VA/DoD Clinical Practice Guideline For The Management Of Dyslipidemia .
VA/DoD CLINICAL PRACTICE GUIDELINE FORTHE MANAGEMENT OF DYSLIPIDEMIA FORCARDIOVASCULAR RISK REDUCTIONDepartment of Veterans AffairsDepartment of DefenseQUALIFYING STATEMENTSThe Department of Veterans Affairs and the Department of Defense guidelines are based upon the bestinformation available at the time of publication. They are designed to provide information and assistdecision-making. They are not intended to define a standard of care and should not be construed asone. 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 and epidemiologicevidence. Developed by a panel of multidisciplinary experts (all practicing clinicians), it provides a clearexplanation of the logical relationships between various care options and health outcomes while ratingboth the quality of the evidence and the strength of the recommendations.Variations in practice will inevitably and appropriately occur when clinicians take into account the needsof individual patients, available resources, and limitations unique to an institution or type of practice.Every health care professional making use of these guidelines is responsible for evaluating theappropriateness of applying them in the setting of any particular clinical situation.These guidelines are not intended to represent TRICARE policy. Further, inclusion of recommendationsfor specific testing and/or therapeutic interventions within these guidelines does not guaranteecoverage of civilian sector care. Additional information on current TRICARE benefits may be found atwww.tricare.mil or by contacting your regional TRICARE Managed Care Support Contractor.Version 3.0—2014December 2014Page 1 of 112
Table of ContentsBackground . 4About this Clinical Practice Guideline . 5Scope of this CPG . 5Population . 5Methods . 6Conflict of Interest . 7Patient-Centered Care . 7Algorithm . 7Populations Excluded from this Guideline . 10Reconciling 2006 CPG Recommendations . 11Implementation . 12Guideline Working Group . 13Recommendations . 14Future Research Needs . 18Assessment of Cardiovascular Risk and Pharmacotherapy for Primary Prevention . 18Statins . 22Fibrates (gemfibrozil, fenofibrate) . 25Bile acid sequestrants . 26Niacin . 26Ezetimibe . 26Long Chain Omega-3 Fatty Acids (Fish oils) . 26Management of Pharmacotherapy for Secondary Prevention. 29Statins . 29Fibrates (gemfibrozil, fenofibrate) . 32Bile acid sequestrants . 32Niacin . 33Ezetimibe . 33Long Chain Omega-3 Fatty Acids (Fish oils) . 33Non-Pharmacologic Approaches. 35Therapeutic Lifestyle Changes Diet. 35Weight Loss . 36Physical Activity . 36Smoking Cessation . 36Nutrition Counseling . 37Mediterranean Diet . 37Monitoring and Follow-up . 40Appendix A: Evidence Review Methodology . 41Population(s) . 41Interventions . 42December 2014Page 2 of 112
Outcomes . 42Conducting the Systematic Review. 42Criteria for Study Inclusion/Exclusion . 45General Criteria . 45Treatment Goals (LDL-C and non-LDL-C Target Levels) (KQ 1-2) . 45Effectiveness and Safety of Cholesterol-modifying Drugs (KQ 3) . 45Cost-effectiveness of Cholesterol-modifying Drugs (KQ 4). 45Additional Risk Stratifying Tests (KQ 6) . 46Supplementary Key Question (KQ7) . 46Literature Search Strategy . 46Electronic Database Searches . 46Hand Searches of Journal and Gray Literature . 47Topic-specific Search Terms. 47Search Strategies . 52Convening the Face-to-Face Meeting . 67Grading Recommendations . 68Appendix B: Evidence Table . 72Drafting and Submitting the Final CPG . 79Appendix C: CVD Risk Calculators . 80Appendix D: Pharmacologic Therapy . 81Additional Supporting Evidence . 86Fibrates (gemfibrozil, fenofibrate) . 86Niacin . 86Statins . 87Why does the VA/DoD Guideline Differ From the ACC/AHA Guideline with Regard to Statin Dose? 95Appendix E: Exercise and Mediterranean Diet . 99Appendix F: Acronym List . 102Appendix G: Participant List . 105References . 106December 2014Page 3 of 112
BackgroundCardiovascular disease (CVD) is a major cause of morbidity and mortality in the United States (US) andglobally. In Western countries, most CVD is due to atherosclerosis. [1] Atherosclerosis is the buildup ofplaque (cholesterol, proteins, calcium and inflammatory cells) in the walls of arteries that carryoxygenated blood to the heart and other parts of the body. This plaque narrows the opening of thearteries, limiting the flow of oxygenated blood and increasing the risk of chronic and acute ischemia. If aplaque ruptures within a vital artery, a blood clot forms on the plaque and may obstruct the flow ofoxygenated blood to the heart or brain, resulting in an acute coronary syndrome (ACS), myocardialinfarction (heart attack; MI) or stroke with potentially irreversible damage to the tissue of the heart orbrain.Control and reduction of atherosclerotic cardiovascular disease (ASCVD) risk factors, including highcholesterol levels, elevated blood pressure (BP), insulin resistance, smoking and a sedentary lifestyle,can contribute to a reduction in ASCVD morbidity and mortality.Dyslipidemia is defined as one or more of the following: low density lipoprotein cholesterol (LDL-C) 130mg/dL, high density lipoprotein cholesterol (HDL-C) 40 milligram per deciliter (mg/dL), or triglyceride(TG) 200 mg/dL. [2] In patients with known CVD or high risk for CVD, even “normal” levels of lipids canbe deemed amenable to intervention for the purpose of reducing CVD risk.Dyslipidemia may remain clinically silent until the development of complications. This condition can bediagnosed with a blood test measuring plasma levels of total cholesterol (TC), HDL-C, TG, or individuallipoproteins. LDL-C is measured directly or determined by the following equation: TC-HDL-(TG/5).Sometimes, non-HDL