VA/DoD CLINICAL PRACTICE GUIDELINE FOR THE MANAGEMENT OF DYSLIPIDEMIA FOR CARDIOVASCULAR RISK REDUCTION Department of Veterans Affairs Department of Defense QUALIFYING STATEMENTS The Department of Veterans Affairs and the Department of Defense guidelines are based upon the best information available at the time of publication. They are designed to provide information and assist decision making. They are not intended to define a standard of care and should not be construed as one. Neither should they be interpreted as prescribing an exclusive course of management. This Clinical Practice Guideline is based on a systematic review of both clinical trial and epidemiological evidence. Developed by a panel of multidisciplinary experts, it provides a clear explanation of the logical relationships between various care options and health outcomes while rating both the quality of the evidence and the strength of the recommendation. Variations in practice will inevitably and appropriately occur when clinicians take into account the needs of individual patients, available resources, and limitations unique to an institution or type of practice. Every healthcare professional making use of these guidelines is responsible for evaluating the appropriateness of applying them in the setting of any particular clinical situation. These guidelines are not intended to represent Department of Veterans Affairs nor TRICARE policy. Further, inclusion of recommendations for specific testing and/or therapeutic interventions within these guidelines does not guarantee coverage. Additional information on current TRICARE benefits may be found at www.tricare.mil or by contacting your regional TRICARE Managed Care Support Contractor. Prepared by: The Management of Dyslipidemia for Cardiovascular Risk Reduction Work Group With support from: The Office of Quality and Patient Safety, VA, Washington, DC & Office of Evidence Based Practice, U.S. Army Medical Command Based on evidence reviewed through May 16, 2019 Table of Contents II. Dyslipidemia is Defined by Risk for Cardiovascular Disease 5 III. About this Clinical Practice Guideline 6 a. Grading Recommendations 7 b. Reconciling 2014 Clinical Practice Guideline Recommendations 8 c. Peer Review Process 9 B. Summary of Patient Focus Group Methods and Findings 9 C. Conflicts of Interest 10 D. Scope of this Clinical Practice Guideline 10 a. Populations Included in this Guideline 10 b. Populations Excluded from this Guideline 10 E. Patient-centered Care 11 F. Highlighted Features of this Clinical Practice Guideline 11 b. Treatment Intensity Instead of Lipid Targets 11 G. Shared Decision Making 12 IV. Guideline Work Group 13 V. Algorithm 14 Algorithm: Management of Dyslipidemia for Cardiovascular Risk Reduction 15 VI. Recommendations 17 A. Screening and Assessment of Cardiovascular Risk 19 B. Pharmacotherapy, Supplements, and Nutraceuticals 25 a. Primary Prevention 25 b. Secondary Prevention 32 c. Other Medications, Supplements, and Nutraceuticals 39 d. Monitoring and Adherence 47 C. Lifestyle Interventions 52 VII. Knowledge Gaps and Recommended Research 56 A. Comparison of Medical Therapies in Primary and Secondary Prevention 56 a. Primary Prevention 56 b. Secondary Prevention 57 B. Effectiveness of Non-statin Monotherapy for Primary Prevention 57 C. Safety of Newer Therapies 57 D. Stratifying Primary Prevention Benefits by Patient Risk Estimates 57 E. Prospective Studies to Improve Statin Adherence 57 F. Prospective Comparative Study of Risk Prediction Strategies 58 G. Prospective Comparison of Risk Calculators in Varied Populations 58 H. Pragmatic, Evidence-based Dietary Studies 58 I. Comparative Studies of Cardiac Rehabilitation Programs 58 Appendix A: Evidence Review Methodology 59 A. Developing the Key Questions 59 B. Conducting the Systematic Evidence Review 65 C. Convening the Face-to-face Meeting 71 D. Grading Recommendations 71 E. Recommendation Categorization 75 F. Drafting and Submitting the Final Clinical Practice Guideline 76 Appendix B: Cardiovascular Disease Risk Calculators 78 Appendix C: Pharmacotherapy 79 Appendix D: Patient Education on the Mediterranean Diet 81 Appendix E: Patient Focus Group Methods and Findings 82 B. Patient Focus Group Findings 82 Appendix F: Evidence Table 84 Appendix G: 2014 Recommendation Categorization Table 88 Appendix H: Participant List 93 Appendix I: Abbreviation List 95 Appendix J: Literature Search Strategy 97 A. EMBASE with EMBASE.com Syntax 97 B. MEDLINE with Ovid Syntax 106 Appendix K: Alternative Text Description of Algorithm 115 Algorithm: Management of Dyslipidemia for Cardiovascular Risk Reduction 115 References 118 I. Introduction The Department of Veterans Affairs (VA) and Department of Defense (DoD) Evidence-Based Practice Work Group (EBPWG) was established and first chartered in 2004, with a mission to advise the Health Executive Committee (HEC) on the use of clinical and epidemiological evidence to improve the health of the population across the Veterans Health Administration (VHA) and Military Health System (MHS), by facilitating the development of clinical practice guidelines (CPGs) for the VA and DoD populations.[1] This CPG is intended to provide healthcare providers with a framework by which to evaluate, treat, and manage the individual needs and preferences of patients with dyslipidemia, thereby leading to improved clinical outcomes. In 2014, the VA and DoD published a CPG for the Management of Dyslipidemia for Cardiovascular Risk Reduction (2014 VA/DoD Dyslipidemia CPG), which was based on evidence reviewed from January 2010 through February 2014. Since then, a growing body of research has expanded the general knowledge and understanding of dyslipidemia and cardiovascular (CV) risk. Consequently, a recommendation to update the 2014 VA/DoD Dyslipidemia CPG was initiated in 2019. The system-wide goal of evidence-based guidelines is to improve the patient s health and well-being. To that end, this CPG is intended to guide providers who care for patients with dyslipidemia along management pathways supported by evidence. The expected outcomes of successful implementation of this guideline include: Emphasizing the use of patient-centered care using risk factors and event history Minimizing preventable complications and morbidity Optimizing each individual s health outcomes and improving quality of life Assessing the patient s condition and collaborating with the patient, family, and caregivers to determine the optimal treatment II. Dyslipidemia is Defined by Risk for Cardiovascular Disease Cardiovascular diseasea (CVD) is a major cause of morbidity and mortality in the United States (U.S.) and globally.[2,3] Most CVD is caused by atherosclerosis, which is the buildup of plaque (i.e., cholesterol, proteins, calcium, and inflammatory cells) in the walls of arteries. This plaque can narrow the lumen of arteries, limiting the flow of oxygenated blood and increasing the risk of chronic and acute ischemia. If a plaque ruptures within a vital artery, a blood clot forms and may obstruct the flow of oxygenated blood to the heart or brain, resulting in an acute coronary syndrome (ACS), myocardial infarction (MI), or stroke, with potentially irreversible damage to the tissue of the heart or brain. Control and reduction of CVD risk factors, including high cholesterol levels, elevated blood pressure, insulin resistance, elevated blood glucose levels, smoking, poor dietary habits, and a sedentary lifestyle, can contribute to a reduction in CVD morbidity and mortality. a The abbreviation CVD will be used throughout this CPG. For the purposes of this guideline, CVD includes atherosclerotic cardiovascular disease. Although serum cholesterol and its components have been well established as independent risk factors for CVD, they contribute only marginally to risk calculators in estimating CVD risk, the principal driver for the management of lipids in the primary prevention of CVD. Aside from familial hypercholesterolemia (FH) and other genetically mediated forms of extreme lipid levels, dyslipidemia has traditionally been defined as one or more of the following: low-density lipoprotein cholesterol (LDL-C) 130 milligrams per deciliter (mg/dL), high-density lipoprotein cholesterol (HDL-C) <40 mg/dL, or triglycerides (TGs) 200 mg/dL. However, in patients with known CVD or