INTRODUCTION

In 2001, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) published its third set of clinical guidelines (ATP III) for the detection, evaluation, and treatment of high levels of blood cholesterol. Since then, through the publication of several randomized, controlled clinical trials, much information has become available on clinical cardiovascular endpoints, especially in patients at high risk, such as those with coronary heart disease (CHD) or CHD risk equivalents. As a result, the NCEP released an updated document in 2004 that evaluates the effect of these trials on lipid management.

In this review, we highlight the salient features outlined in the latest NCEP ATP III recommendations on lipid goals for patients at very high risk, high risk, and moderately high risk for CHD events and provide the supporting evidence for these goals.

RISK GROUPS REDEFINED

The levels of risk for CHD have been redefined. Major risk factors for CHD other than LDL cholesterol that modify LDL goals include hypertension (blood pressure >140/90 or taking an antihypertensive), cigarette smoking, high-density lipoprotein cholesterol (HDL-C) levels less than 40 mg/dL, age older than 45 years (for men) or older than 55 years (for women), and a family history of premature CHD.

High risk

The category of high risk patients (established CHD or presence of clinical atherosclerotic disease – CHD equivalents) remains unchanged. CHD equivalents include symptomatic carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm, and diabetes mellitus. ATP III also created a subset of patients at very high risk. These patients have established CHD and one of the following:

• Multiple major risk factors for cardiovascular disease (CVD)
• Metabolic syndrome (abdominal obesity, triglyceride levels >150 mg/dL, levels of HDL-C <40 mg/dL, blood pressure >130/85 mm Hg, and fasting glucose levels >110 mg/dL)
• Acute coronary syndrome

Moderate risk

People with moderate risk (2 or more major risk factors for CHD [other than LDL] and without CHD or CHD equivalents) are now triaged by Framingham scoring into 3 subcategories.

• Those who have a 10-year score greater than 20% are now elevated to the high risk category.
• Those who have a 10-year score from 10-20% are considered to have moderately high risk.
• Those who have a 10-year score less than 10% are at moderate risk.

Low risk

The category of low risk (0-1 major risk factors for CHD [other than LDL] and without CHD or CHD equivalents) remains unchanged.

TREATMENT ALGORITHM

On the whole, the target level of low-density lipoprotein cholesterol (LDL-C) for patients at high risk remains unchanged (ie, LDL-C <100 mg/dL). However, the new guidelines recommend modifications, including an optional LDL-C goal of less than 70 mg/dL for patients at very high risk, initiation of both LDL-C–lowering drug therapy and therapeutic lifestyle changes in patients with LDL-C levels 100 mg/dL or greater, and the option of LDL-C–lowering drug therapy in patients with LDL-C levels less than 100 mg/dL at baseline.

The target level of LDL-C for patients at both moderately high risk and moderate risk remains at less than 130 mg/dL. However, the updated guidelines also recommend the initiation of drug therapy when LDL-C levels are greater than 130 mg/dL in patients at moderately high risk and when LDL-C levels are greater than 160 mg/dL in patients at moderate risk. Beginning treatment when LDL-C levels are between 100 and 129 mg/dL and achieving a target LDL-C level of less than 100 mg/dL remain optional for patients in this group.

SUPPORTING EVIDENCE

Lower is better when it comes to LDL-C levels in individuals in high-risk categories. Several major randomized clinical trials published in the last 4 years support the need for intense LDL-C level reduction in patients at high risk for CHD.

In the Heart Protection Study (HPS), 20,536 men and women, aged 40-80 years, who had coronary disease, other occlusive arterial disease, or diabetes, were randomized to simvastatin (40 mg/d) or placebo. After a mean follow-up of 5 years, all-cause mortality was significantly decreased in a wide range of patients treated with simvastatin compared with placebo (12.9% vs 14.7%). This decrease was primarily due to a significant reduction in CHD mortality (5.7% vs 6.9%). The benefits of statin therapy also extended to subgroups with baseline LDL-C levels of less than 116 mg/dL (n = 6793).

The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study showed that, in patients who are hospitalized within 10 days for an acute coronary syndrome, “intensive” high-dose LDL-C level–lowering (median LDL-C level = 62 mg/dL) reduced the risk of all-cause mortality or major cardiac events by 16% (p = 0.005), as compared to “moderate” standard-dose lipid-lowering therapy (median LDL-C level = 95 mg/dL).

NEW EVIDENCE

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study established that, in patients with non–ST-segment elevation myocardial ischemia, the initiation of a high dose of atorvastatin (80 mg) within 24-96 hours of admission reduced ischemic events (14.8% vs 17.4%) at 16 weeks compared with the placebo (Schwartz, 2001).

The Treating to New Targets (TNT) study found that, in patients with stable CHD, intensive lipid-lowering treatment with 80 mg/d of atorvastatin (mean LDL-C level = 77 mg/dL) is associated with a 22% risk reduction in major cardiovascular events, compared to treatment with 10 mg/d of atorvastatin (mean LDL-C level = 100 mg/dL).

