Continuing Education Activity
HMG-CoA reductase inhibitors (statins) are lipid-lowering medications used in the primary and secondary prevention of coronary heart disease. 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. This activity also highlights the critical role of the interprofessional team in the management of patients with clinically significant atherosclerotic cardiovascular disease or individuals with risk factors for heart disease who can benefit from statin therapy.
- 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.
In combination with dietary modifications, atorvastatin is FDA approved to prevent cardiovascular events in patients with cardiac risk factors and for patients with abnormal lipid profiles.
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.
For patients with coronary heart disease, atorvastatin has approval as a therapy to reduce the risk of non-fatal myocardial infarction, fatal and non-fatal 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
- 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. 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.
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).
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.
Atorvastatin is highly plasma protein bound (over 98%) and has a volume of distribution of about 380 liters.
Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) to active ortho- and para-hydroxylated metabolites.
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.
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.
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 %.
Both 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.
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.
Patients over 65 years old may have higher plasma concentrations of atorvastatin when compared to young adults. Older patients may be at increased risk of statin-induced myopathies.
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.
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.
The use of atorvastatin with potent CYP3A4 inhibitors can lead to increased plasma concentrations, which may enhance adverse events, including myopathies. OATP1B1 inhibitors can increase the bioavailability of atorvastatin.
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 exposure of norethindrone and ethinyl estradiol.
Common adverse effects for patients taking atorvastatin include arthralgia, dyspepsia, diarrhea, nausea, nasopharyngitis, insomnia, urinary tract infection, and pain in 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. 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. 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. 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. 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. If patients develop serum transaminases over three times the upper limit of normal, plasma concentrations require more frequent monitoring until normalized, or atorvastatin therapy should undergo dose reduction or be discontinued.
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.
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 prior to 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.
Female patients should also avoid atorvastatin if they are nursing. If a patient requires atorvastatin therapy, they should receive direction to discontinue breastfeeding.
Patients starting atorvastatin should have liver function tests and a lipid panel performed at baseline, with a repeat lipid panel after six weeks on 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.
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 of the 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 the treatment of their 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 members of the interprofessional health care team can help identify barriers to adherence. Additional education and counseling around patient concerns and medication benefits may help improve adherence. [Level 3] Healthcare team members need to communicate across disciplinary lines to optimize therapy. Clinicians (MDs, DOs, NPs, PAs) will make the initial assessment and prescribe statin therapy. Nursing can counsel the patients on how to take their medication, and check for adherence to treatment and adverse effects on subsequent visits and report back to the prescriber. Pharmacists can counsel the patients on optimal dosing (e.g., take the drug at bedtime) and check for drug-drug interactions, reporting back to the prescriber or nurse. Pharmacists can also inquire about the most common adverse effects since they often will see the patient more frequently and let nursing know so it can be relayed to the prescriber as well. These are but a few examples of how interprofessional team interaction can optimize atorvastatin therapy. [Level 5]