elevated risk for CVD, even normal lipids levels warrant intervention for CVD risk reduction. Treatment of dyslipidemia involves lifestyle changes and lipid-lowering drugs. However, the management of dyslipidemia has shifted away from treating dyslipidemia itself as a discrete entity and moved toward managing dyslipidemia in the context of overall risk for CVD. For this reason, much of our evidence is based on CV risk reduction and does not require lipid levels for inclusion criteria. This CPG addresses the various treatment and management strategies for managing lipids among patients at risk for CVD morbidity and mortality focusing upon an individual s risk factors and event history. III. About this Clinical Practice Guideline This guideline is aimed at efficiently improving dyslipidemia management for CV risk reduction in the VA and DoD. It is intended for use by all VA and DoD healthcare providers. This CPG is not intended to serve as a standard of care. Standards of care are determined on the basis of all clinical data available for an individual patient and are subject to change as scientific knowledge and technology advance and patterns evolve. This CPG is based on information available on or before May 16, 2019, and is intended to provide general guidance to the best evidence-based practices (see Appendix A for additional information on the evidence review methodology). While this guideline can assist providers, a CPG s content must always be considered as a recommendation, within the context of a provider s clinical judgment and patient values and preferences. The evolution of medical practice and future scientific research will likely impact these recommendations. After assessing the currently available evidence, the Work Group determined future research topics, which are outlined in applicable discussion sections. An abbreviated provider summary, patient summary, and pocket card are available at this link: https://www.healthquality.va.gov/guidelines/CD/lipids/. A. Methods This document is an update to the 2014 VA/DoD Dyslipidemia CPG. The methodology used in developing the 2020 CPG follows the Guideline for Guidelines, a VA and DoD EBPWG document that was updated in January 2019.[4] The Guideline for Guidelines can be downloaded from http://www.healthquality.va.gov/policy/index.asp. This document outlines procedures for developing and submitting guidelines, including the identification and assembly of Guideline Champions ( Champions ) and other subject matter experts from within the VA and DoD (the Work Group ). Appendix A provides a detailed description of the guideline development process. This CPG s Champions and Work Group (see Guideline Work Group) were tasked with developing evidence-based clinical practice recommendations through crafting key questions (KQs) that were the most clinically relevant and important for the management of dyslipidemia. The Champions and Work Group also provided direction on inclusion and exclusion criteria for the evidence review and assessed the level and quality of the evidence. The scientific evidence published since the 2014 VA/DoD Dyslipidemia CPG informed the new KQs. The Champions assisted in: Identifying appropriate disciplines to be included in the Work Group Directing and coordinating the Work Group Overseeing the guideline development and review processes The VA Office of Quality and Patient Safety, in collaboration with the Office of Evidence Based Practice, U.S. Army Medical Command, the DoD proponent for CPGs, identified three clinical leaders, John R. Rick Downs, MD, FACP from the VA and Lt Col Brian Neubauer, MD, MHPE, FACP and COL Patrick G. O Malley, MD, MPH, FACP from the DoD, as Champions for the 2020 CPG. The Lewin Team, including The Lewin Group, Anjali Jain Research & Consulting, Duty First Consulting, ECRI, and Sigma Health Consulting, was contracted by the VA and DoD to support the development of this CPG and conduct the systematic evidence review. In January 2019, the contracting officer s representative (COR), leaders from the VA Office of Quality and Patient Safety and the DoD Office of Evidence Based Practice, and the Champions kicked off the guideline development effort. During this teleconference, participants discussed the guideline initiative s scope, the Champions roles and responsibilities, the project timeline, and the approach for developing and prioritizing specific research questions (i.e., key questions) on which to base a systematic evidence review about the management of patients with dyslipidemia. The specialties and clinical areas of interest included: primary care, cardiology, nursing, clinical pharmacology, internal medicine, family practice, exercise physiology, and dietetics. The guideline development process for the 2020 CPG update included: 1. Formulating and prioritizing KQs 2. Convening a patient focus group 3. Conducting the systematic evidence review 4. Convening a face-to-face meeting with the CPG Champions and Work Group members to review the evidence, craft evidence-based recommendations, and develop an algorithm 5. Drafting and submitting a final CPG on the management of dyslipidemia to the VA/DoD EBPWG a. Grading Recommendations The Champions and Work Group used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to assess the quality of the evidence base and assign a strength for each recommendation. The GRADE system uses these four domains to assess the strength of each Balance of desirable and undesirable outcomes Confidence in the quality of the evidence Values and preferences Other implications, as appropriate, e.g.,: Resource use Equity Acceptability Feasibility Subgroup considerations Using these four domains, the Work Group determined the relative strength of each recommendation ( Strong or Weak ). A Strong recommendation generally indicates high confidence in the quality of the available scientific evidence, a clear difference in magnitude between the benefits and harms of an intervention, similar values and preferences, and understood influence of other implications (e.g., resource use, feasibility). If the Work Group has less confidence after the assessment across these domains and believes that additional evidence may change the recommendation, it generally assigns a Weak recommendation. It is important to distinguish GRADE terminology (i.e., Strong versus Weak ) from a recommendation s clinical importance. For instance, a Weak recommendation indicates the Work Group s assessment of the four domains outlined above. Despite the Weak strength supporting the recommendation, it may still be important to the clinical care of a patient with dyslipidemia. Occasionally, there is insufficient evidence to make a recommendation for or against a particular therapy or preventive measure, such as when there is an absence of studies that met evidence review inclusion criteria, or when studies included in the evidence review report had conflicting or inconclusive results. Using these elements, the strength of each recommendation is presented as part of a continuum: Strong for (or We recommend offering this option ) Weak for (or We suggest offering this option ) No recommendation for or against (or There is insufficient evidence ) Weak against (or We suggest against offering this option ) Strong against (or We recommend against offering this option ) The strength of each recommendation can be found in the Recommendations section. For additional information regarding the use of GRADE, see Appendix A. b. Reconciling 2014 Clinical Practice Guideline Recommendations Evidence-based CPGs should be current, which typically requires revisions of previous guidelines based on new evidence, or as scheduled and subject to time-based expirations.[6] For example, the U.S. Preventive Services Task Force (USPSTF) has a process for refining or otherwise updating its recommendations pertaining to preventive services.[7] This Work Group developed new and updated recommendations based on the evidence yielded from this CPG s key questions. The Work Group also considered the current applicability of the recommendations included in the 2014 VA/DoD Dyslipidemia CPG that were not addressed by the KQs in light of evolving practice in today s environment. Accordingly, some of the 2014 VA/DoD Dyslipidemia CPG s recommendations do not appear in this updated CPG. Recommendation categories were adapted from those used by the National Institute for Health and Care Excellence (NICE).