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Table of Contents

Published May 29, 2002

Keith Ellis, MD

Department
of Cardiology

Dennis L.
Sprecher, MD

Department of Cardiovascular
Medicine

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Definition

Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy

Outcomes

References

DEFINITION

In response to increased plaque volume, arterial remodeling occurs, which results in an outward expansion of the coronary arteries. The arteries expand in an effort to overcome the effects of the blockage allowing blood to flow through the stenosed vessel segment. This expansion continues until the artery reaches its maximum point of flexibility and can no longer accommodate the continued growth of the plaque. This threshold generally occurs when the arterial stenosis reaches 40%. As the plaque ages, an increasing amount of fibrous tissue accumulates, leading to the formation of a fibrous cap, which is vulnerable to rupture. Progressive arterial stenoses eventually lead to ischemic vascular disease, and the rupture of a plaque can cause a myocardial infarction.

The primary clinical manifestations of dyslipidemia are ischemic vascular disease, pancreatitis, and xanthomatosis. The major ischemic vascular diseases are atherosclerosis (primarily CAD), peripheral vascular disease, and cerebrovascular disease. Pancreatitis may be associated with hypertriglyceridemia. Xanthomas are tumor-like collections of lipids (triglycerides and cholesteryl esters) that can arise in the tendons, points of continued trauma, eg, knees and elbows, as well as palms.

Assessing Risk Factors:

An elevated LDL level is a major cause of CAD, and LDL-lowering therapy reduces the risk. Even so, such a reduction in risk might not be clinically relevant in those patients who are at low risk when first evaluated.³ More aggressive intervention is more likely to benefit patients who are at higher risk. Moreover, because CAD is multifactorial, a high LDL level is not a patient's only risk factor, and therefore it should not be the only focus of treatment.

High Risk
The current ATP III guidelines expand the criteria for high risk to include those patients who have either CAD or any one of five CAD "risk equivalents":

• Diabetes mellitus
• Peripheral vascular disease
• Carotid artery disease
• Abdominal aortic aneurysm
• A calculated 10-year risk for a coronary event that exceeds 20%

The calculation of 10-year risk is a new feature of the NCEP guidelines. Simply counting up the number of risk factors is still the primary method of classifying risk; the purpose of this new element is to further refine risk status. As an alternative, the physician can calculate a patient's 10-year risk first, and then count risk factors for those whose calculated 10-year risk is less than 10%.

For instructions on how to calculate 10-year risk, see Table 1. Instructions are also posted on the National Heart, Lung, and Blood Institute's web site:

Intermediate Risk
Patients fall into the intermediate-risk category if two or more of the following are true:

• Blood pressure above 140/90 mm Hg or on antihypertensive therapy
• Smoking history
• HDL level is lower than 40 mg/dL
• Men older than 45 years or women older than 55 years
• First-degree relative with CAD before the age of 55 years in a male relative or 65 years in a female relative

When adding up the number of risk factors, the physician should deduct one risk factor from the equation for any patient whose HDL level is very good—that is, 60 mg/dL or higher.

Low Risk
Patients are considered to be at low risk if they have fewer than two risk factors.

Metabolic Syndrome
Another risk factor identified in the new guidelines is "metabolic syndrome," also known as "insulin resistance" and "syndrome X." A diagnosis of metabolic syndrome is made if a patient has three or more of the following:

• Abdominal obesity (a waist circumference of more than 40 inches [men] or 35 inches [women])
• An elevated triglyceride level (150 mg/dL or higher)
• A low HDL level (less than 40 mg/dL [men] or 50 mg/dL [women])
• A high-normal or high blood pressure level (130/85 mm Hg or higher)
• A high fasting glucose level (110 mg/dL or higher)

Triglyceride Levels
In ATP III, the NCEP redefined its classifications of triglyceride levels:

• Normal: less than 150 mg/dL
• Borderline high: 150 mg/dL to 199 mg/dL
• High: 200 mg/dL to 499 mg/dL
• Very high: 500 mg/dL or higher

Putting the Guidelines into Practice:

Adherence to these recommendations should help reduce the incidence of coronary events, but only if physicians follow them. The ATP II guidelines were poorly followed, and they were considerably simpler and less time-consuming than the new recommendations. So how can a busy physician hope to incorporate the new guidelines into practice? Here are three suggestions:

Set Up a System
Develop a protocol that allows your office staff to take over some of the routine tasks, such as interviewing patients, calculating risk, instructing about diet and exercise, and scheduling return visits.

