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Stricter cholesterol guidelines broaden indications for the `statin' drugs. (Nursing Pharmacology).

In 2001, the third report of the National Cholesterol Education Program (NCEP) established stricter cholesterol level guidelines for preventing cardiovascular disease. The report focused on low-density lipoprotein cholesterol (LDL-C), the major risk factor for atherosclerosis (see Tables 1 & 2). Additionally, elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) levels were acknowledged as independent cardiovascular risk factors. The NCEP expert panel based new recommendations on a review of accumulated research which demonstrates that current acceptable levels of blood cholesterol may be too high.

A growing body of evidence supports the tightening of cholesterol level parameters. Analysis of the Framingham study data shows that although total cholesterol levels of 240 mg/dl or greater conferred a high risk of myocardial infarction (MI), 20% of the coronary events occurred at presumably "safe" levels of less than 200 mg/dl. Further, studies have shown that coronary events often occur in persons with a serum LDL-C level between 130 and 160 mg/dl; these values fall below what previously was considered baseline levels requiring drug therapy. Additionally, studies have shown that coronary artery disease is rarely seen in persons with LDL-C levels below 100 mg/dl (NCEP, 2001). In sum, the NCEP has determined that more aggressive lipid lowering is needed to prevent cardiovascular disease. New medical management guidelines recommend lower acceptable levels of LDL-C and higher levels of HDL-C.

An additional concern is that despite extensive clinical research demonstrating benefits, lipid-lowering drugs are currently underused in clinical practice. In a practice survey of more than 48,000 patient records, only 39% of patients with coronary heart disease received lipid-lowering drug therapy and only 10% had achieved the NCEP target LDL-C level of [less than or equal to] 100 mg/dl (Sueta et al., 1999). According to most recent estimates, 1 out of 5 Americans suffers from hypercholesterolemia (American Heart Association, 2002). Undoubtedly, the new stringent NCEP guidelines will increase the numbers of persons who require lipid-lowering drugs. Statins are the most frequently prescribed class of drugs for this condition (Illingworth, 2001; Sorrentino, 2000). Nurses in all adult health care settings should be aware of the new recommendations and pharmacologic management of hypercholesterolemia.

How Does Hypercholesterolemia Develop?

Cholesterol is an essential component of bile salts, hormones, and cell structure. Blood cholesterol levels are a result of several different body processes. A minor portion of cholesterol in the bloodstream is derived from ingested saturated fats. Saturated fats are mainly found in animal products, such as whole milk, eggs, and meats. Gastrointestinal absorption of saturated fat can increase blood cholesterol concentration by 15% to 25% (Guyton & Hall, 2000). The major portion of blood cholesterol comes from the liver, the prime synthesizer of cholesterol in the body. The liver enzyme 3 hydroxy-3 methylglutaryl Co A reductase (HMG Co A reductase) is the essential enzyme for producing cholesterol (see Figure 1). When the liver "senses" low cholesterol in the body, its "machinery" synthesizes cholesterol to compensate. The liver also clears the bloodstream of cholesterol. More than 80% of LDL-C from the plasma is cleared by the liver (Guyton & Hall, 2000). Thus, the liver is the central organ of production and excretion of cholesterol.

[FIGURE 1 OMITTED]

Genes also influence blood cholesterol levels. Studies show that persons with familial hypercholesterolemia have mutations in genes which control body cell receptors of LDL cholesterol (Guyton & Hall, 2000). These mutated genes direct the body to make defective LDL-C receptors. With defective receptors, the body cells cannot absorb LDL-C, and the liver mistakenly "senses" an absence of cholesterol. The liver in turn heightens production of endogenous cholesterol since it cannot "sense" the existing LDL-C. As a result, LDL-C can accumulate to extremely high levels in the bloodstream of persons with this genetic mutation (Guyton & Hall, 2000). In summary, cholesterol levels in the bloodstream are a result of liver production and excretion, ingestion of saturated fats, and genetic influences.

HDL-C `Good' vs. LDL-C `Bad' Cholesterol

There are various types of cholesterol which circulate in the bloodstream: lipoprotein (a), very low density lipoprotein (VLDL-C), intermediate low density lipoprotein CLDL-C), LDL-C, and HDL-C. The two types considered most important at present are LDL-C and HDL-C. LDL-C is the instigator of atherosclerosis, since it easily deposits on arterial walls. HDL-C absorbs cholesterol crystals prior to their deposition in arterial walls, thereby preventing athero sclerosis. Consequently, LDL-C is designated as "bad" cholesterol and HDL-C is designated as "good" cholesterol by laypersons. Studies show that for each 1 mg/dl decrease in LDL-C, there is a 2% decrease in mortality from atherosclerotic heart disease (Guyton & Hall, 2000). When a person has a high ratio of HDL-C to LDL-C, the likelihood of developing atherosclerosis is reduced (Guyton & Hall, 2000).