[8,9] These categories and their corresponding definitions were used to account for the ways that older recommendations could have been updated. In short, the categories explain whether the evidence related to a recommendation was systematically reviewed, the degree to which the recommendation was modified, and the degree to which a recommendation is relevant in the current care environment and within the scope of the CPG. For additional information regarding these categories and their definitions, see Recommendation Categorization. The 2020 CPG recommendation categories can be found in the Recommendations section. Appendix G outlines the categories for the recommendations carried forward from the 2014 VA/DoD Dyslipidemia CPG. The Work Group recognized there may be practical reasons for incorporating findings from a previous systematic review (SR), previous recommendations,[10] or recent peer-reviewed publications into an updated CPG. However, because this would not involve an original, comprehensive systematic evidence review, it may introduce bias. c. Peer Review Process The CPG was developed through an iterative process (i.e., the Work Group produced multiple drafts). The process for developing the initial draft is detailed in Drafting and Submitting the Final Clinical Practice Guideline. Once the Champions and Work Group agreed upon a near-final draft of the guideline, the draft was posted for a 14-business-day peer review and comment period. The peer reviewers comprised individuals working within the VA and DoD healthcare systems and experts from relevant outside organizations designated by the Work Group members. VA and DoD Leadership contacted internal and external peer reviewers to solicit their feedback on the CPG. The Work Group considered all feedback from the peer reviewers. Modifications made throughout the CPG development process were made in accordance with the evidence. B. Summary of Patient Focus Group Methods and Findings When developing a CPG, consideration should be given to the values of the patients who are primarily impacted.[11,12] Patients bring perspectives, values, and preferences that often vary from those of providers. Focus groups can help collect qualitative data on the perspectives of patients. As part of the effort to update this CPG, VA and DoD Leadership held a patient focus group on March 19, 2019, at the Walter Reed National Military Medical Center in Bethesda, MD. The aim of the focus group was to elicit patient perspectives on a set of topics related to their dyslipidemia. The patient focus group comprised a convenience sample of three people. The Work Group acknowledges this sample is not representative of all patients within the VA and DoD healthcare systems and, thus, findings are not generalizable and did not comprise evidence. For more information on the patient focus group and its key concepts, see Appendix E. C. Conflicts of Interest The project team was required to submit disclosure statements to reveal any areas of potential conflict of interest (COI) in the past 24 months. Verbal affirmations of no COI were further obtained as necessary during meetings throughout the guideline development process. The project team was also subject to random web-based surveillance (e.g., Centers for Medicare & Medicaid Services open payments or ProPublica). No COIs were identified for the Champions or Work Group. If a project team member had reported a COI (actual or potential), then it would have been reported to the VA and DoD program offices. It would have also been discussed with the Dyslipidemia CPG Champions in tandem with their review of the evidence and development of recommendations. The VA and DoD program offices and the Dyslipidemia CPG Champions would have determined the appropriateness of further action (e.g., restricting participation, removal from the Work Group). If it had been deemed necessary, VA and DoD Leadership and the Champions would have taken action. Disclosure forms are on file with the VA Office of Quality and Patient Safety and available upon request. D. Scope of this Clinical Practice Guideline This CPG is designed primarily to assist primary care providers (or other providers as applicable) in managing patients with dyslipidemia for the purpose of CVD risk reduction. This guideline seeks to inform providers with practical evidence-based recommendations for the most common scenarios involving patients at risk for CVD. a. Populations Included in this Guideline The patient population of interest for this CPG is patients >40 years old and eligible for care in the VA and/or DoD healthcare systems. b. Populations Excluded from this Guideline Patients with heart failure with reduced ejection fraction (EF) 35%, a limited life expectancy (<5 years), or end-stage renal disease (ESRD) were excluded from most clinical outcome trials. Although some controlled trial data exists exclusively in patients with ESRD and chronic systolic heart failure, the available evidence is comparatively sparse. Additionally, the data that is available show an absence of CV benefit in these populations. A more nuanced review of this evidence can be found on page 10 in the 2014 iteration of the under section Populations Excluded from this Guideline. [13] Our updated systematic evidence review found no new evidence that would alter this position. Genetic dyslipidemia conditions (e.g., homozygous FH [HoFH], heterozygous FH [HeFH], TGs >500 mg/dL, etc.) were also excluded from the guideline given their uncommon occurrence and sparse clinical trial data. Although younger patients (i.e., <40 years old) are more common in the DoD, this cohort comprises a low short-term risk population that has been excluded from dyslipidemia intervention trials. Thus, the Work Group was unable to provide evidence-based recommendations for these populations and suggests that providers consider basing treatment decisions for these cohorts on comorbidity, quality of life, and patient s values and preferences. Such shared and informed decision making should clearly lay out the uncertainty of benefit and known risks associated with pharmacologic treatment. E. Patient-centered Care Guideline recommendations are intended to consider a patient s needs and preferences and be patient centered, culturally appropriate, and available to people with limited literacy skills, and physical, sensory, or learning disabilities. VA/DoD CPGs encourage providers to use a patient-centered approach (i.e., individualized treatment based on patient needs, characteristics, and preferences). Regardless of the setting, all patients should be able to access evidence-based care that is appropriate to them. Patient- centered care may decrease patient anxiety, increase trust in providers, and improve treatment adherence.[14-16] Good communication is essential and should be supported by evidence-based information tailored to the patient s needs. An empathetic and non-judgmental approach facilitates discussions sensitive to gender, culture, ethnicity, and other differences. The focus is using an individual s risk factors and event history to guide the various treatment and management strategies among patients at risk for CVD morbidity and mortality. F. Highlighted Features of this Clinical Practice Guideline The 2020 edition of the VA/DoD Dyslipidemia CPG is the fourth update to the original CPG. It provides practice recommendations for the management of dyslipidemia. a. Methodology Particular strengths of this CPG include adherence to the National Academy of Medicine s (NAM) eight principles of trustworthy guidelines, including the management of COI, interdisciplinary stakeholder involvement, and representation from the broad spectrum of providers engaged in the treatment and management of dyslipidemia.