A nurse is caring for a client who is taking atorvastatin. which of the following manifestations

Page last reviewed: 19 November 2018
Next review due: 19 November 2021

Statin medications are used in the management and treatment of hypercholesteremia. They are known to be inhibitors of the hydroxymethylglutaryl-CoA reductase enzyme. This activity describes the indications, action, and contraindications for statins as a valuable agent in the treatment of hypercholesteremia. This activity will highlight the mechanism of action, dosing, monitoring pertinent for members of the interprofessional team in the management of patients with hypocholesteremia.

Objectives:

• Identify indications for initiating statin therapy.

• Review contraindications for statin therapy.

• Explain common and uncommon adverse effects associated with statin therapy.

• Outline the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from therapy with statin drugs.

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, lower total cholesterol, low-density lipoprotein (LDL), and triglyceride concentrations while increasing high-density lipoprotein (HDL) concentrations. Clinicians have long used statin medications for the treatment of hypercholesterolemia, hyperlipoproteinemia, and hypertriglyceridemia as an adjunct to diet and exercise. The primary use of these agents is for the primary and secondary prevention of coronary artery disease. The approved FDA indications vary slightly between the medications in this class but, in general, have recommendations for the treatment of atherosclerosis, myocardial infarction prophylaxis, and stroke prophylaxis. The choice of agent should have its basis on patient-specific characteristics, the pharmacokinetic profiles of each medication, and the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.[1][2][3]

Statins are a selective, competitive inhibitor of hydroxymethylglutaryl-CoA (HMG-CoA) reductase, which is the enzyme responsible for converting HMG-CoA to mevalonate in the cholesterol synthesis pathway. By reducing hepatic cholesterol synthesis, an upregulation of LDL-receptors and increased hepatic uptake of LDL-cholesterol from the circulation occurs.

Statin medications can be taken with or without food. Grapefruit juice should be avoided with some statins to minimize CYP3A4 interactions that could result in increased serum concentrations. Due to the diurnal variation in hepatic cholesterol synthesis, synthesis is highest in the early morning hours. An evening dose of some statins is the recommended dosing approach (e.g., fluvastatin, lovastatin, pravastatin, and simvastatin).[4] Atorvastatin, pitavastatin, and rosuvastatin dosing can be without regard to morning or evening administration, but their administration should be at the same time of day.

Statins are usually well-tolerated, with myopathy, rhabdomyolysis, hepatotoxicity, and diabetes mellitus being the most common adverse reactions. The incidence of myopathy is dose-dependent and may present as diffuse myalgias or otherwise unexplainable muscle tenderness or weakness with reversal upon medication discontinuation. Rhabdomyolysis is the most serious complication of statin use, but its occurrence is rare. Rarely, elevated hepatic transaminases can occur. This elevation is usually a transient effect and resolves with continued therapy or after a brief therapy interruption. The FDA no longer supports liver function tests for monitoring the use of these medications without symptoms of hepatotoxicity such as unusual weakness or fatigue, jaundice, or dark-colored urine.[5][6][7]

Coadministration of CYP3A4 substrate statins (atorvastatin, lovastatin, and simvastatin) with medications that are potent 3A4 inhibitors (diltiazem, erythromycin, -azoles) may result in increased serum concentrations with an increased risk of side effects. A reduced dose may be appropriate or a selection of an alternative statin that does not undergo metabolism via the 3A4 pathway. Administration with other drugs associated with myopathy requires caution. Simvastatin and gemfibrozil coadministration is contraindicated because of the risk of rhabdomyolysis. Dose restrictions are recommended with the coadministration of gemfibrozil or other fibrates with statins, and the use of more than one statin is not recommended.[8][9][10]

Statins are contraindicated for use by patients with active hepatic disease or unexplained persistent elevations in aminotransferase levels. Statins are contraindicated during pregnancy and while breastfeeding because of the effects on the cholesterol pathway. Cholesterol is an essential component for fetal and infant synthesis of steroids and cell membrane development.