Statins: Lipid-Lowering Drugs Of Choice

The class of drugs called statins are most effective for lowering LDL cholesterol levels and are considered the first choice for management of hyperlipidemia (Illingworth, 2001; Sorrentino, 2000). Statins exert their pharmacologic effects by inhibiting the liver enzyme essential to the synthesis of cholesterol, HMG CoA reductase (see Figure 1). By inhibiting this hepatic enzyme, statins limit the liver's production of LDL-C significantly. There is also evidence that statins decrease absorption of cholesterol through the intestinal mucosa into the bloodstream by inhibition of a transporter intestinal protein. Statins can reduce LDL-C levels by 33% to 55% which significantly reduces risk of cholesterol deposition on arterial walls. Furthermore, regression of pre-existent atheromatous plaques is observed after therapy with statin medications (Illingworth, 2001; Robinson, Conroy, & Wickemeyer, 2000). Multiple studies have shown that statins safely reduce cardiovascular risk in both healthy persons and in those who have pre-existing cardiovascular disease (Downs et al., 1998; LIPID Study Group, 1998; Sacks et al., 1996; Shepherd et al., 1995). In most research, 1 to 2 years of statin therapy afforded patients significant reductions in ischemic heart disease and death.

[FIGURE 1 OMITTED]

There is new evidence regarding additional beneficial effects of statin therapy. Numerous studies have shown that when patients with pre-existent cardiovascular disease initiate statin therapy, many positive cardiovascular effects occur. Patients have increased endothelial vasodilation, decreased thrombus formation, inhibited platelet aggregation, stabilization of atheromatous plaques, and increased fibrinolysis (Crisby et al., 2001; Dangas et al., 1999; Dupuis, Tardif, Cernacek, & Theroux, 1999; Rosenson & Tangney, 1998). Some statins increase HDL-C levels and decrease triglycerides (Nash, 2002).

Recently, statins have been associated with benefits beyond the cardiovascular system. Animal studies demonstrate that statins can strengthen bones by stimulating osteoblasts. Additionally, there is some evidence that statins can trigger the regression of malignant cells in leukemia. However, further clinical trials are needed to substantiate these findings (Cruz & Gruber, 2002; Wong, Dimitroulakos, Minden, & Penn, 2002).

Pravastatin (Pravachol[R]), the prototype of the statin drugs, has been one of the most scrutinized of the lipid-lowering drugs. Studies have provided conclusive evidence of Pravastatin's long-term safety (Illingworth, 2001). Other statin drugs include lovastatin (Mevacor[R]), simvastatin (Zocol[R]), fluvastatin (Lescol[R]), and atorvastatin (Lipitor[R]). The newest addition to the group is rosuvastatin (Crestor[R]). It decreases LDL-C levels by 65% and has an improved safety profile (Chapman & McTaggart, 2002).

When Do Patients Need Lipid-Lowering Drug Therapy?

Measurement of total cholesterol level and HDL-C to LDL-C ratio is recommended at least every 5 years in adults beginning at age 20 (Sprecher & Frolkis, 2001). Diet modification and lifestyle changes are recommended when adult patients present with cholesterol levels and factors associated with borderline cardiovascular disease risk. Cardiovascular disease risk categories are based on factors which include LDL-C level, smoking, blood pressure, HDL-C level, triglyceride level, family history, and age. An HDL-C level > 60 mg/dl is considered a negative risk factor or cardioprotective factor. According to recent studies, a low HDL-C level can be an independent risk factor for cardiovascular disease (Wierzbicki & Mikhailidis, 2002). Therefore, health care providers should be aware that other lipid-lowering medications, such as bile acid sequestrants, fibric acids, and niacin have the advantageous effect of raising HDL-C level (Illingworth, 2001). These agents are often used in combination with statins.