cholesterol is also determined as TC minus HDL. A TC of less than 180 mg/dL isthought to be optimal. [3] Yet, the average TC for American adults is about 200 mg/dL. [4]The etiology of dyslipidemia involves genetic, lifestyle and other factors. Genetic factors that result ineither overproduction or slow clearance of TGs and LDL-C, or underproduction or fast clearance of HDLC, can lead to dyslipidemia. A sedentary lifestyle with excessive dietary intake of saturated fat, transfats, added sugars, and cholesterol can also lead to dyslipidemia. Other risk factors include insulinresistance, diabetes mellitus (DM or diabetes), central obesity, and chronic kidney disease (CKD).About 71 million adults in the US (33.4%) have high LDL-C and only one out of every three adults withhigh LDL-C has the condition under control. [4]The percentage of American adults with high LDL-C hasremained around 34 percent over the past decade, but treatment of high LDL-C has increased from 28.4percent in 1999–2002 to 48.1 percent in 2005–2008. [4] Treatment usually involves dietary changes andlipid-lowering drugs. However, the management of dyslipidemia has shifted away from treating thedyslipidemia itself as a discrete entity, and moved toward managing dyslipidemia in the context ofoverall risk for CVD.This guideline addresses the various treatment and management strategies for managing overall CVDrisk among patients with dyslipidemia. As TG levels above 300mg/dl are above the 95th percentile, fewpatients in the US will have levels above 300mg/dl. Even fewer patients will have TGs 500mg/dl (99thDecember 2014Page 4 of 112
percentile). Due to the infrequency of clinically significant hypertriglyceridemia this guideline does notaddress hypertriglyceridemia other than to look for secondary causes and non-pharmacologicinterventions. Interested readers can refer to Lederle and Bloomfield’s 2012 article for additionalinformation. [5]About this Clinical Practice GuidelineThe Department of Veterans Affairs (VA) and Department of Defense (DoD) Clinical Practice Guideline(CPG) for the Management of Dyslipidemia is intended to assist health care providers in the mostcommon aspects of patient care. The system-wide goal of evidence-based guidelines is to improve thepatient’s health and wellbeing. The overall expected outcome of successful implementation of thisguideline is to: Formulate an efficient and effective assessment of the patient's condition Optimize the use of therapy to reduce symptoms and enhance functionality Minimize preventable complications and morbidity Emphasize the use of personalized, proactive, patient-driven care Translate the available yet incomplete body of evidence into recommendations that allowclinicians to participate in shared, informed decisions with patientsThis VA/DoD guideline represents a significant step toward achieving these goals for patients covered byVA and DoD health care delivery systems. However, as with other CPGs, remaining challenges involvedeveloping effective strategies for guideline implementation and evaluating the effect of guidelineadherence on clinical outcomes.This guideline is directed toward VA and DoD clinicians involved in the care of beneficiaries who are atrisk for or have CVD. The purpose of this guideline is to: Enhance clinician awareness of risk factors that increase CVD risk Highlight evidence to manage dyslipidemia, a contributor to the development of CVD Identify pharmacologic and non-pharmacologic strategies that improve CVD outcomesScope of this CPGThis CPG is designed to assist primary care providers in managing lipids among patients at risk for CVD.An acronym list of abbreviations used throughout the CPG is provided in Appendix F.PopulationThe patient population of interest for this CPG is adults (men and women) who are eligible for care inthe VA and DoD health care delivery systems. This CPG does not provide recommendations for themanagement of dyslipidemia in children or adolescents.December 2014Page 5 of 112
MethodsThe methodology used in developing the 2014 CPG follows the Guideline for Guidelines, [6] an internaldocument of the VA and DoD Evidence-based Practice Working Group (EBPWG). This documentprovides information regarding the process of developing guidelines, including the identification andassembly of the Guideline Champions (Champions) and other subject matter experts from within the VAand DoD, known as the Work Group, and ultimately, the submission of an updated Management ofDyslipidemia For CVD Risk Reduction CPG.The Champions and Work Group for this CPG were charged with developing evidence-based clinicalpractice recommendations and publishing a guideline document to be used by providers within the VAand DoD health care delivery systems. Specifically, the Champions for this guideline were responsible foridentifying the key questions of greatest clinical relevance, importance, and interest for themanagement of patients with dyslipidemia. The Champions also assisted in: Conducting the evidence review, including providing direction on inclusion and exclusion criteria Assessing the level and quality of the evidence Identifying appropriate disciplines to be included as part of the Work Group Directing the Work Group and the guideline development and review processThe Work Group was responsible for providing their expertise throughout the guideline developmentprocess and participating in developing key questions, reviewing evidence, forming and gradingrecommendations, and drafting the updated CPG.The VA Office of Quality, Safety and Value, in collaboration with the DoD, identified two clinical leaders,Dr. John R. Downs, MD from the VA and COL Patrick O’Malley, MD, MPH from the DoD, as theChampions