Primary Prevention of Coronary Heart Disease

Christie M. Ballantyne

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.


    Primary Prevention of Coronary Heart Disease
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 Primary Prevention of Coronary...
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CORONARY heart disease (CHD) is the leading cause of death in both men and women in the United States, causing almost 500,000 deaths annually (1). Each year, 1.1 million Americans have a myocardial infarction (MI) or fatal CHD; 650,000 are first events, and 50% of men and 63% of women who die suddenly of CHD have no prior symptoms (1). In addition to the enormous human cost, the total economic cost of CHD each year is estimated at $118 billion, including direct costs of $55 billion for hospitals and nursing homes, physicians and other health care professionals, drugs, and home health and other medical durables, as well as indirect costs for lost productivity caused by morbidity and mortality (1).

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 25–35% (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 4–5% and recurrent MI decreased by 2–3% 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 160–189 mg/dL and patients with two or more risk factors who have a LDL-C of 130–159 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 130–190 mg/dL, or 125–129 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 (20–40 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, 143–156 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 1988–1994 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. 1Go). 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 30–34 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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Figure 1. Recent clinical event trials of lipid-lowering therapy. The number needing to be treated (NNT) to prevent one clinical event increases markedly when treating patients without known CHD and with lower cholesterol concentrations. However, the majority of individuals with CHD do not have markedly elevated cholesterol; similarly, the largest number of individuals who will have a CHD event come from the largest population at risk, individuals with only mildly to moderately elevated cholesterol. To ensure that the largest number of individuals who may benefit from therapy receive appropriate treatment, refined risk assessment strategies are necessary. AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study (6 ); CARE, Cholesterol and Recurrent Events study (11 ); LIPID, Long-Term Intervention with Pravastatin in Ischaemic Disease study (10 ); 4S, Scandinavian Simvastatin Survival Study (9 ); WOSCOPS, West of Scotland Coronary Prevention Study (5 ).

 
Although the NCEP guidelines stratify patients on the basis of CHD risk, these three broad categories, based on the presence or absence of CHD, a dichotomization of summed risk factors as less than two or two or more, and LDL-C level, may be inadequate to assess an individual’s actual risk for a CHD event. One approach is to identify groups with extremely high risk, such as individuals with diabetes mellitus (12), and consider their risk to be the same as patients with CHD (i.e. a CHD equivalent) (13), or to redefine levels for risk stratification (e.g. HDL-C <40 mg/dL). If diabetes mellitus is considered a CHD equivalent, then impaired glucose metabolism could potentially be considered a major risk factor. An alternative method is to calculate an individual’s absolute CHD risk taking into account not only each risk factor present but also the severity of each risk factor. One such algorithm has been developed by the investigators of the Framingham Heart Study (14). The Framingham risk prediction equation calculates 10-yr CHD risk based on an individual’s sex, age, cholesterol or LDL-C level, HDL-C level, blood pressure, presence or absence of diabetes, and whether or not the individual smokes. Treatment decisions can then be made on the basis of more precise risk assessment. An analysis comparing the predictive value of previous Framingham equations with the NCEP guidelines found that Framingham was significantly more accurate (area under the receiver operating characteristic curve, 0.85, compared with 0.74 for the NCEP guidelines) and had greater sensitivity (70% compared with 45% for the NCEP guidelines); specificity was only slightly reduced (82% compared with 86%) (15). The most recent Framingham prediction equation has been validated in some (16) but not all (17) populations.

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 1Go). Both guidelines provide tools for estimating an individual’s 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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Table 1. International guidelines for CHD prevention

 
In addition to calculating absolute risk by using more sophisticated algorithms, another method to improve risk assessment is the use of additional diagnostic tests (2). Measurement of nontraditional risk factors, such as lipoprotein(a), high-sensitivity C-reactive protein (20), fibrinogen, homocysteine, plasminogen activator inhibitor 1, and intercellular adhesion molecule 1 levels, may refine risk assessment, as may new technologies such as carotid ultrasound, ultrafast computed tomography, and magnetic resonance imaging. These tests may better stratify individuals who are at intermediate risk for future events based on a Framingham score. Results from the ongoing Subclinical Cardiovascular Disease Study of the United States National Heart, Lung, and Blood Institute should clarify which traditional and nontraditional risk factors and diagnostic tests are useful and cost-effective in identifying high-risk patients.

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.


    Acknowledgments
 
I acknowledge Kerrie Jara for editorial assistance.


    Footnotes
 
"Clinical Perspectives" are an occasional feature of The Journal of Clinical Endocrinology & Metabolism. They present the opposing views of invited contributors on a topic. All reprints must include the complete Clinical Perspective, so that each section can be read in context.

Accepted March 6, 2000.


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