[17] This CPG also uses GRADE methodology, which allows the systematic consideration of factors beyond the strength of the evidence, including balancing desired outcomes with potential harms of the intervention, equity of resource availability, the potential for variation in patient values and preferences, and other considerations (e.g., resource use, subgroup considerations) as appropriate. Applicability of the evidence to VA/DoD populations was also considered. The GRADE methodology allows for explicit recommendations on how primary care providers may improve efficiency in clinic and incorporate patient-centered clinical outcomes. A simple one page algorithm accompanies the guideline and provides an overview of the recommendations in the context of the flow of patient care and to assist with training providers (see the Algorithm section). The algorithm may be used to help facilitate the translation of guideline recommendations into effective practice. Finally, this CPG includes the newest U.S. Food and Drug Administration (FDA) approved dyslipidemia treatments (e.g., bempedoic acid, icosapent ethyl), evaluates use of nutraceuticals and supplements for treatment of dyslipidemia, and has recommendations on practical exercise and the role of cardiac rehabilitation after a CVD event. b. Treatment Intensity Instead of Lipid Targets The Work Group carefully considered whether to use target levels for LDL-C but noted that the evidence relating patient-oriented outcomes to LDL-C levels consisted of trial comparisons between therapy intensities. Most often this consisted simply of active treatment versus placebo. Since no study prospectively evaluated LDL-C goals, the Work Group decided to focus on treatment intensity to match the evidence and simplify point of care decision making. The Work Group chose to use the common convention of moderate- and high-dose statins. Available statin doses are separated into moderate- and high-dose in Sidebar 3 of the algorithm. The Work Group is using the terms dose to represent what has also been called intensity. Both terms appear in the literature. G. Shared Decision Making This CPG encourages providers to practice shared decision making. Shared decision making was emphasized in Crossing the Quality Chasm, an Institute of Medicine (IOM) (now the NAM) report, in 2001.[18] Providers must be adept at presenting information to their patients regarding individual treatments, expected risks, expected outcomes, and levels and/or locations of care, especially as differences between risks and benefits become less clear. Providers are encouraged to use shared decision making strategies to individualize treatment goals and plans based on patient capabilities, needs, and preferences. H. Implementation This CPG and algorithm are designed to be adapted by individual healthcare providers with consideration of unique patient considerations and preferences, local needs, and resources. The algorithm serves as a tool to prompt providers to consider key decision points in the care for a patient with dyslipidemia. The Work Group submits suggested performance metrics for the VA and DoD to use when assessing the implementation of this guideline. Robust implementation will require wide dissemination through publication in the medical literature, online access, educational programs, and ideally electronic medical record programming in the form of clinical decision support tools at the point of care. IV. Guideline Work Group Organization Name* Department of Veterans Affairs John R. Rick Downs, MD, FACP (Champion) Jennifer Ballard-Hernandez, DNP, FNP-BC Andrew Buelt, DO Mark Donahue, MD Cathy Kelley, PharmD Amanda Logan, MPS, RDN, LD Sundar Natarajan, MD, MSc Lance Spacek, MD Department of Defense Lt Col Brian Neubauer, MD, MHPE, FACP (Champion) COL Patrick G. O Malley, MD, MPH, FACP (Champion) CDR Michael J. Arnold, MD, FAAFP Karen Grace, PharmD Joan Ritter, MD, FACP LTC Nikki Smith, DNP, FNP-BC Lauren Thomas, MS, RD, LD Elena Vagichev, PharmD, BCPS, BCACP Office of Quality and Patient Safety Veterans Health Administration M. Eric Rodgers, PhD, FNP-BC James Sall, PhD, FNP-BC Rene Sutton, BS, HCA Office of Evidence Based Practice U.S. Army Medical Command Corinne K. B. Devlin, MSN, RN, FNP-BC Lisa Jones, BSN, RN, MHA, CPHQ The Lewin Group Clifford Goodman, PhD Christine Jones, MS, MPH, PMP Erika Beam, MS Ben Agatston, JD, MPH Nicolas Stettler-Davis, MD, MSCE Ruben Ganesh, BS ECRI James Reston, PhD, MPH Jeff Oristaglio, PhD Joann Fontanarosa, PhD Kristy McShea, MSLIS Benjamin Rouse, MHS Nancy Sullivan, BA Anjali Jain Research & Consulting Anjali Jain, MD Sigma Health Consulting Frances Murphy, MD, MPH Duty First Consulting Rachel Piccolino, BA Megan McGovern, BA MK Curley, BA *Additional contributor contact information is available in Appendix H. V. Algorithm This CPG s algorithm is designed to facilitate understanding of the clinical pathway and decision making process used in identifying patients at risk for CVD who are then eligible for management of their dyslipidemia. This algorithm format represents a simplified flow of the management of patients with dyslipidemia and helps foster efficient decision making by providers. It includes: An ordered sequence of steps of care Recommended decision criteria Decisions to be considered Actions to be taken The algorithm is a step-by-step decision tree. Standardized symbols are used to display each step, and arrows connect the numbered boxes indicating the order in which the steps should be followed.[19] Sidebars provide more detailed information to assist in defining and interpreting elements in the boxes. Shape Description Rounded rectangles represent a clinical state or condition Hexagons represent a decision point in the guideline, formulated as a question that can be answered Yes or No Rectangles represent an action in the process of care Ovals represent a link to another section within the guideline Appendix K contains alternative text descriptions of the Algorithm: Management of Dyslipidemia for Cardiovascular Risk Reduction. Algorithm: Management of Dyslipidemia for Cardiovascular Risk Reduction * There are no evidence-based recommendations for patients under age 40 because there is no evidence for the benefit of lipid screening and treatment within this age group. In patients younger than 40 years old interested in pursuing lipid testing and management, shared decision making is recommended to discuss the risks and unknown benefit of pharmacotherapy, with therapeutic lifestyle changes being the primary focus of CVD primary prevention. Suggest regular aerobic activity of any intensity or duration. Although incremental benefit is associated with increased doses of physical activity, lower doses including leisure time activity (i.e., walking, landscaping, washing dishes) are associated with benefit when compared to mostly sedentary behavior. A provider s considerations when recommending physical activity might include a patient s motivation, functional capacity, and physical activity preferences. Abbreviations: ACS: acute coronary syndrome; CABG: coronary artery bypass grafting; CVD: cardiovascular disease; DM: diabetes mellitus; EF: ejection fraction; ESRD: end-stage renal disease; HF: heart failure; LDL: low-density lipoprotein cholesterol; mg/dL: milligrams per deciliter; MI: myocardial infarction; PCI: percutaneous coronary intervention Sidebar 1: CVD and Equivalents MI or ACS CABG/PCI Stable CAD (angina or equivalent) Atherosclerotic CVA/TIA PAD (claudication or AAA) Does not include asymptomatic incidental finding of potential atherosclerosis (e.g., CAC) Abbreviations: AAA: abdominal aortic aneurysm; ACS: acute coronary syndrome; CABG: coronary artery bypass grafting; CAC: coronary artery calcium; CAD: coronary artery disease; CVA: cerebrovascular accident; CVD: cardiovascular disease; MI: myocardial infarction; PAD: peripheral arterial disease; PCI: percutaneous coronary intervention; TIA: transient ischemic attack Sidebar 2: Higher Risk CVD Patients MI or ACS in past 12 months; or Recurrent ACS, MI, or CVA; or Known CVD (see Sidebar 1) and any of the following: currently smoking, DM, PAD, or CABG/PCI Abbreviations: ACS: acute coronary syndrome; CABG: coronary artery bypass grafting; CVA: cerebrovascular accident; CVD: cardiovascular disease; DM: diabetes mellitus; MI: myocardial infarction; PAD: peripheral arterial disease; PCI: percutaneous coronary intervention Sidebar 3: Drug Doses Generic name Moderate-dose High-dose Simvastatin 20 40 mg N/A Pravastatin 40 80 mg N/A Lovastatin 40 80 mg N/A Fluvastatin 80 mg (XL) or 40 mg BID N/A Pitavastatin 1 4 mg N/A In patients who are intolerant of statins: after washout (e.g., 1 month), re-challenge with same or a different statin or lower