Liver function tests should be assessed before therapy initiation as statins are contraindicated in patients with active hepatic disease. It is not necessary to schedule regular follow-up of the patient's liver function unless clinical symptoms of hepatic disease become apparent. A baseline fasting lipid panel before initiation and a second lipid panel in 6 to 12 weeks should be compared to assess efficacy and adherence. Moderate-intensity therapy should result in LDL reduction 30% to 50% from baseline, and a high-intensity regimen should result in a reduction of more than 50% from baseline. Assessments should be performed every 3 to 12 months after that, as clinically indicated. Other than atorvastatin, statin medications have renal dosing guidelines that require an assessment of serum creatinine and creatinine clearance.[11][12][13]

Statins are now well-established drugs with proven effectiveness for the reduction of adverse cardiovascular and cerebrovascular events. There is no antidote to reverse the myopathy or rhabdomyolysis caused by statins. The general treatment is supportive and comprises immediate discontinuation of the offending drug. Aggressive fluid management is the cornerstone of therapy. The urine output requires monitoring, and a Foley catheter insertion may be necessary. Other supportive measures include correcting any electrolyte disturbances and monitoring the patient with continuous ECG if hyperkalemia is present.

All patients need continual follow-up to monitor for hyperkalemia and acute renal failure. The patient may receive a discharge once electrolytes return to normal and there is no renal dysfunction. The decision to restart a statin requires good clinical judgment. Only the lowest dose of another statin should be used, and one should avoid the concomitant use of fibrates. The patient should be closely monitored for muscle pain and routine urine and blood tests to ensure that muscle breakdown is not recurring. 

Statins have been around for over two decades and have proven effective at lowering cholesterol. When the patient has been prescribed a statin, the nurse and pharmacist should educate the patient on the dose and side effects of the drugs. The pharmacist must regularly check the patient's list of medications to ensure safety and prevent polypharmacy interactions. Nursing staff should verify medication compliance, ask about any new symptoms that may have links to statin use, counsel the patient on administration, and inform the prescriber if there are any concerns. Further, all patients prescribed statins should periodically have their liver function checked because these drugs are known to cause elevations in transaminases. These monitoring practices should occur within an interprofessional team environment so that all members of the team have access to the same information and can make decisions and recommendations based on the latest data for the patient, leading to improved therapeutic outcomes. [Level 5]

Statin therapy has some correlations with an increased risk of diabetes, with the first notable JUPITER trial published in 2008.[14] A meta-analysis study involving 91140 patients published in 2014 showed a 9% increase in the likelihood of developing diabetes mellitus.[15] Studies have found that pitavastatin should be the drug of choice in pre-diabetic patients to reduce the risk of developing diabetes. The REAL-CAD trial published in 2018 found that a higher dose of pitavastatin significantly reduced cardiovascular events in Japanese patients with coronary artery disease when compared with a lower dose of pitavastatin.[16] Recent updated meta-analysis showed that Coenzyme Q10 supplementation reduced statin-associated muscle symptoms.[17] Practitioners should consider coq10 supplementation before discontinuing statin medication. 

Outcomes

Many studies have been conducted on statins and shown them to be effective at lowering cholesterol and the risk of adverse cardiac events. The ALLHAT-LLT trial found no benefit in the primary prevention in older adults above 75 years of age with statin therapy and hyperlipidemia.[13] Statin therapy should still resume in elderly patients with a history of coronary artery disease, stroke, and diabetes mellitus. [Level 5]

Review Questions

1.

Range JT, LaFontaine PR, Ryder PT, Polston M. Factors Associated With Adherence to Statin Medications of Patients Enrolled in a Self-insured University Health Plan. Clin Ther. 2018 Oct;40(10):1692-1700. [PubMed: 30231972]

Bakhai S, Bhardwaj A, Sandhu P, Reynolds JL. Optimisation of lipids for prevention of cardiovascular disease in a primary care. BMJ Open Qual. 2018;7(3):e000071. [PMC free article: PMC6109820] [PubMed: 30167469]

Getting the most out of your heart medications. Harv Heart Lett. 2018 Aug;28(12):3. [PubMed: 30160777]

Kamal SM. Effects of single-dose morning and evening administration of pravastatin on antioxidant markers in cholesterol-fed rabbits. J Exp Pharmacol. 2011;3:51-8. [PMC free article: PMC4863309] [PubMed: 27186110]