Under the new NCEP guidelines, health care providers must analyze lipid profiles and evaluate the patient in a comprehensive manner to assign cardiovascular disease risk. The calculation of the 10-year cardiovascular disease risk is an added feature of the new guidelines. The calculation method is available on www.nhlbi.nih.gov/guidelines/cholesterol/profmats.htm. Drug therapy in addition to diet and lifestyle modifications are indicated when the patient's calculated 10-year risk is 10% to 20% and the LDL-C level is [greater than or equal to] 130 mg/dl. Alternatively, drug therapy is advised if the patient's calculated 10-year risk is less than 10% and LDL-C level is [greater than or equal to] 160 mg/dl (Sprecher & Frolkis, 2001). Statin drugs are the most commonly prescribed initial lipid-lowering agents unless there are contraindications in the patient history.

Lipid-Lowering Drugs Used in Combination

The statin drugs are excellent reducers of LDL-C levels. However, many persons with hypercholesterolemia cannot attain NCEP goal levels of LDL-C with statin monotherapy (Illingworth, 2001). In addition, many persons have the added risk factors of hypertriglyceridemia and low HDL-C levels (Illingworth, 2001). For these patients, statins are used in combination with other lipid-lowering agents.

The bile acid sequestrant drugs are often prescribed as an adjunct to statin therapy (Illingworth, 2001). Bile acids are cholesterol-based substances secreted by the liver to digest fat. The liver secretes the bile acids into the intestine and after fat digestion, a large portion of the bile acids are reabsorbed into the bloodstream and returned to the liver via the portal circulation (see Figure 1). Bile acid sequestrants act as resins which attach to the bile acids while they are in the intestine. The sequestrants bind to the bile acids, block their reabsorption into the portal circulation, and render them excretable via the bowel. Common bile acid sequestrants are cholestyramine (Questran[R]) and colestipol (Colestid[R]). The bile acid sequestrants can help further reduce blood levels of LDL-C in conjunction with statins and diet. However, they have not been shown to decrease triglycerides. Patient compliance can be problematic because these drugs often cause gastrointestinal side effects such as constipation, bloating, and cramping (Medical Economics, 2002).

The fibric acid class of drugs include gemfibrozil (Lopid[R]), fenofibrate (Tricor[R]), and clofibrate (Atromid[R]). These drugs can lower LDL-C, raise HDL-C, and reduce triglycerides. Fibric acids inhibit peripheral fat breakdown, block the liver synthesis of triglycerides and cholesterol, and enhance cholesterol excretion. Fibric acids can synergistically act to treat hypercholesterolemia with statins. However, when used in combination with the statin drugs, rhabdomyolysis risk is increased. Other side effects associated with fibric acid drugs are the development of gallstones and gastrointestinal upset.

Niacin, a B vitamin, is another agent used to lower cholesterol and is often used in combination with statin drugs. Niacin and statin drugs have synergism in reducing LDL-C levels (Stein, 2002). Niacin can also raise HDL-C levels and reduce triglycerides. Niacin works by inhibiting cholesterol synthesis by the liver and peripheral fat breakdown, and enhancing triglyceride clearance from plasma. When using statins and high doses of niacin, there is an increased risk of myopathy.

Possible Adverse Effects of Statin Drugs

Statins have similar safety profiles and are generally well tolerated. The two potentially serious but rare side effects are liver toxicity and myopathy (Sinzinger, 2002). Myopathy presents as muscle pain or weakness associated with elevated levels of creatine phosphokinase (CPK). Symptoms include a flu-like syndrome of fever, muscle and joint aches, and general malaise (Sinzinger, 2002). If unrecognized, myopathy can lead to rhabdomyolysis and renal failure. Recently, a statin medication, cerivastatin (Baycol[R]) was withdrawn due to its association with two deaths from rhabdomyolysis. When statin metabolism is inhibited as in liver dysfunction or drug interaction, the risk of myopathy is increased. When statins are co-prescribed with fibric acid drugs or niacin, myopathy risk is also increased (Williams & Feely, 2002).

Drug-drug interactions are significant risks with statin use. The liver cytochrome P450 enzyme system plays an important role in the metabolism of the statins. Since many other drugs are metabolized by this liver enzyme system, statins can have clinically relevant interactions with other drugs (Dresser, Spence, & Bailey, 2000). The drugs known to have interactions with statins include cyclosporine, erythromycin, ketoconazole, itraconazole, HIV protease inhibitors, amioradone, and some anti-hypertensive drugs. These drugs can inhibit statin metabolism and increase bloodstream concentrations tenfold. Interestingly, grapefruit juice can cause inhibition of the cytochrome P450 liver enzyme system and consequently inhibit metabolism of the statins, raising blood levels and increasing risk of myopathy (Dresser et al., 2000). Alternatively, statins can alter the concentrations of other drugs, such as warfarin and digoxin (Williams & Feely, 2002). Statins can increase blood levels of warfarin or digoxin which can lead to serious side effects. Therefore, careful monitoring is required when statins are used in combination with other drugs.

