Continuing Education Activity

HMG-CoA reductase inhibitors (statins) are lipid-lowering medications used in the primary, secondary, and tertiary prevention of coronary heart disease. Atorvastatin competitively inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. By preventing the conversion of HMG-CoA to mevalonate, statin medications decrease cholesterol production in the liver. Atorvastatin also increases the number of LDL receptors on the surface of hepatic cells. This activity reviews the indications, contraindications, and mechanism of action of atorvastatin to manage coronary heart disease and familial dyslipidemias, covering the indications, contraindications, activity, adverse events, and other key elements of atorvastatin therapy.

Objectives:

• Describe the indications for atorvastatin therapy.
• Identify potential adverse events when using therapy with atorvastatin.
• Outline the appropriate follow-up and monitoring of lipid-lowering therapy with atorvastatin.
• Review interprofessional team strategies for improving care coordination and communication to enhance patient adherence to atorvastatin in treating coronary artery disease and hyperlipidemia.

Indications

Combined with dietary modifications, atorvastatin is FDA-approved to prevent cardiovascular events in patients with cardiac risk factors and abnormal lipid profiles.[1]

Secondary Prevention

For patients without coronary heart disease but with multiple risk factors, the FDA has approved atorvastatin to reduce the risk of myocardial infarction, stroke, revascularization procedures, and angina.

For patients diagnosed with type 2 diabetes mellitus without coronary heart disease but with multiple risk factors, atorvastatin has FDA approval to reduce the risk of myocardial infarction and stroke.  

Tertiary Prevention

For patients with coronary heart disease, atorvastatin has received approval as a therapy to reduce the risk of nonfatal myocardial infarction, fatal and nonfatal stroke, revascularization procedures, hospitalizations for congestive heart failure, and angina. 

Atorvastatin has FDA approval for the treatment of the following dyslipidemias: 

• Adults with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia
• Hypertriglyceridemia
• Primary dysbetalipoproteinemia
• Homozygous familial hypercholesterolemia
• Pediatric patients with heterozygous familial hypercholesterolemia (after failing dietary modifications)

Atorvastatin has not been studied in Fredrickson Type I and V dyslipidemias.

Mechanism of Action

Atorvastatin competitively inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.[2] Statin medications decrease cholesterol production in the liver by preventing HMG-CoA conversion to mevalonate. Atorvastatin also increases the number of LDL receptors on the surface of hepatic cells. 

In patients with homozygous or heterozygous familial hypercholesterolemia, mixed dyslipidemia, isolated hypertriglyceridemia, or nonfamilial hypercholesterolemia, atorvastatin has been shown to reduce total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), very-low-density lipoprotein (VLDL-C) and triglycerides (TGs) while increasing high-density lipoprotein cholesterol (HDL-C). 

In patients with dysbetalipoproteinemia, atorvastatin has been shown to decrease intermediate-density lipoprotein (IDL-C).   

Pharmacokinetics

The pharmacokinetic attributes of atorvastatin are covered below.[3] 

Absorption 

Atorvastatin is rapidly absorbed after oral administration with a peak plasma concentration at 1 to 2 hours. The bioavailability is low at 14% due to extensive first-pass metabolism.

Distribution

Atorvastatin is highly plasma protein bound (over 98%) and has a volume of distribution of about 380 liters. 

Metabolism

Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) to active ortho- and para-hydroxylated metabolites. 

Excretion

Atorvastatin and its metabolites get eliminated in bile. Atorvastatin is not known to go through enterohepatic recirculation. The half-life of atorvastatin is about 14 hours, while its active metabolites have a half-life of about 20 to 30 hours. 

Administration

Atorvastatin is available as atorvastatin calcium tablets in strengths of 10, 20, 40, and 80 mg.  

This medication can be administered with or without food and should be taken at the same time every day. It is generally recommended to administer statins at bedtime since endogenous cholesterol synthesis is cyclical, with the highest production levels during fasting as at night. However, the longer half-life of atorvastatin compared to other shorter half-life statins (e.g., lovastatin, fluvastatin, and simvastatin) offers greater flexibility regarding dosing times.

Adult Dosing 

The dosing of atorvastatin can have its basis in LDL-C lowering ability (intensity), or doses are titratable to specific lipid goals. 

The American College of Cardiology/American Heart Association Guidelines recommends either moderate intensity (atorvastatin 10 to 20 mg) or high intensity (atorvastatin 40 to 80 mg) therapy, depending on the statin benefit group to which a patient belongs. Moderate-intensity statins should lower LDL-C by about 30 to 50%, while high-intensity statins should lower LDL-C by over 50%.[4]

The National Lipid Association and the American Association of Clinical Endocrinologists recommend utilizing statin therapy to reach specific lipid goals based on atherosclerotic cardiovascular disease risk.[5][6]

Pediatrics 

Doses above 20 mg do not have study data for pediatric patients with heterozygous familial hypercholesterolemia. Doses up to 80 mg have been used in a limited number of pediatric patients with familial hypercholesterolemia. Studies have not evaluated atorvastatin use in pre-pubescent patients or those under ten years old. 

Geriatrics

Patients older than 65 may have higher plasma concentrations of atorvastatin than young adults. Older patients may be at increased risk of statin-induced myopathies. 

Renal Impairment 

Atorvastatin and its metabolites do not undergo renal elimination, so no dose adjustments are required with reduced renal function. Hemodialysis will not likely remove atorvastatin due to plasma protein binding. 