In the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study, patients with previous myocardial infarction (MI) who were treated with intensive lowering of LDL-C levels did not experience a significant reduction in the primary outcome of major coronary events. However, such treatment did reduce the risk of other composite secondary end points and nonfatal acute MI.

PATIENTS AT MODERATELY HIGH RISK

Two recent trials (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm [ASCOT-LLA] and Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT-LLT]) indicated that further reduction of the LDL-C threshold resulted in additional benefits for patients in the moderately high-risk category.

The ASCOT-LLA studied the cholesterol level–lowering effect of 10 mg/d of atorvastatin compared to placebo in hypertensive patients with 3 other CHD risk factors and a nonfasting total cholesterol level of 251 mg/dL or lower. The study was stopped prematurely because of the significant reduction (36%) in the incidence of fatal and nonfatal MI in the treatment group. In addition, a 27% fatal and nonfatal stroke risk reduction was observed in the treatment arm.

In the ALLHAT-LLA trial, individuals aged 55 years or older, with moderate hypercholesterolemia, hypertension, at least 1 additional risk factor, and a fasting LDL-C level of 120-189 mg/dL, were subjected to either pravastatin 40 mg/d or standard care. Even though no overall difference in the all-cause mortality or CHD events existed between the two groups, in the treatment arm, the African-American subgroup had a lower incidence of CHD.

HELPING PATIENTS ACHIEVE NEW NCEP GOALS

Drug therapy

Statins are the only class of drugs to demonstrate clear improvements in overall mortality in primary and secondary prevention. Therefore, statins are usually the first choice in all patients with elevated cholesterol levels.

For every 1% reduction in LDL-C level, the relative risk of CHD is reduced by 1% (LaRosa, 1999). Initial treatment with statins should achieve at least a 30-40% reduction in the LDL-C level (Grundy, 2004). Standard doses of currently available statins can produce these reductions. Standard daily doses of statins are listed as atorvastatin, 10 mg; lovastatin, 40 mg; pravastatin, 40 mg; simvastatin, 20-40 mg; fluvastatin, 40-80 mg; and rosuvastatin, 5-10 mg (Andrews, 2001).

Once initiated, statin doses must be titrated every 4-6 weeks to achieve the LDL goal. Doubling the statin dose adds an extra 6% to the LDL level reduction (Roberts, 1997). Atorvastatin and rosuvastatin are the most potent statins approved for use in the United States; they decrease LDL levels by approximately 60% at doses of 80 mg/d and 40 mg/d, respectively (Jones, 2003). If patients fail to reach the target goals despite increased statin dosing, consider adding other agents, such as fenofibrates (Tricor), ezetimibe (Zetia), or niacin (Niacor, Niaspan). Higher doses of statins may be associated with increased adverse effects, particularly in elderly patients who have chronic renal disease and who are on other multiple medications. Good clinical judgment is necessary in these special cases.

Once the target goal is reached, LDL-C levels need to be checked every 6-12 months in patients who are compliant with lifestyle changes. Monitoring of liver function tests (LFTs) at baseline and 4-6 months into treatment is indicated, as is the education of patients on the symptoms of myopathy.

Therapeutic lifestyle changes

Therapeutic lifestyle changes should be included as a part of treatment in a multifaceted approach to lowering cholesterol levels. Everyone should attempt therapeutic lifestyle changes, especially persons at high or moderately high risk for CHD who have a lifestyle-related risk factor such as obesity, sedentary lifestyle, elevated triglyceride levels, low HDL-C levels, or metabolic syndrome. Lifestyle changes include the following:

1. Diet: Reduction of saturated fat, cholesterol, and plant stanol/sterol (<2 g/d); increased ingestion of soluble fiber (>10-25 g/d)
2. Increased physical activity
3. Weight control (Consider referring all patients to a dietitian for medical nutrition therapy to achieve optimal results.)

Treatment strategies for other lipid abnormalities

Patients at high risk who have elevated triglyceride levels and low HDL-C levels should be targeted for therapy irrespective of their LDL-C levels. When triglyceride levels are greater than 200 mg/dL, non–HDL-C level (total cholesterol level minus HDL-C level) becomes a secondary target, with an endpoint of 30 mg/dL higher than the corresponding LDL-C goals (Grundy, 2004). Fibrates and nicotinic acid are adjunctive agents to statins for patients with high triglyceride levels and low HDL-C levels. Some statins have a stronger effect than others on lowering triglyceride levels (Jones, 2003).

CONCLUSION

At present, ample evidence highlights the benefits of aggressive lipid-lowering; individual physicians must widely implement the target goals for their patients— especially patients at high risk—to reduce the risk of cardiac events. Options include selecting the correct statin at the correct dose to achieve an LDL-C level reduction of 30-40%, adding a second agent if needed, and encouraging therapeutic lifestyle changes. Broad implementation of the newer ATP III guidelines is a challenge that must be faced head on to make substantial improvements in the secondary prevention of CVD.

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