Some patients taking statins develop elevated liver enzymes. Elevations of AST and ALT liver transaminases up to three times normal level can occur without patient symptoms (Illingworth, 2001). These elevations are often dose dependent and lowering dosages may remediate the problem. Elevated liver transaminases necessitates monitoring at 6 to 8 week intervals during the first 6 months of statin therapy. Very often, liver enzymes will return to normal after dose stabilization (Illingworth, 2001).

All of the statin drugs are contraindicated in pregnancy and should be discontinued if pregnancy is confirmed. In the pediatric population, a study has shown that lovastatin effectively reduces cholesterol in adolescent boys with familial hypercholesterolemia. However, statin drugs have not been approved for use in children (Stein et al., 1999).

Nursing Implications of Statin Drug Use

Patients are often first diagnosed with hypercholesterolemia and placed on a statin drug in primary care settings. However, nurses in all health care settings need knowledge about the indications, actions, and possible side effects of statin drugs. In the hospital setting, patients suffering from acute coronary syndromes should be started on statin drugs immediately upon admission (Acevedo & Sprecher, 2002). In home care settings, nurses must assess patients on statin therapy for adverse effects to counteract possible serious long-term complications. A recent study of a telephone-based, computerized patient management system demonstrated significantly improved patient outcomes in a primary care practice. Nurses tracked patients with hypercholesterolemia using computerized reminders and telephone contact to assess their medication compliance, reinforce lifestyle modifications, and remind patients about periodic lab tests. The proportion of patients who maintained an LDL-C level of [less than or equal to] 100 mg/dl increased by 60% using this system (Robinson et al., 2000).

The statin drugs are all oral preparations with similar dose ranges and peak effects (see Table 3). Pravastatin, the prototype of statin drugs, is available in 10 mg, 20 mg, and 40 mg tablets. After ingestion, pravastatin is rapidly absorbed, and peak blood levels occur in 1 to 1.5 hours. A single daily dose is recommended in the evening, because hepatic cholesterol is synthesized mainly at night. Tablets can be taken with or without meals. The statin drugs are cleared by the kidney and the liver and eliminated via the urine and the feces. A therapeutic response is usually seen within 1 week and a maximum response is seen after 4 weeks (Medical Economics, 2002).

All patients with the diagnosis of hypercholesterolemia require counseling and education regarding cardiovascular disease prevention. Statin drugs are an adjunct therapy to diet and lifestyle modification. Nurses need to assess patients for modifiable cardiovascular risk factors. These include smoking, weight, diet, blood lipid levels, blood pressure, diabetes control, and exercise. It is important to raise patients' awareness regarding the presence of alterable risk factors and assist them to implement strategies to lower cardiovascular disease risk. To lower LDL-C levels and increase HDL-C levels, patients should be on a low saturated fat diet and a daily exercise regimen. NCEP guidelines recommend a goal of less than 7% of total calories from saturated fats to lower total cholesterol. Also, a daily exercise routine as minimal as brisk walking for 30 minutes can help raise HDL-C levels.

Nurses need to review all current medications taken by patients. Patients should understand that some drugs can interact with statins. Some drugs inhibit statin metabolism and will raise blood levels; increasing risk of side effects. Statins can also interfere with the metabolism of drugs such as digoxin and warfarin. A review of the literature indicates that atorvastatin and simvastatin have the most number of possible adverse drug-drug interactions (see Figure 2). Patients also should avoid drinking grapefruit juice since it inhibits hepatic metabolism of statins. Grapefruit juice can alter metabolism of several classes of drugs (Kane & Lipsky, 2000).

[FIGUREN 2 OMITTED]

Myopathy and rhabdomyolysis are rare adverse effects of statins; however, patients need to be cautioned about the potential for these conditions. Patients receiving statins in combination with other drugs have a greater risk of myopathy; particularly those on niacin or fibric acid agents (see Figure 2). Myopathy symptoms can present as muscle pain or a flu-like syndrome of fever, myalgias, and general malaise. Nurses must be vigilant of the similarity of symptoms between flu and myopathy. An elevated skeletal muscle creatine phosphokinase (CPK) level assists in diagnosing myopathy. Myopathy can lead to rhabdomyolysis and myoglobinuria which can result in kidney failure. Since severe acute illnesses can predispose to kidney failure, statins should be withheld in patients suffering from sepsis, major surgery, trauma, or severe metabolic, endocrine, or electrolyte disturbances (Medical Economics, 2002).

