Keeping an eye on cardiovascular risk

A practical, case-study approach to assessment in office practice

David T. Nash, MD

VOL 111 / NO 4 / APRIL 2002 / POSTGRADUATE MEDICINE

CME learning objectives

• To understand treatment options for various cardiovascular risk factors
• To become familiar with noninvasive techniques used to measure cardiovascular risk
• To improve recognition of patients with less dramatic risk factor status

Dr Nash has been an investigator in clinical trials sponsored by Warner-Lambert, Pfizer, Merck, and Bristol-Myers Squibb.

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Preview: More and more patients thought to be at relatively low risk for heart disease are being seen in emergency departments or hospitals because of an unanticipated coronary event. What can the primary care physician do to help avert such occurrences? In this article, Dr Nash discusses how coronary risk assessment can be incorporated in day-to-day patient management without the need for expensive tests or tools.
Nash DT. Keeping an eye on cardiovascular risk: a practical, case-study approach to assessment in office practice. Postgrad Med 2002;111(4):107-20

More than half the coronary deaths and most of the cases of myocardial infarction (MI) in the United States occur in persons who would be considered at low or intermediate risk for a coronary event (1). On that basis alone, assessing cardiovascular risk is appropriate for virtually any patient who seeks medical treatment. The expensive, invasive, or esoteric procedures available only at tertiary care centers are rarely needed for evaluation. Indeed, most patients can be assessed for risk on the basis of history taking, physical examination, and routine diagnostic tests.

Concepts of risk assessment

The last two decades have seen the development of various strategies for predicting risk of coronary artery disease (CAD). Data on blood pressure, smoking, cholesterol levels, and other risk factors derived from observational studies, such as the Framingham reports, have been integrated into regression equations to estimate global cardiovascular risk, the essential first step in primary prevention (2,3).

The degree of risk determines how aggressive intervention should be. Risk factors contribute to development of CAD through a number of mechanisms, many still conjectural. These risk factors may be categorized according to their currently known role as causal, conditional, or predisposing. For example, five independent risk factors are believed to have a major and directly causal role in promoting atherosclerosis and predisposing a person to CAD (table 1) (3).

Table 1. Categories of risk factors for coronary artery disease

Major causal Cigarette smoking Hypertension Elevated total cholesterol and LDL-C levels Diabetes Low HDL-C level Conditional Elevated triglyceride level Small LDL-C particles Abnormal levels of lipoprotein(a) Abnormal levels of homocysteine Abnormal levels of coagulation factors Predisposing Obesity Physical inactivity Family history of premature CAD Socioeconomic, ethnic, behavioral factors Male sex Insulin resistance CAD, coronary artery disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Adapted from Grundy (3).

According to the Framingham study and other prospective studies, most of the excess CAD risk in high-risk societies is the result of these five causal risk factors (3). Risk factors that have an uncertain causal link to CAD are termed conditional, but their presence correlates with increased risk. Predisposing risk factors all interact with the causal risk factors and some conditional factors through complex pathways. Obesity has been singled out as the foremost predisposing risk factor for CAD in the US population (3).

The National Cholesterol Education Program (NCEP) has taken an active role in dispensing information about CAD risks to both the public and the medical community (4). Age was added as a coronary risk factor in the NCEP's second report (5), although it more reliably predicts coronary risk in a population than it estimates atherosclerotic severity in an individual person. However, it is still used in risk assessment as a surrogate marker for plaque burden, which increases with age. Coronary calcium scores could replace age as a risk factor in the future when standardized techniques become available (3).

Evaluating risk in clinical practice

The major risk factors can be readily identified in office practice: age and smoking status can be determined by simply questioning the patient; blood pressure, lipid levels, and fasting plasma glucose concentration are easily measured, and the latter two are part of a standard laboratory chemistry panel. Most of the predisposing risk factors also can be identified through history taking and physical examination. Body mass index (BMI), which reflects weight in kilograms divided by height in meters squared, is an index of total body fat, and overweight is defined as a BMI of 25 kg/m² or more (6). The degree of insulin resistance correlates with waist circumference; more than 100 cm (40 in) for men and more than 90 cm (36 in) for women are probably significant (3). In any event, a waist circumference of 94 cm (36.7 in) or more in men and 80 cm (31 in) or more in women is an indication for dietary therapy (6).

