Statin Therapy for Primary and Secondary Prevention of Cardiovascular Disease

Abstract

 

Many people in the United States die each year from heart disease. An accumulation of plaque (fatty deposits) in arterial walls can reduce blood flow to the heart, which increases the risk for serious cardiac events. Controlling this risk factor can prevent heart disease. Along with lifestyle modifications, statin drugs can help to lower low-density lipoprotein (LDL) cholesterol and triglyceride levels and raise high-density lipoprotein (HDL) cholesterol levels. The U.S. Preventive Services Task Force (USPSTF) has endorsed using statins for adults at risk for cardiovascular disease in order to lower LDL cholesterol. Side effects of statin drugs are minor and can often be eliminated by lowering the dose or switching to a different statin drug. Potential harm from low-to-moderate dose statin use is small, and the protective benefits far outweigh the risks. The underuse of statin therapy is due to physicians’ lack of prescribing statins to patients at risk for cardiovascular disease, patients’ reluctance to take statin therapy due to misconceptions and fear of adverse side effects, and other healthcare related limitations. The key to solving this problem lies in ongoing patient education, improved patient-physician communication and improved patient monitoring to find the right statin for each patient.

Keywords:

Cardiovascular disease, atherosclerosis, LDL cholesterol, statin therapy, side effects, communication, education.

Statin Therapy for Primary and Secondary Prevention of Cardiovascular Disease

According to The Center for Disease Control and Prevention (CDC), heart disease is a major cause of mortality for both men and women in the United States (2017). The U.S. Preventive Services Task Force (USPSTF) report that “in 2011, an estimated 375,000 adults died of coronary heart disease and 130,000 died of cerebrovascular disease. Coronary heart disease is responsible for approximately one-fifth of deaths among adults aged 45 to 64 years and one-fourth of deaths among those 65 years and older” (USPSTF, 2016, para 43). Atherosclerosis refers to a buildup of plaque in arteries that causes blood vessels to become stiff and hard, which results in a narrowing of the vessel walls over time resulting in a decrease in blood supply to the heart (Davidson, Gandhi, Ohsfeldt & Fox, 2009). Davidson et al. note that an elevated LDL cholesterol level can lead to atherosclerosis, and controlling this risk factor can in turn reduce the risk for heart disease.

According to The American Heart Association (AHA) (2017), cholesterol is a waxy, fatty substance that is produced by the liver or ingested in foods, such as meats, poultry and full-fat dairy products. The AHA note that HDL cholesterol is referred to as good/happy cholesterol as it helps to reduce the bad LDL cholesterol, which can build up in arteries and cause heart disease. Statin drugs can help to reduce elevated levels of LDL cholesterol (hypercholesterolemia) to the optimal level of < 100 mg/dL by blocking an enzyme in the liver (HMG CoA reductase) responsible for producing cholesterol. A lower level of bad cholesterol prevents the formation or progression of plaques (atherosclerosis) that can block arteries and lead to serious cardiac events (Min et al., 2019).

Almeida and Budoff (2019) note that atherosclerotic plaque can accumulate in coronary, cerebrovascular or peripheral arteries. These lesions can develop a fibrous cap that, depending on its thickness, can rupture and form a thrombus or clot that can break away and travel through blood vessels causing partial or complete occlusion of blood flow and a serious cardiac event (Almeida & Budoff, 2019). According to Almeida and Budoff, statin therapy has been shown to reinforce the fibrous cap thereby increasing the resistance to rupture. Heart disease can be prevented by reducing LDL cholesterol levels, and statins are the preferred class of drugs to achieve this (Min et al., 2019). Statins are prescribed worldwide and can reduce heart attacks by 25% to 45% (Jukema, Cannon, de Craen, Westendorp & Trompert, 2012).

Current Health Promotion Guidelines

“The USPSTF recommends that adults without a history of cardiovascular disease (CVD) (i.e., symptomatic coronary artery disease or ischemic stroke) use a low- to moderate-dose statin for the prevention of CVD events and mortality when all of the following criteria are met: 1) they are aged 40 to 75 years; 2) they have 1 or more CVD risk factors (i.e., dyslipidemia, diabetes, hypertension, or smoking); and 3) they have a calculated 10-year risk of a cardiovascular event of 10% or greater” (USPSTF, 2016, para 1). This recommendation was given a “B” rating indicating a moderate to substantial benefit in following this recommendation.