Patients need to have periodic monitoring of liver and kidney function while on statin therapy. ALT and AST liver enzyme elevations have been seen in some patients (Medical Economics, 2002). These usually cause no symptoms, can be reversed, and do not have long-term effects. Often dose adjustment is necessary. Statins are contraindicated in persons with active liver disease or in those persons who use alcohol excessively (Medical Economics, 2002).

Statins are also contraindicated during pregnancy and breastfeeding. Premenopausal women should be counseled that it is ideal to discontinue statins for a month previous to becoming pregnant. If pregnancy is confirmed while the patient is on statin therapy, discontinuing the drug is recommended. Statins have not been approved for use in children.

Future Directions

Investigators are searching for alternative therapies for patients who cannot tolerate statins and for drugs that could act synergistically with statins. Agents such as bile acid sequestrants, niacin, and fibric acid compounds are commonly added to the statin drug regimen to further cholesterol reduction. However, most are only modestly synergistic and may cause drug-drug interactions. A new selective cholesterol absorption inhibitor, ezetimibe, is undergoing clinical trials (Gagne, Gaudet, & Bruckert, 2002; Stein, 2002). This drug works at the intestinal mucosa to directly block cholesterol absorption into the bloodstream. Clinical trials have demonstrated that ezetimibe is safe both as monotherapy and in combination with some statins. Ezetimibe in combination with a low dose of statin drug can reduce cholesterol levels equivalent to that seen with an eight-fold higher statin dose. No adverse drug-drug interactions have been seen with ezetimibe and statin drugs thus far. This new drugs has the potential to optimize the pharmacologic management of hypercholesterolemia (Gagne et al., 2002; Stein, 2002)

Conclusion

The American Heart Association estimates that one in every five Americans has hyper-cholesterolemia. In 2001, the NIH National Cholesterol Education Program announced stricter guidelines for cholesterol levels in the battle againts heart disease. Because low-density lipoprotein (LDL-C) is the main perpetrator of atherosclerosis, researchers are exploring new strategies for reducing this type of cholesterol. In many patients, diet and exercise are not sufficient to decrease lipid levels to the new rigorous recommendations. More aggressive treatment modalities will be instituted which include lipid-lowering drugs. The statins are the most effective and most frequently prescribed medications to lower LDL-C. Nurses across all health care settings should understand the rationale for using statin drugs because increasing numbers of patients will be placed on this type of long-term lipid-lowering therapy in the future. To manage patients safety and effectively, nurses need to help patients follow dosing regiments, report side effects and prevent adverse drug actions and interactions. Working together, patients and the health care team can decrease unsafe blood cholesterol levels and reduce associated morbidity and mortality.
Table 1.
New Cholesterol Guidelines and Cardiovascular
Disease Risk Classification

Classification         LDL-C           Total Cholesterol

Optimal                < 100 mg/dl     < 160 mg/dl
Desirable              100-129 mg/dl   160-199 mg/dl
Borderline high risk   130-159 mg/dl   200-239 mg/dl
High risk              > 160 mg/dl     [greater than or
                                       equal to] 240 mg/dl

Adapted from: 2001 Executive summary of the third report of the NCEP
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III).

Table 2.
LDL-C Target Levels According to Cardiovascular Risk Status

Patient's Risk Status                          LDL-C Goal

Zero to one risk factor, no cardiac disease    < 160 mg/dl
Two risk factors or more, no cardiac disease   < 130 mg/dl
Existing cardiovascular disease or diabetes    < 100 mg/dl

Adapted from: 2001 Executive summary of the third report of the NCEP
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III).

Table 3.
Statin Drugs

Statin Drug                  Dose Range    Peak Effect

Pravastatin (Pravachol[R])   10 mg-40 mg   1-1.5 hours
Lovastatin (Mevacor[R])      20 mg-80 mg   2 hour
Simvastatin (Zocor[R])       20 mg-80 mg   1-2.5 hours
Atorvastatin (Lipitor[R])    10 mg-80 mg   1-2 hours
Fluvastatin (Lescol[R])      20 mg-80 mg   1 hour
Fluvastatin (Lescol[R])
  Extended Release           80 mg         3 hours

Adapted from: Nurse Practitioner's Drug Handbook. (4th ed). (2002).
Philadelphia: Lippincott Williams & Wilkins


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Teri Capriotti, DO, MSN, CRNP, is a Clinical Assistant Professor, Villanova University College of Nursing, Villanova, PA.
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