BACKGROUND

According to the American Heart Association (AHA), approximately 90% of patients diagnosed with coronary heart disease (CHD) have at least 1 major risk factor for development of the disease. Important major risk factors include a high total blood cholesterol level or current therapy with a cholesterol-lowering medication. Approximately 38 million American adults have cholesterol levels of 240 mg/dL or higher (AHA, 2005). The World Health Organization (WHO) reports that high cholesterol levels contribute to 56% of the cases of CHD worldwide and to an estimated 4.4 million deaths each year.

Although the total cholesterol level has been linked with coronary artery disease (CAD) (Lloyd-Jones, 2003; Shepherd, 1995), large randomized trials conducted over the last decade have conclusively demonstrated that the risk of developing disease is mediated mostly by the low-density lipoprotein cholesterol (LDL-C) component. The 2004 update of the Executive Summary of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP/ATP III) demonstrated that serum LDL-C levels have a strong positive correlation with CHD in a log-linear relationship (Grundy, 2004; Huang and Hoogwer, 2005) (see Figure 1). Since the original ATP III report was published in 2001, several major clinical trials have demonstrated that LDL-C–lowering statins reduce morbidity rates. The important implications of these studies on the treatment of patients with lipid disorders, particularly high-risk patients, are discussed in the Important Trials After ATP III (2001) section.

Figure 1. Relationship Between LDL-C Levels and Relative Risk of CHD

Pravastatin or Atorvastatin Evaluation and Infection Therapy--Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22), Heart Protection Study (HPS), Cholesterol and Current Events (CARE) Study, Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS), Scandinavian Simvastatin Survival Study (4S), West of Scotland Coronary Prevention Study (WOSCOPS)

CLINICAL GUIDELINES

The ATP III algorithm classifies people into 3 risk categories.

Established CHD and CHD risk equivalents (high risk)

• Diabetes
• Multiple CHD risk factors with a 10-year CHD risk of greater than 20%
• Symptomatic carotid artery disease
• Peripheral arterial disease
• Abdominal aortic aneurysm

The LDL-C goal for high-risk individuals is less than 100 mg/dL.

Multiple (>2) risk factors

• Cigarette smoking
• Hypertension (BP >140/90 mm Hg or on antihypertensives)
• Low HDL-C level (<40 mg/dL in men, <50 mg/dL in women)
• Family history of premature CHD (first-degree male relative <55 y, first-degree female relative <65 y)
• Age (men >45 y, women >65 y)

The ATP III recommends that Framingham risk stratification be performed for all patients with 2 or more risk factors. Individuals are classified into 1 of 3 categories for 10-year risk of hard CHD events, with their LDL-C targets based on this risk.

• Greater than 20% (high risk) - LDL-C level less than 100 mg/dL
• Ten-20% - LDL-C level less than 130 mg/dL
• Less than 10% - LDL-C level less than 160 mg/dL

Importantly, the update states that an LDL-C goal of less than 70 mg/dL should be considered in patients at “very high risk.” These patients include those with known CAD and any of the following: (1) multiple risk factors, especially diabetes; (2) severe and poorly controlled risk factors, especially smoking; (3) multiple risk factors of the metabolic syndrome, including elevated triglyceride levels (>200 mg/dL), elevated non–HDL-C levels (>130 mg/dL), and low HDL-C levels (<40 mg/dL); and (4) acute coronary syndrome.

Low risk

Most patients with no risk factors or 1 risk factor will be low risk by Framingham score classification. The LDL-C level for these patients should be less than 160 mg/dL.

In addition to total cholesterol and LDL-C levels, remnant lipoproteins in patients with hypertriglyceridemia also have atherogenic potential. Elevated triglyceride levels (defined as >200 mg/dL) are a secondary target of the ATP III guidelines. Based on the stratification guidelines outlined above, the non–HDL-C goal is 30 mg/dL higher than the LDL-C goal (NCEP/ATP III, 2001; Grundy, 2004) (see Figures 2 and 3). Note that statins not only lower LDL-C levels but can also have a significant influence on non–HDL-C levels.

Figure 2

Figure 3

IMPORTANT TRIALS AFTER ATP III (2001)

Heart Protection Study (HPS)

More than 20,000 patients in the United Kingdom (including ~6000 diabetics) who were at high risk for a CHD event were randomly assigned to receive either 40 mg of simvastatin or a placebo daily, regardless of their cholesterol levels. In the group assigned to simvastatin, the all-cause mortality rate was significantly reduced by 13%, regardless of whether patients’ LDL-C levels were less than 100 mg/dL. Also, significant reductions in major vascular events, coronary deaths, nonfatal or fatal strokes, and cardiovascular revascularization were observed. This study provided insights into the benefit of statin therapy in patient subgroups, such as elderly people, women, and those with carotid and peripheral vascular disease (Farmer, 2003; HPS Collaborative Group, 2002; Grundy, 2004).

Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

This study examined 5804 elderly patients (mean age, 75 years; 52% women) for the efficacy of pravastatin treatment in older men and women with histories of, or risk factors for, CHD and stroke. Patients were randomly assigned to receive 40 mg of pravastatin or a placebo daily. Pravastatin reduced LDL-C levels by 34%. Major coronary events, defined as nonfatal myocardial infarction (MI) and CHD death, fell by 19%, and CHD mortality fell by 24%. The authors concluded that these results allow statin therapy to be extended to older persons (Shepherd, 2002; Grundy, 2004).

Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA)

In this study, 19,342 patients with hypertension and at least 3 other CHD risk factors were randomly assigned to 1 of 2 antihypertensive regimens. Of these patients, 10,305 were randomly assigned to receive 10 mg of atorvastatin or a placebo daily. In the atorvastatin group, total cardiovascular events and fatal and nonfatal strokes were significantly reduced (29% and 27%, respectively). In addition, an insignificant trend toward reduction of the total mortality rate in the atorvastatin group was observed (Sever, 2003; Grundy, 2004).

Pravastatin or Atorvastatin Evaluation and Infection—Thrombolysis in Myocardial Infarction 22 (PROVE IT—TIMI 22)

This study was performed to determine whether intensive LDL-C lowering would reduce the number of major coronary events, including deaths, in high-risk patients compared to standard LDL-C lowering with statin therapy. Patients were randomly assigned to receive either 80 mg of atorvastatin daily (intense therapy) or 40 mg of pravastatin daily (standard care). Among study participants were 4162 who had been hospitalized with an acute coronary syndrome within the prior 10 days. After 2 years, the composite cardiovascular end point was reduced by 16% with intense therapy (mean LDL-C level, 77 mg/dL) versus standard therapy (mean LDL-C level, 101 mg/dL). This result suggests that more intensive LDL-C lowering reduces the risk of major cardiovascular events in patients with an acute coronary syndrome (Cannon, 2004; Grundy, 2004).

Collaborative Atorvastatin Diabetes Study (CARDS)

This trial is the first primary prevention study to focus on the role of a statin for cholesterol lowering in patients with type 2 diabetes mellitus who have not experienced a cardiovascular event and who have only average or below average cholesterol levels. This trial was a prospective, double-blind, randomized trial with 2383 patients with type 2 diabetes randomized to either 10 mg of atorvastatin or a placebo daily. Upon entry in the study, the mean LDL-C level of the treated group was 116 mg/dL, and 25% of the patients in both the treated and the control group had LDL-C levels of less than 100 mg/dL. Atorvastatin 10 mg reduced LDL-C levels by 40% on average; at 4 years, atorvastatin showed a 37% relative risk reduction in the primary combined end points of acute CHD death, fatal or nonfatal MI, unstable angina requiring hospitalization, resuscitated cardiac arrest, coronary revascularization procedures, and stroke. The total mortality rate was reduced by 27%, acute coronary events by 36%, coronary revascularization by 31%, and strokes by 48% (Owen, 2005; Colhoun, 2004).

Treating to New Targets (TNT)

The recently published TNT is a randomized trial that examined intensive lipid lowering in stable CHD patients. This trial randomly assigned 10,001 patients to receive either 10 mg of atorvastatin daily (low dose) or 80 mg of atorvastatin daily (high dose). The average final LDL-C level in the low-dose group was 101 mg/dL compared to an average of 77 mg/dL in the high-dose group. The primary composite end point of death from CHD, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke revealed a reduction of 22% in the high-dose atorvastatin group. The authors concluded that lowering the LDL-C level to 77 mg/dL provides greater clinical benefit than lowering the LDL-C level to just 100 mg/dL (LaRosa, 2005).

CONCLUSION

The increased risk of CAD due to hypercholesterolemia is primarily a result of LDL-C. The most recent update to the NCEP/ATP III guidelines recommends tighter control of LDL-C in high-risk patients (ie, those with LDL-C level <100 mg/dL), with a target level of 70 mg/dL or less in patients considered very high risk. Clinicians should assess their patients’ risk and appropriately lower LDL-C levels to a target goal based on these new guidelines (Huang, 2005).

References

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