factors in the NCEP algorithm for primary prevention are age (45 yr
in men;
55 yr, or premature menopause without estrogen-replacement
therapy, in women), family history of premature CHD (MI or sudden death
before age 55 in father or other male first-degree relative, or before
age 65 in mother or other female first-degree relative), current
cigarette smoking, hypertension (
140/90 mm Hg, or on antihypertensive
medication), low high-density lipoprotein cholesterol (HDL-C) (<35
mg/dL), and diabetes mellitus. High HDL-C (
60 mg/dL) is a negative
risk factor in the algorithm; if present, one risk factor is subtracted
from the total number of risk factors.
In the most recent NCEP guidelines for primary prevention, initiation levels for therapy and goals of treatment are determined by whether the total number of risk factors for an individual is less than two or two or more. In patients with less than two risk factors and low-density lipoprotein cholesterol (LDL-C) 160 mg/dL or greater, dietary therapy should be initiated with a goal of reducing LDL-C to less than 160 mg/dL. In patients with two or more risk factors, dietary therapy should be initiated if LDL-C is 130 mg/dL or greater, with a goal of reducing LDL-C to less than 130 mg/dL. Drug therapy should be considered in patients with less than two risk factors whose LDL-C remains 190 mg/dL or greater on diet therapy and in patients with two or more risk factors whose LDL-C remains 160 mg/dL or greater on diet. As with diet therapy, the goal of drug therapy is to reduce LDL-C to less than 160 mg/dL and less than 130 mg/dL, respectively. The NCEP guidelines recommend delaying drug therapy in men younger than 35 yr of age and in premenopausal women, unless LDL-C is 220 mg/dL or greater or unless additional risk is present.
In addition to individuals qualifying for drug therapy on the basis of the above cutpoints, the NCEP guidelines recommend the use of clinical judgment in determining whether to initiate drug therapy in individuals whose LDL-C is below the initiation level for drug therapy yet above goal despite diet therapy. Included for primary prevention are patients with less than two risk factors who are middle-aged or older and have a LDL-C of 160189 mg/dL and patients with two or more risk factors who have a LDL-C of 130159 mg/dL.
Clinical trial evidence
At the time the most recent NCEP guidelines were written, most of the available clinical trial evidence on lipid-lowering therapy was limited to patients with severe hypercholesterolemia and agents with low efficacy that was exacerbated by poor compliance because of adverse effects. Consequently, these agents did not show a beneficial effect on total mortality, and the relative benefits and risks of using lipid-lowering drug therapy, particularly in primary prevention, remained unclear. Since that time, however, widespread use of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has provided long-term data establishing the safety and efficacy of statin therapy. Five major clinical event trials enrolling almost 31,000 patients have provided data that have greatly influenced evidence-based clinical judgment, establishing the benefit of statin therapy on CHD morbidity and mortality in primary as well as secondary prevention, and in patients with mild to moderate as well as severe LDL-C elevations.
West of Scotland Coronary Prevention Study (WOSCOPS).WOSCOPS studied the effects of pravastatin as primary prevention in 6595 men with severely elevated LDL-C of 155 mg/dL or greater on two assessments and 174 mg/dL or greater on at least one assessment (5). Pravastatin (40 mg/day) reduced mean LDL-C from 192 mg/dL to 159 mg/dL. At a mean follow-up of 5 yr, the primary end point of nonfatal MI or CHD death as a first event was significantly reduced by 31% with pravastatin, and total mortality was reduced by 22%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).AFCAPS/TexCAPS extended the benefit of lipid-lowering therapy as primary prevention to patients whose LDL-C was only mildly to moderately elevated (6). Lipid criteria included LDL-C of 130190 mg/dL, or 125129 mg/dL with total cholesterol/HDL-C more than 6, and HDL-C 45 mg/dL or less in men and 47 mg/dL or less in women. Mean baseline LDL-C in the 6605 patients randomized was 150 mg/dL; eighty-three percent of the study population had baseline LDL-C below the initiation level for drug therapy in the NCEP guidelines. Lovastatin (2040 mg/day) reduced LDL-C to 115 mg/dL, an average reduction of 25%. The primary end point, first acute major coronary event (fatal or nonfatal MI, unstable angina, or sudden cardiac death), was significantly reduced by 37% with lovastatin, and fatal or nonfatal MI was significantly reduced by 40%. For the primary end point, similar relative risk reductions occurred across all tertiles of baseline LDL-C: 142 mg/dL or less, 143156 mg/dL, and 157 mg/dL or greater.