The USPSTF recommends “clinicians may choose to offer a low- to moderate-dose statin to certain adults without a history of CVD when all of the following criteria are met: 1) they are aged 40 to 75 years; 2) they have 1 or more CVD risk factors (i.e., dyslipidemia, diabetes, hypertension, or smoking); and 3) they have a calculated 10-year risk of a cardiovascular event of 7.5% to 10%” (USPSTF, 2016, para 2). This recommendation was given a “C” rating indicating that initiation of statin therapy in this group should be considered on an individual basis related to current health situation.

“The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of initiating statin use for the primary prevention of CVD events and mortality in adults 76 years and older without a history of heart attack or stroke” (USPSTF, 2016, para 3). This recommendation was given an “I” rating indicating there is not enough evidence to conclude a risks-versus-benefit analysis of statin therapy in this group.

This guideline replaces the USPSTF (2008) recommendation for lipid screening for men and women as follows:

1)  Strong recommendation for lipid screening for men age 35 and older. This recommendation was given an “A” rating indicating a positive net benefit.

2)  Recommendation for lipid screening for men ages 20 to 35 with an increased risk for heart disease. This recommendation was given a “B” rating indicating a moderate to substantial net benefit.

3)  Strong recommendation for lipid screening for women ages 45 and older with an increased risk for heart disease. This recommendation was given an “A” rating indicating a positive net benefit.

4)  Recommendation for lipid screening for women ages 20 to 45 be with an increased risk for heart disease. This recommendation was given a “B” rating indicating a moderate to substantial net benefit (USPSTF, 2008).

Whereas the 2008 guidelines focused on who should be screened for dyslipidemia, the 2016 guidelines focus on identifying people at risk for heart disease and then initiating statin therapy (USPSTF, 2016).

Summary of Research

Lovastatin, derived from filamentous fungi, was the first commercial statin to receive US Food and Drug Administration approval in 1987 (Endo, 2008). Endo reports that lovastatin was followed by simvastatin and then pravastatin in 1989, and subsequently the five other types of synthetic statins were developed — fluvastatin, cerivastatin, atorvastatin, rosuvastatin and pitavastatin). Since its introduction in 1987, several studies have confirmed that statin therapy helps to reduce the risk for heart disease (Kavalipati, Ramakrishan & Vasnawala, 2015).

A systematic review performed by the USPSTF to determine the risks versus benefits of statin therapy for reducing the risk of heart disease proved their efficacy (Chou, et al., 2016). A 1194 study conducted in Scandinavia confirmed that treating patients with simvastatin resulted in reduced LDL cholesterol levels (Almeida & Budoff, 2019). Almeida and Budoff also refer to the West of Scotland Prevention Study that showed that men diagnosed with hyperlipidemia who were treated with pravastatin had reduced incidents of myocardial infarction and death.  The Heart Protection Study (HPS) concluded that patients on statin therapy with low baseline cholesterol levels had a reduced risk for cardiovascular disease, which confirms that in addition to lowering LDL cholesterol levels, statin therapy also reduces cardiac risk by stabilizing plaque, reducing CRP levels, reducing inflammation and reducing blood and plasma viscosity (Sinatra, Teter, Bowden, Houston & Martinez-Gonzalez, 2014). In accordance with USPSTF guidelines, Sinatra et al. also recommend that statin therapy should be used cautiously in very low-risk populations in order to avoid adverse side effects.

One million patients with atherosclerosis were chosen to study methods of treating hypercholesterolemia and monitoring of LDL cholesterol levels in the clinical setting (Davidson, Gandhi, Ohsfeldt & Fox, 2009). This study by Davidson et al. determined that the majority of these patients were being sub-optimally treated for their elevated cholesterol levels (hypercholesterolemia), and these results highlighted the need for improved statin therapy to reduce cholesterol levels to less than 100 mg/dL. The goal of a similar survey, called the Lipid Treatment Assessment Project (L-TAP), was to monitor the results of treating patients with hypercholesterolemia, and this study found that only 38% of patients had achieved the target level set by the National Cholesterol Education Program (NCEP) (Davidson et al., 2009). Both of these studies confirm the need to treat patients at risk for heart disease with statin therapy to reduce their cholesterol level to less than 100 mg/dL (Davidson et al., 2009).