dose, and if that fails, a trial of intermittent (nondaily) dosing Intensified patient care (e.g., phone calls, emails, patient education, drug regimen simplification) may improve adherence to lipid-lowering medications Statin doses listed as moderate are equivalent to moderate intensity; statin doses listed as high are equivalent to high intensity Abbreviations: BID: twice per day; mg: milligrams; XL: sustained release VI. Recommendations Topic Sub- topic # Recommendation Strengtha Categoryb Primary Prevention: Screening and Assessment of Cardiovascular Risk 1. For primary prevention in patients over age 40 and not on statin therapy who have not developed new cardiovascular risk factors (e.g., diabetes, hypertension, tobacco use), we suggest against offering a cardiovascular disease risk assessment more frequently than every five years. Weak against Reviewed, Amended 2. For primary prevention in patients not on statin therapy, we suggest against routinely ordering a lipid panel more frequently than every 10 years. Weak against Reviewed, New- added 3. For cardiovascular risk assessment in primary prevention, we suggest using a 10-year risk calculator. Weak for Reviewed, Amended 4. We suggest against the routine use of coronary artery calcium testing. Weak against Reviewed, Not changed 5. We suggest against the routine use of additional risk markers (e.g., high-sensitivity C-reactive protein, ankle-brachial index, coronary artery calcium) when assessing cardiovascular risk. Weak against Reviewed, New- replaced Pharmacotherapy, Supplements, and Nutraceuticals a. Primary Prevention 6. For primary prevention, we recommend offering a moderate- dose statin in patients with a >12% 10-year cardiovascular risk or low-density lipoprotein cholesterol >190 mg/dL or diabetes. Strong for Reviewed, New- replaced 7. For primary prevention, we suggest offering a moderate-dose statin for patients with a 10-year cardiovascular risk between 6% and 12% following a discussion of risks, limited benefit, and an exploration of the patient s values and preferences. Weak for Reviewed, New- replaced 8. For primary prevention in patients on moderate-dose statins, we suggest against maximizing the statin dose due to the lack of evidence proving added cardiovascular benefits and the risks of higher dose statins. Weak against Reviewed, New- replaced 9. For primary prevention, there is insufficient evidence to recommend for or against using ezetimibe with or without statins. Neither for nor against Reviewed, New- replaced 10. For primary prevention, we recommend against offering PCSK9 inhibitors due to unknown long-term safety, inconclusive evidence for benefit, and high cost. Strong against Reviewed, New- added b. Secondary Prevention 11. For secondary prevention, we recommend using at least a moderate-dose statin.* Strong for Reviewed, New- replaced 12. For secondary prevention in higher risk patients** who are willing to intensify treatment, we suggest offering high-dose statins for reducing non-fatal cardiovascular events after discussion of the risk of high-dose statins and an exploration of the patient s values and preferences. Weak for Reviewed, New- replaced Topic Sub- topic # Recommendation Strengtha Categoryb Pharmacotherapy, Supplements, and Nutraceuticals (cont.) b. Secondary Prevention (cont.) 13. For secondary prevention in higher risk patients** who are willing to intensify treatment, we suggest adding ezetimibe to either moderate- or high-dose statins for reducing non-fatal cardiovascular events following a discussion of the risks, additional benefits, and an exploration of the patient s values and preferences. Weak for Reviewed, New- replaced 14. For secondary prevention in higher risk patients** who are willing to intensify treatment, we suggest offering a PCSK9 inhibitor in addition to a maximally tolerated statin dose with ezetimibe for reducing non-fatal cardiovascular events following a discussion of their uncertain long-term safety, additional benefits, and an exploration of the patient s values and preferences. Weak for Reviewed, New- replaced c. Other Medications, Supplements, and Nutraceuticals 15. For primary or secondary prevention, we recommend against using niacin (i.e., supplements or prescriptions). Strong against Reviewed, New- replaced 16. For primary or secondary prevention, we suggest against adding fibrates to statins. Weak against Reviewed, New- replaced 17. There is insufficient evidence to recommend for or against using bempedoic acid with or without statins for either primary or secondary prevention. Neither for nor against Reviewed, New- added 18. For primary prevention, there is insufficient evidence to recommend for or against icosapent ethyl in patients on statin therapy with persistently elevated fasting triglycerides. Neither for nor against Reviewed, New- added 19. For secondary prevention, we suggest offering icosapent ethyl in patients on statin therapy with persistently elevated fasting triglycerides >150 mg/dL to reduce cardiovascular morbidity and mortality. Weak for Reviewed, New- added 20. For primary or secondary prevention, we suggest against the use of omega-3 fatty acids as a dietary supplement to reduce cardiovascular disease risk. Weak against Reviewed, New- added 21. There is insufficient evidence to recommend for or against the use of fiber, garlic, ginger, green tea, and red yeast rice supplements to reduce cardiovascular risks. Neither for nor against Reviewed, New- added d. Monitoring and Adherence 22. We suggest against the routine monitoring of lipid levels in patients taking statins. Weak against Reviewed, New- replaced 23. For patients who cannot tolerate a statin, we suggest a washout period followed by a re-challenge with the same or a different statin or lower dose, and if that fails, a trial of intermittent (nondaily) dosing. Weak for Reviewed, New- added 24. We suggest offering intensified patient care (e.g., phone calls, emails, patient education, drug regimen simplification) to improve adherence to lipid-lowering medications. Weak for Reviewed, New- added Topic Sub- topic # Recommendation Strengtha Categoryb Lifestyle Interventions 25. For primary and secondary prevention of cardiovascular disease, we suggest a dietitian-led Mediterranean diet. Weak for Reviewed, New- replaced 26. For primary and secondary prevention of cardiovascular disease, we suggest regular aerobic physical activity of any intensity and duration. Weak for Reviewed, New- added 27. We recommend a structured, exercise-based cardiac rehabilitation program for patients with recent occurrence of coronary heart disease (i.e., myocardial infarction, diagnosis of coronary artery disease, coronary artery bypass grafting, or percutaneous coronary intervention) to reduce cardiovascular morbidity and mortality. Strong for Reviewed, New- added a For additional information, see Grading Recommendations. b For additional information, see Recommendation Categorization and Appendix G. * Statin doses listed as moderate are equivalent to moderate intensity; statin doses listed as high are equivalent to high intensity ** Higher risk patients include those with (1) MI or ACS in past 12 months; (2) recurrent ACS, MI, or CVA; or (3) established CVD and with additional risk factors (e.g., currently smoking, DM, PAD, or CABG/PCI). A. Screening and Assessment of Cardiovascular Risk Recommendation 1. For primary prevention in patients over age 40 and not on statin therapy who have not developed new cardiovascular risk factors (e.g., diabetes, hypertension, tobacco use), we suggest against offering a cardiovascular disease risk assessment more frequently than every five years. (Weak against | Reviewed, Amended) Discussion Cardiovascular risk assessment models are widely used in clinical practice as a strategy for identifying patients who are most likely to benefit from treatment for the primary prevention of CVD. Risk equation models incorporate both modifiable and non-modifiable risk factors including age, gender, ethnicity, blood pressure, tobacco use, cholesterol levels, and diabetes mellitus (DM) to calculate 10-year and lifetime CVD risk. For primary prevention of CVD in low-risk patients not on statin therapy, frequent cholesterol screening or CV risk assessment is unlikely to reclassify 10-year risk or influence clinical management. In the absence of new CV risk factor development, it is reasonable to perform a CV risk assessment every five years. For patients whose 10-year CV risk score is 6 12%, it is reasonable to repeat CV risk assessment at earlier time intervals to capture patients who may benefit from the initiation of appropriate statin therapy as a change in age alone may alter CV risk score, thus enhancing the provider-patient CVD primary prevention discussion. This CPG s systematic evidence review identified two prospective cohort studies evaluating the timing of repeat screening for CV risk in primary prevention populations based on prediction of CV events or reclassification of CV risk.