Serum cholesterol, particularly low-density lipoprotein cholesterol (LDL-C), is the most atherogenic lipoprotein, receives the most attention in risk assessment, and should be the primary target of the most intense risk factor modification. In fact, coronary events often occur in persons with a serum LDL-C level between 130 and 160 mg/dL (3.36 and 4.14 mmol/L) (7), which is below the level recommended for primary prevention with drug therapy, according to NCEP guidelines (8).

Data from the Framingham study (2,8) indicated that although total cholesterol levels of 240 mg/dL (6.21 mmol/L) or higher clearly conferred a high risk of MI, 20% of coronary events occurred at presumably "safe" levels of less than 200 mg/dL (5.17 mmol/L). Specifically, in men 50 to 84 years of age, a significant number of coronary events occurred even though serum levels of total cholesterol and LDL-C were well below those recommended for treatment. Serum total cholesterol levels in men in whom CAD developed averaged only 223 to 227 mg/dL (5.77 to 5.87 mmol/L), and LDL-C levels averaged only 146 to 151 mg/dL (3.78 to 3.9 mmol/L). Interestingly, most patients in whom MIs occurred at low cholesterol levels had high-density lipoprotein cholesterol (HDL-C) levels below 35 mg/dL (0.91 mmol/L) (8).

The intensity of primary prevention efforts is guided by the degree of absolute risk--the likelihood that CAD will develop in a patient within a specific period of time. Patients should be considered at high, moderate, or low risk depending on their probability of developing clinical CAD in the next 10 years. An absolute risk for major coronary events approaching that of patients with established CAD designates high risk--a 20% or higher probability of having an MI in the next 10 years. Positive exercise stress tests, multiple risk factors, and atherosclerotic disease in peripheral arteries (including symptomatic carotid disease) are among the indicative signs. Patients in this risk category merit aggressive medical intervention similar to that needed by a patient who has already had a cardiac event (3,9).

Framingham study investigators recently published a scoring system for estimating 10-year absolute risk on the basis of major risk factors (2). A European joint task force, assembled from several cardiology-related professional associations, has also published specific guidelines for primary and secondary prevention in clinical practice (6). Although these scoring systems have been of academic interest, the vast majority of physicians merely eyeball the risks and decide on therapy.

Case reports

The three case histories that follow illustrate how office assessment can identify high-risk patients and point the way to intensity of treatment. The last of these also discusses a less-than-routine test that is not yet standardized for risk assessment but that can be expected to gain increasing availability and wider currency in primary care practice.

Case 1. Smoking and impaired glucose tolerance
A 51-year-old postmenopausal woman with a family history of breast cancer was concerned about the advisability of beginning hormone replacement therapy (HRT). After discussing the risks and benefits relative to her symptoms and family history, she elected to have a bone densitometry study and look at options other than HRT if the results warranted treatment.

The patient smoked one pack of cigarettes per day and weighed 146 lb. She noted that her weight had been stable at 125 lb until she was 45 years of age. Her family history was negative for heart disease. Fasting blood glucose level was 119 mg/dL (6.61 mmol/L); total cholesterol, 248 mg/dL (6.41 mmol/L); LDL-C, 190 mg/dL (4.91 mmol/L); HDL-C, 38 mg/dL (0.98 mmol/L); and triglycerides, 150 mg/dL (1.69 mmol/L).

