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Guideline-directed patient care recommendations are based upon studies that make observations on groups of subjects who have specific characteristics and exhibit variable degrees of benefit or harm in response to various interventions. While the data derived from clinical trials provide information on the mean response of those taking a specified treatment versus those on placebo or alternate therapy, the results may not necessarily apply to a specific patient with unique clinical characteristics. When the evidence base that would otherwise direct care falls beyond the scope of well-designed clinical trials, or when patients who have uncommon conditions are encountered in clinical practice, clinicians often seek guidance that requires an interpretation of how the best available data can be used to facilitate clinical decision-making.

As advocated by a 2014 ACC Presidential Task Force, a new focus was to be placed on the development of concise decision pathways and/or key points of care. Stakeholder input was to be considered via roundtables or think tank meetings and then writing groups were to be convened to provide "Expert Consensus Decision Pathways" (ECDP's), the purpose of which was to develop clinical policy based upon "expert opinion in areas in which important clinical decisions are not adequately addressed by the available existing trials." These ECDP's were developed to complement existing guidelines and provide clinical guidance between new versions of the Guidelines.

In accordance with the above plan of action, the ACC held the second "LDL: Address the Risk Think Tank" on September 16, 2015. This meeting included expert clinicians and stakeholders from key patient advocacy groups, health plans, pharmacy benefit managers, drug manufacturers, electronic health record vendors, and health systems to discuss the impact that newer data might have on the care of high risk patients with dyslipidemia. The National Lipid Association (NLA) was an invited stakeholder organization at this meeting, and NLA representation was requested on the Writing Group that was subsequently convened to create the2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk.¹

The process employed in the creation of the ECDP document was supported by the ACC without external funding. All members of the Writing Group volunteered their time to create the document. The document was formulated based upon multiple conference calls among committee members and ACC staff. A formal review was completed based upon ACC policy, including expert reviewers nominated by the ACC. Two NLA reviewers were sought to provide input on behalf of the organization. A public comment period was also held to provide additional feedback. All comments were adjudicated by the Writing Committee, and then the final document was evaluated and approved for publication by the ACC governing bodies and the NLA Board of Directors.

The document began by endorsing the basic recommendations of the 2013 ACC/AHA Blood Cholesterol Guideline.² The evidence base employed in that Guideline was randomized controlled trials (RCT's) with ASCVD outcomes and systematic reviews and meta-analyses of RCT's with ASCVD outcomes. As stated in the Guideline, "A limited number of expert opinion recommendations were made only when RCT evidence was not present and after a thorough consideration of what the Expert Panel had learned from the RCT's." The Guideline recommended that in individuals on maximally-tolerated statin therapy with a less-than-anticipated response to those agents, and in high-risk categories, including:

• clinical ASCVD <age 75 years;
• LDL-C ≥190 mg/dL; and
• age 40-75 years with diabetes,

consideration may be given to the use of non-statin cholesterol drugs if ASCVD risk-reduction benefits outweigh the potential for adverse effects. The Guideline also advised that preference should be given to cholesterol-lowering drugs shown to reduce ASCVD events in RCT's.

The three questions that the ECDP Writing Group addressed were the following:

1. In what patient populations should non-statin therapies be considered?
2. In what situations should non-statin therapies be considered, i.e., when is the amount of LDL-C lowering (percent LDL-C reduction or absolute LDL-C level achieved on therapy) less than anticipated, less than desired, or inadequate, and which treatment options should be considered in patients who are truly statin intolerant? And
3. If non-statin therapies are to be added, which agents or therapies should be added and in what order?

Key aspects of the document and points of shared agreement between the ACC and the NLA include:

1. an emphasis on lifestyle intervention as the first step in preventive cardiovascular care for ASCVD;
2. an approach to statin intolerance that considers the guidance of both the ACC/AHA guideline² and the NLA's 2014 Statin Intolerance Panel³ for the comprehensive evaluation and management of potential statin-related side effects;
3. consideration of the use of dietary adjuncts such as phytosterols and viscous dietary fibers for those unable to achieve sufficient LDL-C lowering after employing evidence evidence-based statin therapy;
4. the value of patient-provider interaction in clinical decision making when non-statin therapies are considered, examining the extent of available scientific evidence for net clinical benefit, safety and tolerability, potential for drug-drug interactions, efficacy of additional LDL-C lowering, cost, convenience and medication storage, pill burden, route of administration, and patient preferences;
5. the importance of ongoing LDL-C monitoring to assess response to therapy; and
6. consideration of referral to lipid specialists of those at very high-risk of ASCVD, complex lipid disorders, statin intolerance, multiple lipid medication intolerance or familial hypercholesterolemia.

A new feature of the ECDP document is the employment, in selected high-risk patients, of LDL-C treatment thresholds as one of several factors to consider in determining the potential net clinical benefit of adding non-statin therapies to statins. While the Writing Group endorses the evidence-based findings of statin efficacy from the 2013 ACC/AHA Blood Cholesterol Guideline as a ≥50% reduction in LDL-C for high-intensity statin therapy and 30-49% reduction for moderate intensity therapy, it also recognizes that patients in the RCT's demonstrating safety and efficacy of LDL-C lowering therapy tended to achieve absolute LDL-C levels within a given range. Those individuals with LDL-C levels above that range might be candidates for additive non-statin therapy. Thus, the Writing Group provides levels of LDL-C, or thresholds, in terms of both percentage of LDL-C reduction and absolute on-treatment LDL-C measurement as factors that might affect the decision to consider the use of non-statin therapies. The document states that these treatment thresholds should not be construed as firm triggers for adding medication, but should be interpreted as factors that may be considered within the broader context of the patient's clinical situation.