[20,21] Chamnan et al. (2016) evaluated 12,197 patients for CVD event rates utilizing the Framingham Risk Score (FRS). Prediction of CVD events based on the FRS did not change significantly between the baseline and second visit (mean: 3.7 years).[20] Angelow et al. (2015) evaluated 1,112 patients by estimating CVD risk utilizing the Systematic Coronary Risk Evaluation (SCORE)-Germany prediction model inputting both a 5- or 10-year old total cholesterol (TC) to predict high CV risk. [21] The authors observed only minor changes in TC over time. Moreover, they reported that utilizing 5- or 10-year old TC levels had high sensitivity and specificity to identify patients at high CV risk and resulted in low misclassification rates. The authors concluded that measuring TC at five-year intervals is sufficiently accurate for primary CVD prevention.[21] Cardiovascular disease risk assessment models provide a foundation for shared decision making to review the anticipated benefit of preventative interventions while minimizing the potential harm from overtreatment. As CV risk scoring influences treatment decisions and frequently involves laboratory testing, excessive monitoring may lead to unnecessary testing and/or treatments. Therefore, avoiding frequent risk assessments has the potential to optimize medical resource use, reduce costs, and enhance patient participation at checkups. Given the lack of evidence for improved health outcomes, the harms/burdens of CV risk assessment screenings more than every five years outweigh potential benefits. As this is a Reviewed, Amended recommendation, the Work Group systematically reviewed evidence related to this recommendation.[20,21] The Work Group s confidence in the quality of the evidence was low. The main study limitations were high attrition rates, differing patient characteristics between those who drop out and those who remained, and a change in lipoprotein measurement methods in one study. Thus, the Work Group decided upon a Weak against recommendation. There is a paucity of evidence about the optimal timing and frequency for CV risk assessment in specific subgroups of patients (i.e., age-, ethnicity-, and comorbidity-based subgroups). More research is needed to evaluate CV risk assessment in specific subgroups and its effect on critical outcomes such as CV mortality. Recommendation 2. For primary prevention in patients not on statin therapy, we suggest against routinely ordering a lipid panel more frequently than every 10 years. (Weak against | Reviewed, New-added) Discussion The frequency that providers obtain lipid profiles in their patients varies widely. A systematic review by Perera et al. (2015) found little within-patient change in annual lipid measurements.[22] Test-to-test variations often do not represent a real change in risk. Studies assessing individual cholesterol levels found variation as high as 18% in three successive TC measurements.[21] Frequent testing of lipid profiles may lead to over-diagnosis and an increased number of patients who receive unnecessary treatment. Evidence suggests annual lipid testing, when compared to testing every three years, results in unnecessary treatment in 7 per every 1,000 patients.[22] It is unclear how frequently testing should be conducted to eliminate false positives and false negatives.[23] For primary prevention, Perera et al. (2015) found the true variation from testing exceeds the random variation from repeated testing (signal-to-noise ratio exceeds 1.0) when testing is spaced by 9 10 years.[22] Also, cholesterol is a relatively minor contributor to CV risk scores compared to other patient characteristics, which further supports longer testing intervals. Most of the change in CV risk over time is because of the development or change in risk factors (e.g., DM, blood pressure, age) rather than changes in lipid levels. Individuals who progressed to a higher CVD category over a 10-year timeframe lacked a significant change in their cholesterol.[21] In addition to limiting the number of patients inappropriately placed on therapy, less frequent testing can decrease patient anxiety about lipid levels. The Work Group encourages provider and patient education regarding the limited utility and potential harms of frequent lipid screening. The Work Group recognizes there may be situations where patients and providers wish to repeat testing more frequently. For example, a patient may wish to attempt lifestyle changes before starting statin medication. In this case, the change in lipids may provide the information on which to base shared decision making. The common use of this technique is tempered by the limited effect of lipid levels on risk. Alternatively, it may be useful for the provider to posit an improvement in lipid levels and show the limited effect on risk scores to illustrate the reasons for recommending statins. As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation.[21-23] The Work Group s confidence in the quality of evidence was low. The body of evidence had some limitations (e.g., poor study designs).[21,22] Major concerns about the frequency of lipid testing included cost, judicious use of healthcare resources, and lack of patient benefit from frequent testing. The risk from more frequent lipid panels (i.e., over-diagnosis) outweighed any potential benefit of refining risk assessment, especially given the minor effect of lipid levels on risk score. The Work Group anticipated large variation in patient values and preferences since some expect and/or desire frequent testing. Thus, the Work Group decided upon a Weak against recommendation. More research is needed on the optimal frequency of lipid testing in primary prevention among individuals not on statin therapy. Recommendation 3. For cardiovascular risk assessment in primary prevention, we suggest using a 10-year risk calculator. (Weak for | Reviewed, Amended) Discussion Two systematic reviews and 11 model performance studies evaluated various methods to stratify CV risk for primary prevention patients. The equations included the FRS, Pooled Cohort Equations (PCE), version two of the QRISK cardiovascular disease risk algorithm (QRISK 2), SCORE, Progetto Cuore Score, and Reynolds Risk Score.[24-27] The Veterans Affairs Risk Score for Cardiovascular Disease (VARS-CVD) is an option to calculate a five-year risk using the fully calibrated version to improve the accuracy of the CVD risk estimation.[28] Although several risk calculators exist, the Work Group does not recommend one over another as comparison studies were not evaluated.[26] Below are the commonly used risk calculators that providers should consider to calculate the 10-year risk and determine the need for lipid-lowering medication. Providers should consider their patient population characteristics when selecting a risk calculator. However, it should be noted that there is a potential for over- or under-estimation of 22 24% of CV risk with each risk calculator, which may result in over- or under-treatment.[26] Since every calculator has limited accuracy, providers will inevitably prescribe medications for patients who may not benefit from pharmacotherapy and withhold medications from patients who may have otherwise benefited from treatment.