Refer
When confronted with a high risk patient with abnormalities involving multiple lipoproteins or a high risk patient not responding to standard therapy, referral to a specialized lipid clinic is appropriate.

Use Technology
Physicians can use the National Heart, Lung and Blood Institute's program found at their website and download it to their personal computers (the downloadable version requires Microsoft Excel 95 or 2000 or a comparable spreadsheet program). This web site also has the same program in a format suitable for personal digital assistants that operate on the Palm OS operating system. Physicians can also make copies of the relevant tables and keep them in the examination room.

Reaching Target Levels:
Current guidelines tailor the aggressiveness of therapy to each patient's LDL level and overall degree of risk (Figure 1).

High-risk
The target LDL level for high-risk patients is less than 100 mg/dL. Current guidelines recommend starting dietary therapy for high-risk patients whose LDL levels are greater than 100 mg/dL and initiating drug therapy for those whose LDL levels are 130 mg/dL or higher. The new guidelines further state that immediate drug therapy is optional for high-risk patients whose LDL levels range between 100 mg/dL and 130 mg/dL.

Intermediate Risk
The target LDL level for intermediate-risk patients is less than 130 mg/dL. Patients who exceed this level can be started on therapeutic lifestyle changes (TLC), provided that their calculated 10-year risk is less than 10%. (For an explanation of TLC, see "Lifestyle modification" in the "Therapeutic Options" section below.) But if their calculated 10-year risk is between 10% and 20%, then drug treatment should be initiated. Immediate drug therapy is also recommended for intermediate-risk patients whose LDL levels are 160 mg/dL or higher, even if their calculated 10-year risk is less than 10%.

Low-risk
An LDL level of 160 mg/dL or less is the target for patients who are at low risk. Low-risk patients whose LDL levels fall between 160 mg/dL and 189 mg/dL should begin TLC. If a 3-month trial of TLC fails to lower the LDL level to less than 160 mg/dL, drug therapy can be considered (optional). Low-risk patients whose LDL levels are 190 mg/dL or higher should be started on drug treatment.

Metabolic Syndrome
Metabolic syndrome is a secondary target of therapy. The recommended treatment regimen is to intensify weight management, increase physical activity, control hypertension, prescribe aspirin for CAD patients, reduce high triglyceride levels, and/or increase low HDL levels with medical therapy.

Triglyceride Levels
Although the primary focus of therapy is on LDL levels, ATP III also recommends aggressive treatment of elevated triglyceride levels through intensified weight management and increased physical activity. Patients whose triglyceride levels remain at 200 mg/dL or higher after they have reached their LDL goal should seek to achieve a secondary goal based on their "non-HDL" level—that is, based on their total cholesterol level minus their HDL level. Their non-HDL goal should be 30 mg/dL higher than their LDL goal. The basis for attempting to reach this secondary goal is that all non-HDL particles are potentially atherogenic. This can be achieved through activities of daily living or the use of niacin and fibrates.

Therapeutic Options:

Drug Treatment
Four major classes of medications are used to treat hyperlipidemia:

• HMG-CoA reductase inhibitors (statins)
• Bile acid sequestrants
• Nicotinic acid
• Fibric acids

The statins can lower LDL levels by 18% to 55% and triglyceride levels by 7% to 30%. They also can raise HDL levels by 5% to 15%. Their major side effects include myopathy and an elevation of liver enzyme levels. Many clinical trials have shown that the statins reduce the incidence of major coronary events, coronary heart disease (CHD) death, and stroke. They also reduce the need for coronary procedures, and lower total mortality.