Discussion: This apparently healthy woman, knowledgeable about the risks of HRT relative to her family history, would raise few clinical alarms. Nonetheless, she had several cardiovascular disease risks--notably smoking, a major cause of CAD among young and middle-aged women. The absolute effect of cigarette smoking escalates in women with other risk factors. Therefore, primary prevention efforts for this patient must be directed at smoking cessation. Aggressive urging and counseling about the markedly increased risk of premature death from CAD if smoking is continued convince some patients to give up the habit. The benefits of smoking cessation are dramatic and almost immediate; CAD mortality rates drop to those of nonsmokers within 12 months (3).

This patient, who had elevated total cholesterol and LDL-C levels, has hyperlipidemia and is at high risk for CAD (table 2). Her fasting blood glucose level, although not strictly indicative of diabetes, does indicate impaired glucose tolerance, which is a well-established atherogenic risk factor. Her weight gain also is worrisome. The American Heart Association designates obesity as a major risk factor for cardiovascular disease--one that predisposes to elevated blood pressure; high serum total cholesterol and triglyceride levels; low HDL-C levels; small, dense LDL particles; a prothrombic state; and type 2 diabetes. Clustering of these CAD risk factors, which occurs commonly in overweight and obese persons, has attracted much attention and many names (eg, syndrome X, metabolic syndrome, insulin resistance syndrome) (9).

Table 2. Stratification of risk of coronary artery disease, based on cholesterol levels
Classification	LDL-C level, mg/dL (mmol/L)	Total cholesterol level, mg/dL (mmol/L)
Optimal	<100 (2.59)	<160 (4.14)
Desirable	100-129 (2.59-3.34)	160-199 (4.14-5.15)
Borderline high risk	130-159 (3.36-4.11)	200-239 (5.17-6.18)
High risk	>160 (4.14)	>240 (6.21)
LDL-C, low-density lipoprotein cholesterol. Adapted from Grundy (15).

In the Framingham Offspring Study (10), a prospective community sample that included 2,569 women, clustering of three or more risk factors was associated with 48% of the CAD events in women. This clustering tendency suggests that many risk factors are metabolically linked offshoots of some fundamental process. Weight gain in this study increased the clustering tendency, conferring a greatly increased risk of coronary disease in both sexes.

Management of this patient involves smoking cessation measures, exercise, and dietary therapy, including caloric restriction to achieve and maintain ideal body weight and reduce the LDL-C level. Increasing ingestion of soluble fiber and possibly plant stanols should be considered. If a short course of this nonpharmacologic therapy fails, the patient should be considered for drug therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ("statin") to lower her cholesterol level to 130 mg/dL (3.36 mmol/L) or less, since she is essentially a patient with at least two risk factors for CAD.

Case 2. Dyslipidemia and peripheral vascular disease
A 65-year-old man complained of chronic back pain that accompanied everyday tasks. The severity of the pain prevented him from gardening, a favorite activity, and he had intermittent claudication after walking three blocks. He had smoked 35 pack-years, from age 20 to 55. His lipid profile was as follows: total cholesterol, 220 mg/dL (5.69 mmol/L); LDL-C, 140 mg/dL (3.62 mmol/L); HDL-C, 40 mg/dL (1.03 mmol/L); and triglycerides, 200 mg/dL (2.25 mmol/L). His ankle-brachial artery pressure index was 0.8. An exercise stress test could not be completed because leg pain occurred within 3 minutes. He was referred to a physical therapist for his back pain.

Discussion: The incidence of intermittent claudication, consistent with this patient's history of smoking, increases sharply in late middle age. Intermittent claudication should be considered in a systemic context; peripheral arterial disease is a potent predictor of cardiovascular disease morbidity and mortality. Patients with intermittent claudication have a 40% to 60% prevalence of CAD and a mortality rate two and a half times that of an age-matched general population (11,12).

The ankle-brachial index (normal, >1) is obtained noninvasively and is an effective gauge of the severity of peripheral arterial disease. A ratio of less than 0.8 has been correlated with an increased occurrence of cardiovascular events and all-cause deaths (13). The Cardiovascular Health Study found a low ankle-arm index to be an important predictor of a first coronary event in men aged 65 or older who had no cardiovascular disease at baseline.