The ECDP Writing Group makes specific recommendations that may help to guide lipid management for patients in the four statin benefit groups identified in the 2013 ACC/AHA Blood Cholesterol Guideline and is more granular in its identification of specific patient subgroups. When considering indications for non-statin therapy in those with clinical ASCVD, the addressed patient categories for those on high-intensity or maximal-tolerated statin therapy include those with:

• uncomplicated ASCVD;
• NYHA Class II-III heart failure due to ischemic heart disease;
• ASCVD and diabetes mellitus;
• recent (<3 months) acute coronary syndromes or atherothrombotic stroke;
• ASCVD events while already taking a statin; and
• ASCVD and concomitant familial hypercholesterolemia.

Next, patients with LDL-C ≥190 mg/dL on high-intensity or maximally-tolerated statin therapy are addressed and are divided into:

1. those with uncomplicated LDL-C elevation;
2. those with additional major ASCVD risk factors; and
3. those considering pregnancy or who are already pregnant.

For the third statin benefit group, individuals age 40-75 years with diabetes mellitus on statin therapy for primary prevention, two categories are considered:

1. those with 10-year ASCVD risk <7.5% and without concomitant major ASCVD risk factors; and
2. patients with 10-year ASCVD risk >7.5%.

Two categories were considered for the final statin benefit group, those individuals age 40-75 years without diabetes and a 10-year ASCVD risk ≥7.5%:

1. patients without high-risk markers; and
2. those with high-risk markers (10-year ASCVD risk >20%, primary LDL-C >160 mg/dL at baseline, poorly-controlled other ASCVD risk factor, family history of premature ASCVD with or without Lp(a), evidence of accelerated subclinical atherosclerosis, elevated hs-CRP, or other risk-modifying conditions such as chronic kidney disease, HIV, or chronic inflammatory disorders).

The details of the recommended approach to each of these groups are provided in easy-to-use algorithms and an app is in development by the ACC.

Unlike the ACC/AHA Blood Cholesterol Guideline, but consistent with the NLA Recommendations Part II,⁴ the ECDP gives recommendations on the order in which specific non-statin therapies should be considered, providing a perspective that is useful to the practicing clinician. Generally, ezetimibe is recommended as the initial add-on agent, based upon its demonstrated efficacy in ASCVD risk reduction, tolerability, safety and low pill burden. Bile acid resins are generally reserved for those who require additive therapy, but are unable to tolerate ezetimibe. PCSK9 inhibitors are recommended for consideration solely in high risk individuals with ASCVD or LDL-C ≥190 mg/dL after therapy with the previously mentioned agents fail to provide sufficient additional LDL-C lowering, but these agents are not recommended in those with these conditions who are pregnant or imminently contemplating pregnancy. When male homozygous familial hypercholesterolemia (HoFH) patients or female HoFH patients on appropriate contraceptive therapy and not considering imminent conception have persistently elevated LDL-C levels despite maximal traditional lipid therapy, a trial on evolocumab is recommended for consideration prior to the use of lomitapide, mipomersin or LDL apheresis. LDL apheresis is suggested to be reserved for HoFH, severe heterozygous FH patients who are inadequately responsive to the above pharmacologic therapies, or for pregnant patients with HoFH or severe HeFH and concomitant ASCVD.

The 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-C Lowering in the Management of ASCVD emphasizes that the recommendations made in this document are based on the consensus of the panel members, reflecting the best available data, recognizing that additional studies and future Guideline documents will help to shape future ACC recommendations for lipid management for ASCVD prevention. In an era in which political discord has dominated the headlines, the concordant perspectives of the ACC and the NLA on these difficult clinical scenarios supports the welcome perspective that key stakeholder organizations can work together to formulate patient care recommendations that are based on good clinical judgment and are useful in everyday medical practice.

References

1. Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly Jr DD, DePalma SM, Minissian MB, Orringer CE, Smith SC. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2016 April 1 [E-pub ahead of print]; http://content.onlinejacc.org/article.aspx?doi=10.1016/j.jacc.2016.03.519.
2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:S1-S45.
3. Guyton JR, Bays HE, Grundy SM et al. An Assessment by the Statin Intolerance Panel: 2014 Update. Journal of Clinical Lipidology 2104;8:S72-81.
4. Jacobson TA, Maki KC, Orringer CE et al. National Lipid Association Recommendations for the Patient-Centered Management of Dyslipidemia: Part II. Journal of Clinical Lipidology 2015; 9:S1-S122.

Keywords: Acute Coronary Syndrome, Algorithms, Antibodies, Monoclonal, Anticholesteremic Agents, Atherosclerosis, Benzimidazoles, Bile Acids and Salts, Blood Component Removal, Cholesterol, Cholesterol, LDL, Coronary Artery Disease, Diabetes Mellitus, Drug Interactions, HIV Infections, Heart Failure, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Life Style, Patient Advocacy, Patient Care, Pharmaceutical Preparations, Phytosterols, Primary Prevention, Renal Insufficiency, Chronic, Risk Factors, Risk Reduction Behavior, Stroke

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