The bile acid sequestrants lower LDL levels by 15% to 30%, and raise HDL levels by 3% to 5%. They have no effect on triglyceride levels. Their major side effects include gastrointestinal (GI) distress, constipation, and a decrease in the absorption of other drugs. Clinical trials have shown that these agents reduce the incidence of major coronary events and CHD death.

Nicotinic acid lowers LDL levels by 5% to 25% and triglyceride levels by 20% to 50%. Nicotinic acid also raises HDL levels by 15% to 35%. The major side effects of nicotinic acid include flushing, hyperglycemia, hyperuricemia, GI distress, and hepatotoxicity. Clinical trials have shown that they can prevent major coronary events.

Fibric acids lower LDL levels by 5% to 20% and triglyceride levels by 20% to 50%, and raise HDL levels by 10% to 20%. Their major side effects include dyspepsia, gallstones, myopathy, and unexplained noncardiac death. Clinical trials have shown that they, too, lower the risk of major coronary events.

Hormone replacement therapy. ATP III makes it clear that hormone replacement therapy (HRT) is no substitute for lipid-lowering drugs in dyslipidemic women. Although HRT lowers LDL levels, studies have not shown that it reduces the risk of coronary events.

Lifestyle Modification
The TLC( therapeutic lifestyle changes) modifications proposed in ATP III go beyond those in ATP II. The new guidelines recommend a more rigorous TLC diet. Less than 7% of daily calories should come from saturated fat and 25% to 35% from total fat (provided that most of it is from unsaturated fat). Furthermore, patients should restrict their dietary cholesterol intake to less than 200 mg/day. The TLC diet also encourages patients to eat foods that contain plant stanols and sterols (eg, certain margarines and salad dressings) and soluble fiber (eg, cereal grains, beans, peas, legumes, fruits, and vegetables). Lastly, the TLC recommendations also call for weight control and increased physical activity.

The Most Important Elements
(The opinions expressed in this section are those of the authors and not necessarily those of the National Heart, Lung, and Blood Institute.) The authors believe that many physicians might initially find the risk-stratification scheme derived from Framingham data and the treatment algorithm a bit cumbersome for use in a busy everyday practice. If so, it is our opinion that these physicians should at least concentrate on what we believe are the three most important points:

• Patients with CAD are at high risk, and their LDL level should be lower than 100 mg/dL.
• Patients with diabetes mellitus, peripheral vascular disease, or carotid artery disease have a risk that is equal to that of patients with CAD, and their LDL levels should also be lower than 100 mg/dL.
• Other patients can be treated on the basis of their number of risk factors. If they have two or more and their LDL level is 130 mg/dL or higher, they would begin treatment, including drug therapy, in an effort to lower the LDL level to less than 130 mg/dL. This strategy might mean treating a few more patients than if the ATP III guidelines were followed strictly, but we believe it is more appropriate to treat a few more patients more aggressively than to not treat some who need it.

Do the new guidelines go far enough? They are based on estimates of 10-year risk, but perhaps we should be looking farther ahead. Most 35-year-old people have a fairly low risk of experiencing a cardiac event within 10 years. Yet we know that atherosclerosis is chronic and progressive, and we know that elevated cholesterol levels in the young predict symptomatic coronary disease in later years. Perhaps we should think about estimating 20-year risk and intervening earlier. This might be a worthwhile topic for future ATP committees to consider.

It has not been long since the ATP III guidelines have gone into effect, and it remains to be seen if they will result in a healthier public. Nevertheless, we all hope that these types of guidelines-as opposed to mandates-will enhance awareness and generally promote prevention in medical care.

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1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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). JAMA. 2001;285:2486-2497.
   
   
2. National Cholesterol Education Program. Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:1333-1445.
   
   
3. Sprecher DL. Where to draw the line using statins: Lessons from 4S to AFCAPS/TexCAPS [commentary]. Cleve Clin J Med. 2000;67:169-171.
   

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