Treatment of this patient assumes the presence of subclinical cardiovascular disease and dictates an aggressive approach to modifying his risk factors. The primary lipid treatment goal would be to bring his LDL-C level down to less than 100 mg/dL (2.59 mmol/L), which is the goal for persons with CAD (table 3). Drug therapy, such as taking a statin, to achieve this goal is strongly recommended on the basis of impressive reductions in the number of clinical events in atherosclerotic patients taking statins.

Table 3. LDL-C goals and levels at which to initiate lifestyle changes and drug therapy
Category	LDL-C goal, mg/dL (mmol/L)	LDL-C level at which to initiate therapeutic lifestyle changes, mg/dL (mmol/L)	LDL-C level at which to consider drug therapy, mg/dL (mmol/L)
CAD, CAD risk equivalents, or 10-yr risk of >20%	<100 (2.59)	>100 (2.59)	>130 (3.36); at 100-129 (2.59-3.34), drug therapy is optional
>2 risk factors and 10-yr risk of <20%	<130 (3.36)	>130 (3.36)	>130 (3.36) if 10-yr risk of 10%-20%
			>160 (4.14) if 10-yr risk of <10%
0-1 risk factor	<160 (4.14)	>160 (4.14)	>190 (4.91); at 160-189 (4.14-4.89), drug therapy is optional
CAD, coronary artery disease; LDL-C, low-density lipoprotein cholesterol. Adapted from Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (4).

Case 3. Obesity, smoking, and family history of CAD
The presenting complaint of a 42-year-old man was a purulent nasal discharge, accompanied by frequent headaches over a 2-week period. He was diagnosed with sinusitis and treated empirically with an antibiotic.

His family history included a father who had survived an MI at age 51 and a paternal uncle who had been in apparent good health but who died suddenly at age 48. The patient had smoked about one and a half packs of cigarettes a day, starting in adolescence and continuing until 6 weeks before this office visit.

BMI was 28 kg/m², and waist circumference 95 cm (38 in). His lipid profile was as follows: total cholesterol, 195 mg/dL (5.04 mmol/L); LDL-C, 139 mg/dL (3.59 mmol/L); HDL-C, 36 mg/dL (0.93 mmol/L); and triglycerides, 101 mg/dL (1.14 mmol/L). The calcium score on electron-beam computed tomographic (EBCT) scan was 135.

Discussion: According to the NCEP's guidelines, this patient's total cholesterol level of 195 mg/dL is in the desirable range, and his LDL-C level is indicative of only borderline high risk. However, this patient can still be considered a current smoker, and he is overweight on the basis of both his BMI and waist circumference. His family history of heart disease signifies that his risk may be higher than it appears. Family studies in the 1960s and 1970s observed clustering of CAD in families, although no evidence of a Mendelian pattern of inheritance was found.

The EBCT scan was useful in assessing this patient's risk status. This 15-minute, noninvasive procedure requires neither undressing nor special preparation. It estimates the severity of coronary artery atherosclerosis by quantifying its correlate, coronary calcium. It is generally accepted that calcium scores higher than 130 are associated with calcified plaque (14). Calcium scores can reliably estimate the total coronary plaque burden, overcoming the weakness of using chronological age to assess risk (14). This approach offers a more reliable evaluation of middle-aged patients who appear to be at only moderate risk (1,3,15). Currently, however, there are no national guidelines on how to use data on coronary calcium scores.

The presence of calcium in this patient's coronary arteries can be taken as prima facie evidence of atherosclerosis and merits aggressive treatment, despite a borderline LDL-C level. Initial treatment should include dietary therapy and an exercise program for weight loss and reduction of the LDL-C level to 100 mg/dL (2.59 mmol/L) or less. Although a cholesterol-lowering diet remains a cornerstone of lipid-lowering therapy, it is most effective when used with drug treatment. The BMI goal is 21 to 25 kg/m². Follow-up in 3 months determines whether to begin drug therapy if the LDL-C level at that time is still higher than 100 mg/dL. Therapy with niacin could also be considered if statin therapy does not raise the HDL-C level above 40 mg/dL (1.03 mmol/L), as recommended by the new NCEP guidelines (4).