Brown AS, Watson KE. Statin Intolerance. Rev Cardiovasc Med. 2018;19(S1):S9-S19. [PubMed: 30207553]

Caughey GE, Gabb GM, Ronson S, Ward M, Beukelman T, Hill CL, Limaye V. Association of Statin Exposure With Histologically Confirmed Idiopathic Inflammatory Myositis in an Australian Population. JAMA Intern Med. 2018 Sep 01;178(9):1224-1229. [PMC free article: PMC6142971] [PubMed: 30073275]

Chee WJ, Abdullahi H, Chan Y, Rattle A, Snedden S, Junckerstorff R. Retrospective evaluation of statin prescription in the elderly. Intern Med J. 2018 Dec;48(12):1463-1471. [PubMed: 29869449]

Wilkins B, Hullikunte S, Simmonds M, Sasse A, Larsen P, Harding SA. Improving the Prescribing Gap For Guideline Recommended Medications Post Myocardial Infarction. Heart Lung Circ. 2019 Feb;28(2):257-262. [PubMed: 29523466]

Lee JS, Gonzales R, Vittinghoff E, Corbett KK, Fleischmann KE, Sehgal N, Auerbach AD. Appropriate Reconciliation of Cardiovascular Medications After Elective Surgery and Postdischarge Acute Hospital and Ambulatory Visits. J Hosp Med. 2017 Sep;12(9):723-730. [PubMed: 28914276]

Arnold SV, Spertus JA, Tang F, Krumholz HM, Borden WB, Farmer SA, Ting HH, Chan PS. Statin use in outpatients with obstructive coronary artery disease. Circulation. 2011 Nov 29;124(22):2405-10. [PMC free article: PMC3527107] [PubMed: 22064595]

Coste J, Billionnet C, Rudnichi A, Pouchot J, Dray-Spira R, Giral P, Zureik M. Statins for primary prevention and rhabdomyolysis: A nationwide cohort study in France. Eur J Prev Cardiol. 2019 Mar;26(5):512-521. [PubMed: 29799296]

Moctezuma-Velázquez C, Abraldes JG, Montano-Loza AJ. The Use of Statins in Patients With Chronic Liver Disease and Cirrhosis. Curr Treat Options Gastroenterol. 2018 Jun;16(2):226-240. [PubMed: 29572618]

Han BH, Sutin D, Williamson JD, Davis BR, Piller LB, Pervin H, Pressel SL, Blaum CS., ALLHAT Collaborative Research Group. Effect of Statin Treatment vs Usual Care on Primary Cardiovascular Prevention Among Older Adults: The ALLHAT-LLT Randomized Clinical Trial. JAMA Intern Med. 2017 Jul 01;177(7):955-965. [PMC free article: PMC5543335] [PubMed: 28531241]

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ., JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207. [PubMed: 18997196]

Chogtu B, Magazine R, Bairy KL. Statin use and risk of diabetes mellitus. World J Diabetes. 2015 Mar 15;6(2):352-7. [PMC free article: PMC4360430] [PubMed: 25789118]

Taguchi I, Iimuro S, Iwata H, Takashima H, Abe M, Amiya E, Ogawa T, Ozaki Y, Sakuma I, Nakagawa Y, Hibi K, Hiro T, Fukumoto Y, Hokimoto S, Miyauchi K, Yamazaki T, Ito H, Otsuji Y, Kimura K, Takahashi J, Hirayama A, Yokoi H, Kitagawa K, Urabe T, Okada Y, Terayama Y, Toyoda K, Nagao T, Matsumoto M, Ohashi Y, Kaneko T, Fujita R, Ohtsu H, Ogawa H, Daida H, Shimokawa H, Saito Y, Kimura T, Inoue T, Matsuzaki M, Nagai R. High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial. Circulation. 2018 May 08;137(19):1997-2009. [PMC free article: PMC5959207] [PubMed: 29735587]

Qu H, Guo M, Chai H, Wang WT, Gao ZY, Shi DZ. Effects of Coenzyme Q10 on Statin-Induced Myopathy: An Updated Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc. 2018 Oct 02;7(19):e009835. [PMC free article: PMC6404871] [PubMed: 30371340]