Controversy

Jukema, Cannon, de Craen, Westendorp and Trompert (2012) note that adverse effects of statin therapy include muscle aches, weakness, elevated liver enzymes, and at times a more severe muscle injury called rhabdomyolysis. Jukema et al. note that statin drugs may also increase the risk for diabetes mellitus, Parkinson’s disease and impaired memory. The U.S. Food and Drug Administration have warned that “statin use may lead to cognitive impairment” (Jukema et al., 2012, para 1). Jukema et al. note that studies have not found any concrete evidence to support the claim that statin use causes cancer or cognitive impairment; however, a small increased risk for developing diabetes mellitus was noted.  Despite this, it was concluded that the benefits of statin therapy for reducing the risk of heart disease outweigh the small risk for developing diabetes mellitus (Jukema et al., 2012).

The USPSTF (2016) reported that the use of low-to-moderate statin use in adults 40 to 75 years was not associated with any evidence of cancer, severely elevated liver enzymes, or severe muscle injury; however, use of high-dose statin therapy may pose an increased risk of developing diabetes mellitus. The USPSTF also reported that clinical trials have not shown any correlation between statin use and decline in cognitive function. The HOPE-3 trial reported an increased risk for cataracts with the use of statin therapy (USPSTF, 2016).

Clinical studies by Mancini et al. (2013) ­­­­confirmed that there is no available evidence to link statin therapy with cancer, cognitive decline, renal disease, liver disease, lung disease, CK elevation or cataracts. Mancini et al. report that statin therapy may cause muscle pain, weakness and fatigue, which is thought to be a result of oxidative stress and a decreased level of coenzyme Q10 (a compound that helps to generate energy in cells). A more serious muscle injury (rhabdomyolysis) may occur, which causes a breakdown of muscle tissue and may cause damage to the liver and/or kidneys and possibly death; however, the risk of rhabdomyolysis from statin therapy is minimal at 0.04%-0.2% (Mancini et al., 2013).

Authors Stoekenbroek and Kastelein (2017) report that blind studies of statin use versus placebo use have demonstrated a higher incidence of muscle complaints among patients who thought they were taking statins but were actually taking the placebo, which might be linked to a nocebo effect due to negative expectations based on misinformation. It is imperative for physicians to identify patients whose muscle symptoms are due to statin use in order to consider a different management strategy (Stoekenbroek & Kastelein, 2017).

Dissemination of Information

Statins are frequently prescribed in high-income and middle-income countries, and they have been proven to be effective in reducing LDL cholesterol and the risk for heart attacks; however, the Journal of the American Medical Association (JAMA) reported that patients who are eligible for statin therapy are not being prescribed (or even offered ) statin therapy by their primary care physicians (Hill, 2019). This study also revealed that patients who were prescribed a statin were not given enough guidance from their providers on how to take the medication effectively (Heath, n.d.). Heath notes that a survey of 5000 patients to study medication adherence and non-adherence found that: 1) The majority of patients who were not taking statin medication said it was because their physician had never recommended statin therapy, 2) Patients who had been started on statin therapy had discontinued it within one year of treatment initiation because of negative side effects, and 3) A  number of patients decline statin therapy due to fear of negative side effects (Heath, n.d.). These results indicate a problem with patient-provider communication and patient teaching; therefore, physicians need to keep an open dialogue with their patients in order to address their concerns (Heath, n.d.).

Authors Maningat, Gordon, and Breslow (2013) note that poor adherence to statin therapy can be as a result of:

1)     Patient related due to lack of understanding of the disease being treated, fear of negative side effects or adverse events, skepticism regarding the effectiveness of the treatment, or cognitive impairment.

2)     Physician related due to lack of understandable guidance regarding how to take the medication, how the medication treats the underlying health condition, potential side effects or adverse events, and multiple prescribers.

3)     Healthcare related due to limited time that a physician has to fully educate patients regarding their medication regimen, cost of medication, and the involvement of multiple physicians writing multiple prescriptions (para. 13, 17, 18).

Proposed interventions to improve medication adherence include improved and comprehensive patient education, improved patient-physician communication, and improved patient monitoring and follow-up (Maningat et al., 2013).