Implications affecting treatment decisions
The AFCAPS/TexCAPS investigators estimate that approximately 8 million Americans without CHD have lipid profiles similar to the patients in AFCAPS/TexCAPS, including an estimated 6 million Americans who would not currently be recommended for drug therapy using the NCEP cutpoints presented above (6). Although clinical trials of statin therapy have demonstrated benefits in patients whose LDL-C would generally be considered borderline high, extending treatment to everyone who might potentially benefit based on the AFCAPS/TexCAPS results would require enormous resources. A recent analysis of National Health and Nutrition Examination Survey data (NHANES III) for 19881994 estimates that including all patients for whom the NCEP guidelines recommend the use of clinical judgment in determining whether to initiate drug therapy would require treating 28.4 million Americans, including 17.5 million without CHD but who have two or more risk factors in the NCEP algorithm (7). Therefore, clinical judgment must be informed not only by scientific evidence but also by cost-effectiveness issues (2, 8).
The number of patients who need to be treated to prevent one clinical
event increases dramatically as one moves from secondary to primary
prevention and from severe to milder LDL-C elevations (Fig. 1). For example, among the severely
hypercholesterolemic CHD patients enrolled in the Scandinavian
Simvastatin Survival Study (9), 12 would need to be treated to prevent
one event, compared with 3034 in the Long-Term Intervention with
Pravastatin in Ischaemic Disease study (10) and the Cholesterol and
Recurrent Events trial (11), which were conducted in CHD patients with
milder LDL-C elevations. In contrast, 46 WOSCOPS patients and 50
AFCAPS/TexCAPS patients needed to be treated to prevent each event. In
both WOSCOPS and AFCAPS/TexCAPS, higher-risk patients could be
identified if other risk factors besides LDL-C were examined. The
benefit of therapy as measured by the absolute risk reduction or the
number needing to be treated to prevent one event is more dependent on
the absolute risk for CHD than the level of LDL-C in any population
studied. It is, therefore, imperative to identify the highest-risk
patients to ensure appropriate therapy and the optimum use of health
care resources.
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Absolute risk is used to determine intensity of treatment in guidelines
developed by the International Task Force for Prevention of Coronary
Heart Disease/International Atherosclerosis Society (18) and by the
Joint Task Force of the European Society of Cardiology, European
Atherosclerosis Society, European Society of Hypertension,
International Society of Behavioural Medicine, European Society of
General Practice/Family Medicine, and European Heart Network (19)
(Table 1). Both guidelines provide tools
for estimating an individuals risk for a CHD event; the former also
stratifies LDL-C treatment goal on the basis of absolute risk, whereas
the latter uses risk to determine the need for lipid-lowering drug
therapy. Although lipid lowering for the prevention of CHD is the focus
here, both these international guidelines emphasize the multifactorial
nature of CHD and the need for reduction of all modifiable risk
factors.
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Conclusions
Although the NCEP guidelines, by providing for the use of clinical judgment in determining whether to initiate lipid-lowering drug therapy in patients with borderline LDL-C elevations, allow for evolving information on the benefits and safety of lipid-lowering drugs, the guidelines remain limited because of their simplified risk stratification algorithm. Emerging clinical trial data indicate that patients with LDL-C levels ranging from mildly to seriously elevated receive benefit from lipid-lowering therapy but that other risk factors besides LDL-C are important in assessing CHD risk and benefit from therapy. Risk prediction tools that reflect the substantial contribution of risk factors in addition to LDL-C can provide more refined risk assessment, which in turn can improve cost-effectiveness by identifying high-risk patients and targeting them for more aggressive intervention.
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Acknowledgments |
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Footnotes |
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Accepted March 6, 2000.
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References |
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