The case for lowering LDL-C concentration

An elevated LDL-C level, operating as it does at every stage of the atherosclerotic process, appears to be the primary CAD risk factor. In the United States, CAD is rarely seen in persons with LDL-C levels below 100 mg/dL (2.59 mmol/L). Populations with low LDL-C levels have a correspondingly low CAD prevalence, even when cigarette smoking, hypertension, and diabetes are present (16).

Compelling evidence of the atherogenic role of LDL-C comes from studies in animals; evaluation of epidemiologic, laboratory, and clinical data; and studies of genetic forms of hypercholesterolemia. The resulting body of data prompted the NCEP to issue its treatment guidelines, identifying LDL-C as the major causal agent for CAD and the primary target for lipid-lowering therapy.

The value of statin therapy for lowering LDL-C concentration and effecting significant reductions in coronary morbidity and mortality is well established in both primary and secondary prevention populations. One recent primary prevention trial also demonstrated that statin therapy confers additional benefits even at LDL-C values below the level recommended by the NCEP for initiating treatment (17). Thus, statin use not only decreases the risk of the first or subsequent atherosclerotic events, but also can avert events altogether and may prevent recurrences. Furthermore, some statins effect a significantly greater decrease in total cholesterol and LDL-C levels (eg, atorvastatin calcium [Lipitor], simvastatin [Zocor]) or are better at getting patients to NCEP goals with the starting dose (eg, atorvastatin) (18), although pravastatin sodium (Pravachol) has a very large database of double-blind clinical trials in both primary and secondary prevention. Finally, compared with other lipid-lowering drugs, including fibric acid derivatives, bile acid sequestrants, and niacin, statins have the lowest discontinuation rates (19).

Summary

Primary care physicians typically encounter patients who are not at obvious risk for CAD but who nonetheless need and can benefit from lipid-lowering therapy. Applying algorithms or scoring systems can be helpful in estimating an individual patient's risk, but the basic tools available in everyday clinical practice can be used to alert physicians to elevated CAD risk in their patients. Those patients whose LDL-C level is at or above 220 mg/dL (5.69 mmol/L) should routinely and deservedly get clinical attention, but they account for only 2.5% to 5% of the population (8). Those with an "average" LDL-C level number in the millions, and from this patient pool come the coronary events that fill clinics and hospitals.

Aggressive treatment approaches are required to meet NCEP objectives, and every indication suggests that these goals are just the minimum. The third report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (4) has broadened the indications for drug therapy, reclarifying diabetes and peripheral vascular or cardiovascular disease equivalents and using a global evaluation concept, which will identify 30 million Americans in need of drug treatment.

The statins safely and effectively lower LDL-C levels, which is the basis for instituting drug therapy, according to NCEP guidelines. Using these drugs also raises HDL-C levels, which is somewhat protective, and decreases triglyceride levels. The efficacy of statin therapy in both primary and secondary prevention of CAD is now well established. If used more often when dietary therapy fails, which happens quite often, and in doses sufficient to work effectively, statins have the power to turn the corner on the prevention and treatment of atherosclerotic coronary disease in the United States.

References

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16. Grundy SM. Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation 1997;95(1):1-4
17. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279(20):1615-22
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19. Insull W. The problem of compliance to cholesterol altering therapy. J Intern Med 1997;241(4):317-25

Dr Nash is a fellow of the Council on Epidemiology, American Heart Association, and clinical professor of medicine, State University of New York Health Science Center at Syracuse College of Medicine. Correspondence: David T. Nash, MD, Presidential Plaza, Suite 204, 600 E Genesee St, Syracuse, NY 13202. E-mail: davidnash@aol.com.

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