The USPSTF published their recommendations on using statin drugs to prevent heart attacks in 2016, and the ACA/AHA published cholesterol guidelines with recommendations for statin therapy in 2019. Scientific evidence has proven the benefit of statin drugs to lower cholesterol levels; however, these success stories are clouded by reports of terrible side effects and misinformation found on the internet (Hill, 2016). Hill (2016) reports that both the risks versus benefits of statin therapy hve been studied in detail for an extended period of time, yet the debate/controversy over statin use continues.

Stakeholders

Statin drugs have been proven to be effective at reducing the risk for heart attacks in adults at moderate risk for ischemic heart disease with or without known risk factors (Henock, Aschmann, Kaufmann, & Puhan, 2019). Henock et al. (2019) note that while statins do increase the risk for myopathy, and may lead to kidney or liver damage, it is felt that the benefits of statin therapy outweigh the risks. The results of a study on the use of Rosuvastatin (JUPITER) released in November of 2008 showed a reduction in the risk for heart attack by 44% (Schaiff, Moe & Krichbaum, 2008).

The 2018 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the managing hypercholesterolemia made more patients eligible for statin therapy and provided clinicians with more detailed risk assessment tools, dosing guidelines, and new cholesterol-lowering drug options for treating hypercholesterolemia (ACC, 2018). The new ACC/AHA guidelines consider additional risk factors and certain health conditions when deciding whether or not to initiate statin therapy in order to make sure that statins are only prescribed to patients who need them (ACC, 2018). new guideline gives more attention to percentage reduction in low-density lipoprotein cholesterol as a treatment goal and to long-term monitoring of therapeutic efficacy. To simplify monitoring, nonfasting lipid measurements are allowed.new guideline gives more attention to percentage reduction in low-density lipoprotein cholesterol as a treatment goal and to long-term monitoring of therapeutic efficacy. To simplify monitoring, nonfasting lipid measurements are allowed.In addition, the new ACC/AHA guidelines focus on reduction of the percentage of LDL cholesterol as a treatment goal and as means to monitor statin therapy efficacy. These new guidelines have offered clinicians evidence-based guidelines to offer safe and effective, patient-centered cholesterol-lowering therapy to help reduce the risk of heart attacks (ACC, 2018).

Authors Ngo-Metzer, Zuvekas and Biermann (2018) report that “The Affordable Care Act (ACA) mandates USPSTF recommendations with an “A” or “B” grade receive insurance coverage without copayment” (para 1). Ngo-Metzger et al. (2018) also noted that “ACA’s mandate for insurance coverage resulted in a $193 million shift in out-of-pocket cost for statins from patients to private insurers” (para 5). They note that all marketplace health plans must cover the cost of statin drugs for adults age 40 to 75 at high risk for heart attacks without charging a copayment or coinsurance. Elimination of out-of-pocket costs for statins medication will reduce financial barriers, improve compliance and reduce risk of cardiovascular events (Ngo-Metzger, Zuvekas & Biermann, 2018).

Impact on Future Practice

Secondary to encouraging modification of lifestyle habits to reduce the risk for heart disease (such as healthy diet, regular exercise, tobacco cessation), as a healthcare provider, I would prescribe statin drugs to my patients with increased risk for heart disease after assessing their 10-year risk and other comorbid conditions. The choice of statin (as there are currently six statins on the market, and not all statins are the same), would be based on dosing considerations, drug interactions and adverse events. Ongoing patient education and an open dialogue would be implemented to monitor results of therapy, ensure patient satisfaction with the choice of therapy and to promote continued statin use in combination with healthy lifestyle choices.

Conclusion

Statin drugs are prescribed worldwide to reduce elevated cholesterol levels and reduce the risk of having a heart attack. The USPSTF has endorsed the use of statins for adults at risk for cardiovascular disease in order to lower LDL cholesterol. Statin use may not be indicated for some patients; therefore, prescribing statin drugs should be considered on an individual basis in collaboration with a healthcare provider. Side effects of statin therapy include muscle pain, fatigue, weakness, renal or liver damage, and/or increased risk for diabetes; however, the USPSTF guidelines note that potential harm from low-to-moderate dose statin use was small, and the protective benefits far outweigh the risks. The underuse of statin therapy is due to a lack of encouragement on the part of healthcare providers, combined with patient misconceptions of how statins work and how they can be of benefit in preventing a heart attack. The key to solving this problem lies in ongoing patient education, improved patient-physician communication and improved patient monitoring to find the right statin for each patient. Satin therapy is a practical and effective way to reduce the risk of heart disease in high-risk patients.

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