[27] FRS: a tool used to estimate the 10-year risk of having a CV event (not including stroke)b PCE: a central tool recommended by the American College of Cardiology/American Heart Association (ACC/AHA) based on a 10-year CVD risk estimation from a pooled cohort equationc VARS-CVD: a five-year risk score calculator only for the VA population using the information available in the VA Electronic Health Record (EHR)d For more information on CVD risk calculators, see Appendix B. Despite the known imprecision of risk calculators, they help identify patients who may benefit the most from treatment for primary prevention with statin therapy. In clinical practice, providers commonly use the FRS or the PCE to calculate a 10-year CV risk estimation. Evidence supports the use of the revised or updated PCE for African American men and women and those with a history of DM.[27] The revised PCE has higher accuracy than the FRS for CV risk estimates because it considers race and history of DM, while the FRS does not. As this is a Reviewed, Amended recommendation, the Work Group systematically reviewed evidence related to this recommendation.[24-28] The Work Group s confidence in the quality of the evidence was low because of inconsistency, imprecision, and the unknown applicability of risk calculators other than FRS and PCE in the VA/DoD setting. The benefits of using a 10-year risk calculator likely outweigh the harms because they identify high risk patients better than provider judgment alone. The Work Group recognized that under- and over-estimation of CV risk is a concern and may lead to improper prescribing of lipid- lowering medications. However, patients may prefer awareness of their CV risk to make informed decisions. Thus, the Work Group decided upon a Weak for recommendation. More research is needed on comparative effectiveness, particularly in terms of the estimation accuracy, of the various CV risk calculators in selected populations. Recommendation 4. We suggest against the routine use of coronary artery calcium testing. (Weak against | Reviewed, Not changed) Discussion Coronary artery calcium (CAC) can supplement a 10-year risk calculator to further refine the risk assessment of CVD and the potential need for treatment. The ideal CV risk assessment would correctly reclassify all intermediate risk individuals into a low or high risk category based on future CVD event rates. Individuals at intermediate CV risk have the greatest potential benefit for any test that improves the b The FRS is available at: https://www.thecalculator.co/health/Framingham-Risk-Score-Calculator-for-Coronary-Heart-Disease- c The PCE is available at: https://clincalc.com/cardiology/ascvd/pooledcohort.aspx d The VARS-CVD is available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561663/ performance of a 10-year risk calculator. However, there is no prospective evidence that additional risk refinement tools improve patient-centered outcomes. Lin et al. (2018) demonstrated that the addition of CAC to the FRS improved 10-year CVD event prediction by a very small change in the C statistic (change in area under the curve [AUC]: 0.02, 95% confidence interval [CI]: not reported).[29] This systematic review found similar results when CAC was added to the calibrated Pooled Cohort Equation (cPCE) (change in AUC: 0.02, 95% CI: 0.0 0.05).[29] Yeboah et al. (2016) was the largest of the retrospective studies included in Lin et al. related to the addition of CAC testing.[30] It assessed net reclassification improvement by adding CAC to the cPCE within the pre-existing study data from the Multi-Ethnic Study of Atherosclerosis cohort of over 5,000 subjects.[30] When actual patient events were compared with CAC scoring results, 58 patients were correctly reclassified, and 292 patients were incorrectly reclassified. Assuming a statin relative risk reduction of 25% for major adverse cardiac events (MACE), 15 patients who experienced a future event would benefit, whereas the remaining 335 patients would potentially be subjected to risks of treatment without benefit. The Work Group encourages shared decision making on the risks and benefits surrounding the use of CAC for enhancing CV risk assessment. Prospective studies of CAC screening do show improvement in the net reclassification index.[29] The use of CAC screening may result in overtreatment and unnecessary radiation exposure. No significant benefit in the incidence of MI, CVD, or overall mortality has been demonstrated with the addition of CAC scoring to a traditional risk score. Even in retrospective studies showing a favorable net reclassification index, many more patients were incorrectly reclassified to a higher risk category than were correctly The risk of radiation exposure from CAC scoring is not negligible. Although not included in our systematic evidence review and, thus, not considered in determining the strength of this recommendation, Kim et al. (2009) estimated a single CAC screening at the age of 40 would result in a lifetime excess cancer risk of 9 per 100,000 for males and 28 per 100,000 for females.[31] As this is a Reviewed, Not changed recommendation, the Work Group systematically reviewed evidence related to this recommendation.[29] The Work Group s confidence in the quality of the evidence was low. Other considerations regarding this recommendation include patient preference in understanding the risk and benefits of CAC. Patient values and preferences vary but often align with a desire for more testing. The Work Group encourages a patient-provider conversation regarding the risk of over-diagnosis, cost, and radiation exposure in relation to a very small potential net benefit associated with CAC testing. Thus, the Work Group decided upon a Weak against recommendation. In the absence of individual patient data, it is unclear which patients will benefit from CAC testing. The Work Group recommends prospective studies designed to assess the benefit of adding CAC to traditional risk scoring systems for the prediction of future atherosclerotic CVD endpoints. Recommendation 5. We suggest against the routine use of additional risk markers (e.g., high-sensitivity C-reactive protein, ankle-brachial index, coronary artery calcium) when assessing cardiovascular risk. (Weak against | Reviewed, New-replaced) Discussion Traditional CV risk assessment relies on the use of multivariate models that integrate data from known risk factors and biomarkers to predict the development of CVD in an individual patient. While numerous models exist, all tend to misestimate (i.e., under- or over-estimate) risk.[26,32]In addition, patients and providers remain interested in improving risk prediction for populations identified as intermediate risk by the currently used models. The use of non-traditional biomarkers to improve the estimation of CV risk assessment has been extensively studied. Non-traditional biomarkers include genetic, serologic, psychosocial, and physiologic markers (e.g., ankle-brachial index [ABI], electrocardiogram [ECG], apolipoproteins [Apo], high-sensitivity C-reactive protein [hsCRP], physical activity, and socioeconomic status). Numerous biomarkers and other variables were assessed in this review, including ABI, lipoprotein(a), Apo A1, Apo B, CAC score, ECG, fibrinogen, HDL-C, N-terminal-pro hormone brain natriuretic peptide (NT-proBNP), hsCRP, physical activity, socioeconomic status, and Apo C3.[29,33-35] Several biomarkers have demonstrated slight additive predictive risk (e.g., hsCRP, CAC, and ABI); however, the model performance studies that demonstrate these differences are hampered by low or very low quality evidence. Also, the potential clinical impact is unknown. For example, the addition of ABI to either the FRS or PCE improves model discrimination (change in AUC: -0.006 0.112 for FRS, 0.01 for PCE) but does not significantly improve calibration or risk reclassification.[29] The addition of hsCRP to either the FRS or PCE results in minimally improved discrimination (changes in AUC: 0 0.027).[29] Other than CAC scoring, none of the other risk markers reviewed demonstrated any additive predictive risk value to traditional risk assessment models. No prospective study has shown that incorporating any additional risk marker into CV risk assessment improves outcomes.[29,33-35] The only theoretical utility of these tests would be for intermediate risk situations where there is uncertainty about the benefit of treatment. There is no prospective evidence to validate any additional risk score method as a means of clarifying intermediate risk. Incorporating additional risk factors in CV risk assessment should occur in the context of a shared decision making framework with a clear discussion about the uncertainty in how lipid management decisions will be affected by the results. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation.[26,29,32-35] The Work Group s confidence in the quality of evidence was very low. The body of evidence had several limitations (i.e., short follow-up period, low number of outcome events per variable, and lack of adequate statistical reporting).[29,33] Some variation in patient and provider values and preferences is likely since some individuals prefer as much information as possible when determining CVD risk. Other factors influencing this recommendation included resource use (e.g., staffing, time burden), the limited benefit of additive predictive risk, and potential harms from overtreatment. Thus, the Work Group decided upon a Weak against recommendation. B. Pharmacotherapy, Supplements, and Nutraceuticals a. Primary Prevention Recommendation 6. For primary prevention, we recommend offering a moderate-dose statin in patients with a >12% 10-year cardiovascular risk or low-density lipoprotein cholesterol >190 mg/dL or diabetes. (Strong for | Reviewed, New-replaced) 7. For primary prevention, we suggest offering a moderate-dose statin for patients with a 10-year cardiovascular risk between 6% and 12% following a discussion of risks, limited benefit, and an exploration of the patient s values and preferences. (Weak for | Reviewed, New-replaced) Discussion Evidence suggests moderate-dose statins lower CV mortality, all-cause mortality, and CV events. The largest systematic review, Yebyo et al. (2019), included 40 primary prevention trials (n=94,283).[36] The summary effect size indicated a 20% relative risk reduction in all-cause mortality over one year (number needed to treat [NNT] = 908), an 11% relative risk reduction in CV mortality over one year (NNT=715), and a 26% relative risk reduction in major CV events over one year (NNT=833). A major limitation was the limited follow-up in many trials. This systematic review included a network meta-analysis that did not find a significant difference between statin drugs.[36] Although the absolute benefit of statin treatment for primary prevention is limited in the general population, the benefit becomes more substantial as time and risk levels increase. Another systematic review of primary prevention trials, Chou et al. (2016), included 19 studies (n=71,344) of adult patients with increased CVD risk and found the same effect of moderate-dose statins (i.e., reducing all-cause mortality, CV mortality and events) but with greater absolute benefits in patients at baseline higher risk.[37] For CV mortality over the 2 to 6 year treatment period of the trials, the NNT was 233; for all-cause mortality over 1 to 6 years, the NNT was 250; and for fatal and non-fatal MI over 2 to 6 years, the NNT was 123. Dedicated studies [38,39] and subgroup analyses show the benefit of statins for primary prevention does not vary with gender, age, race, baseline lipid levels, presence of DM, CKD, or hypertension.[37] Determining the cardiac risk cutoff to recommend statin treatment is a simplified strategy to most closely resemble the risk profiles of those included in the trials which demonstrated reduction in CV risk. While no studies used CV risk scores as part of the inclusion criteria, the studied populations had a high prevalence of CV risk factors, and some studies showed an increasing absolute benefit of statins with increased baseline CV risk. The 12% threshold we chose most closely resembles the lower limit of risk of populations in the clinical trials for which the benefits clearly outweighed the risks. The major primary prevention trials showed an event rate between 6 7.5%. Since these trials lasted 2 to 6 years (roughly equivalent to 12 15% ten-year event rate), the Work Group chose a 12% ten-year risk threshold to match the available data. There are no clinical trials that specifically address the <6% risk category, which would be represented by a control group event rate of approximately 3%. Using the same methodology, only two trials included patients with risks between 6 12%, although these trials did include nearly 30,000 patients.[40-43] The Work Group decided to retain the 12% ten-year CV risk score as a threshold for recommending initiation of treatment with statins in primary prevention along with shared decision making within the 6 12% risk range from the 2014 VA/DoD Dyslipidemia CPG. The addition of patients with an LDL-C level >190 mg/dL is intended to include patients with possible familial hypercholesterolemia. In an analysis of the 20-year follow-up of the West of Scotland primary prevention trial, Vallejo-Vaz et al. (2017) demonstrated that patients with LDL-C levels >190 mg/dL treated with moderate-dose statins had significant 20-year reductions in CV mortality (3%) and all-cause mortality (5%), more than double the reductions in the population with lower initial LDL-C levels.[44] Thus, this study provided the first prospective evidence on the long-term benefit of moderate-dose statins. Diabetes is similarly maintained as an indication for statin therapy because a systematic review by de Vries et al. (2012) showed a 3% reduction in CV events in diabetics with moderate-dose statins for primary prevention Moderate-dose Statin Safety While there are known risks associated with the use of moderate-dose statins, most feel these risks are low and that the benefits of statins outweigh these risks in patients at risk for CVD.[40-42,46] It should be noted, however, that most randomized controlled trials (RCTs) of statins did not systematically assess for adverse events routinely. In a systematic review by Chou et al. (2016) of primary prevention RCTs reporting statin-induced adverse events, there was no increased risk for new-onset DM in patients treated with moderate-dose statins versus placebo (relative risk [RR]: 1.05, 95% CI: 0.91 1.2).[37] However, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, used a high-dose statin for primary prevention and reported a higher risk for DM than placebo (RR: Another systematic review by Engeda et al. (2019) of statins for primary prevention demonstrated a borderline significant increase in DM risk in 78,039 patients from RCTs (RR: 1.11, 95% CI: 1.00 1.22) and a significant increase in DM incidence in nearly four million patients from observational studies (RR: 1.55, 95% CI: 1.39 1.74).[48] A systematic review by Macedo et al. (2014) of 90 observational studies of all statin doses for primary and secondary prevention showed a trend towards an increased risk for DM that did not reach significance (odds ratio [OR]: 1.31, 95% CI: 0.99 1.73).[49] While statins may increase the risk of DM, the risk has not been demonstrated in RCTs of moderate-dose statins. Observational studies suggest a low risk of DM attributable to moderate-dose statins. Other adverse effects of statins reported in clinical trials may include muscle-related complaints and elevation of liver transaminases. However, in the Chou et al. (2016) systematic review of primary prevention trials, there was no increase in serious adverse events, cancer or fatal cancer, myalgias or elevation of liver transaminases, or the risk for withdrawal because of adverse events.[37] Although there was no increased risk for rhabdomyolysis or myopathy, some trials reported these adverse events. This meta-analysis included all statin doses.[37] Macedo et al. (2014) reviewed observational studies of statins and found that statin use was not associated with an increased risk of neurologic or psychological effects, eye disorders, or renal impairment.[49] There was a higher incidence of reported myopathy (OR: 2.63, 95% CI: 1.5 4.61) and liver transaminase elevation (OR: 1.54, 95% CI: 1.47 1.62) with statins in these trials. The observational studies evaluated were heterogeneous in type and dose of statin, and the meta-analysis suffered from imprecision of the summary effects.[49] In a systematic review of primary prevention trials by Yebyo et al. (2019), discontinuation of statins for adverse effects was not different than placebo but there was a higher risk for myopathy, hepatic enzyme elevation, and renal dysfunction with statins.[36] Overall, there may be a risk of liver enzyme elevation and myopathy with statins, which appears inconsistent, even among large reviews. 