Hepatic Impairment

Increased plasma concentrations of atorvastatin have occurred in patients with chronic alcoholic liver disease. Drug exposure is four times higher in patients with Child-Pugh Class A and 11x higher in patients with Child-Pugh Class B. Atorvastatin is contraindicated in patients with active liver disease.[7]

Drug Interactions

Using atorvastatin with potent CYP3A4 inhibitors can lead to increased plasma concentrations, which may enhance adverse events, including myopathy. OATP1B1 inhibitors can increase the bioavailability of atorvastatin.[9]

CYP3A4 inducers may cause decreased plasma concentrations of atorvastatin. 

Patients taking digoxin should undergo monitoring when starting atorvastatin as plasma concentrations of digoxin may increase.

Atorvastatin may also increase drug concentrations of norethindrone and ethinyl estradiol.[8] 

Adverse Effects

Common adverse effects for patients taking atorvastatin include arthralgia, dyspepsia, diarrhea, nausea, nasopharyngitis, insomnia, urinary tract infection, and pain in the extremities.

Myopathies have occurred in patients taking atorvastatin, including muscle aches, muscle tenderness, or muscle weakness, with elevated creatine phosphokinase greater than ten times the upper limit of normal. Rhabdomyolysis has been reported in patients using atorvastatin.[10] Patients with impaired renal function may be at increased risk of developing rhabdomyolysis. Using atorvastatin in combination with other medications that increase atorvastatin plasma concentrations increases the risk for myopathies and rhabdomyolysis.[11] Management of statin-induced myopathies includes temporarily holding therapy, switching to an alternative statin, or reducing the dose. 

Some data suggest that statins may increase the risk of developing diabetes mellitus. In 2012, the FDA added safety label changes to statin safety labeling, indicating that they have been shown to increase glycosylated hemoglobin and fasting serum glucose.[12] The ACC/AHA guidelines group and other experts state that the risk-reducing benefits of statin therapy outweigh the generally mild rise in serum glucose levels or new-onset diabetes.[13] Clinicians are encouraged to use this opportunity to discuss healthy lifestyle measures with their patients, including weight loss, engaging in an exercise program, and consuming a healthy diet.

Atorvastatin can cause liver function test abnormalities.[7] If patients develop serum transaminases over 3 times the upper limit of normal, plasma concentrations require more frequent monitoring until normalized or atorvastatin therapy should undergo dose reduction or be discontinued. 

Contraindications

Atorvastatin contraindications include patients with hypersensitivity to any of its components.

While atorvastatin contraindications also include patients with active liver disease, the benefits of lipid-lowering therapy in chronic liver diseases, such as non-alcoholic fatty liver disease and hepatitis, likely outweigh the possible risks.[14]

Atorvastatin is contraindicated during pregnancy or in female patients who may become pregnant. All female patients of childbearing age should receive counseling on the potential risks to a fetus should they become pregnant while on atorvastatin. This risk is most pronounced in the first trimester, so current guidelines recommend ceasing statin therapy for at least 3 months before becoming pregnant. The patient should discontinue this medication immediately if they become pregnant. However, a recent meta-analysis has called this restriction into question; more research will be necessary to accurately assess the risk-benefit ratio of using statins during pregnancy.[15]

Female patients should also avoid atorvastatin if they are nursing. If patients require atorvastatin therapy, they should receive direction to discontinue breastfeeding. 

Monitoring

Patients starting atorvastatin should have liver function tests and a lipid panel performed at baseline, with a repeat lipid panel after six weeks of therapy. Liver function tests should be repeated as clinically indicated. Once the patient is stable, lipids can be checked every 6 to 12 months. It may also be prudent to periodically monitor serum blood glucose levels in patients with diabetes or at risk for diabetes.

Toxicity

There are no antidotes available for atorvastatin overdose. Patients should be monitored for adverse events and provided with supportive care. 

Enhancing Healthcare Team Outcomes

The success of statins in lowering lipids or preventing cardiovascular events depends on the patient's medication adherence. Some barriers to successful statin therapy include experiencing adverse effects, lack of understanding of the importance of statin therapy, and cost; these factors may prevent patients from taking these medications as prescribed. It is also crucial for the interprofessional team to emphasize the importance of lifestyle modification in treating hyperlipidemia. This includes eating a proper, healthy diet, adding exercise or activity several times a week, and losing weight if necessary. A dietician or nutritionist may be a valuable addition to the healthcare team to help guide patients through the necessary dietary changes.

All interprofessional healthcare team members can help identify barriers to adherence. Additional education and counseling around patient concerns and medication benefits may help improve compliance.[16]  Healthcare team members must communicate across disciplinary lines to optimize therapy. Clinicians make the initial assessment and prescribe statin therapy. Nurses can counsel the patients on taking their medication, check for adherence to treatment and adverse effects on subsequent visits, and report back to the prescriber. Pharmacists can guide the patients on optimal dosing (eg, take the drug at bedtime) and check for drug-drug interactions, reporting to the prescriber or nurse. Pharmacists can also inquire about the most common adverse effects since they will see the patient more frequently and let nursing know so it can be relayed to the prescriber as well; open communication between all interprofessional team members combined with accurate record keeping is crucial to optimal care and improved patient outcomes. These are a few examples of how interprofessional team interaction can optimize atorvastatin therapy.