for the 2014 CPG. The Lewin Team, including The Lewin Group, DutyFirst Consulting, ECRIInstitute, and Sigma Health Consulting, LLC, was contracted by the VA and the DoD to support thedevelopment of this CPG. The Lewin Team held the first conference call on September 30, 2013, withparticipation from the Contracting Officer’s Representatives (CORs), leaders from the VA and DoDevidence-based guideline development program, and the Champions. During this call, the project teamdiscussed the scope of the guideline initiative, the roles and responsibilities of the Champions, theproject timeline, and the approach for developing specific research questions on which to base asystematic review on the management of dyslipidemia. The group also identified a list of clinicalspecialties and areas of expertise that are important and relevant to the management of dyslipidemia,from which the Work Group members were recruited. These specialties and clinical areas included:Internal Medicine, Health Information Technology, Electronic Health Record Documentation, PreventiveCardiology, Pharmacy, Dietetics, Primary Care, Nursing, and Family Practice.December 2014Page 6 of 112
The guideline development process for the 2014 CPG consisted of the following steps: Formulating evidence questions (key questions) Conducting the systematic review Convening a three and a half day face-to-face meeting with the CPG Champions and WorkGroup members Drafting and submitting a final CPG to the VA/DoD EBPWGAppendix A provides a detailed description of each of these tasks.Conflict of InterestAt the start of this guideline development process and at other key points throughout, the project teamwas required to submit disclosure statements to reveal any areas of potential conflict of interest (COI) inthe past two years, including verbal affirmations of no conflict of interest at regular meetings. Theproject team was also subject to random web-based surveillance (e.g., ProPublica). If there was apositive (yes) conflict of interest response (actual or potential), then action was taken by the co-chairsand evidence-based practice program office, based on level and extent of involvement, to mitigate theCOI. Actions ranged from restricting participation and/or voting on sections related to a conflict, toremoval from the Work Group. Recusal was determined by the individual, co-chairs, and evidence-basedpractice office. One DoD Work Group Member was removed for potential COI. No member of the finalproject team had any COI.Patient-Centered CareGuideline recommendations are patient-centered. Regardless of setting, or the availability ofprofessional expertise, all patients in the VA and DoD health care systems should be provided with theinterventions that are recommended in this guideline, if found to be appropriate to the patient’s specificcondition and needs.Good communication between health care professionals and the patient is essential. Patient-centereddecisions should be supported by evidence-based information tailored to the patient’s needs. Theinformation about treatment and care should be culturally appropriate and available to people who donot speak or read English, or with limited literacy skills. It should also be accessible to people withadditional needs such as physical, sensory or learning disabilities.AlgorithmThis CPG includes an algorithm, which is designed as a quick reference for clinicians at the point of careto maximally facilitate clinical decision-making for the management of CVD risk in the most commonclinical situations involving dyslipidemia. The use of the algorithm format was chosen based on theunderstanding that such a format can allow for expeditious diagnostic and therapeutic decision-makingand has the potential to improve patterns of resource use. The algorithmic format allows the provider toDecember 2014Page 7 of 112
follow a linear approach to obtaining the critical information needed at major decision points in theclinical care process, and includes: An ordered sequence of steps of care Recommended observations Decisions to be considered Actions to be takenA clinical algorithm describes a guideline in a step-by-step decision tree. Standardized symbols are usedto display each step in the algorithm, and arrows connect the numbered boxes indicating the order inwhich the steps should be followed. [7]Rounded rectangles represent a clinical state or condition.Hexagons represent a decision point in the guideline, formulated as a questionthat can be answered Yes or No.Rectangles represent an action in the process of care.This CPG is not intended to serve as a standard of care. Standards of care are determined on the basisof all clinical data available for an individual patient and are subject to change as scientific knowledgeand technology advances. This CPG is based on information available at the date of publication, and isintended to provide a general guide to best practices. This guideline can assist providers in care ofpatients, but the recommendations must always be considered suggestions, within the context of aprovider’s clinical judgment, in the care of an individual patient.December 2014Page 8 of 112
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Populations Excluded from this GuidelinePatients with Severe Systolic Chronic Heart Failure (CHF), End Stage RenalDisease (ESRD) and on Dialysis, or a Limited Life ExpectancyPatients with moderate-to-severe systolic chronic heart failure (CHF), a limited life expectancy (LE) ( 5years), or end stage renal disease (ESRD) and on maintenance dialysis were excluded from most clinicaloutcome trials; therefore, available data are not applicable to such patients. Thus, the guideline panelwas unable to provide evidence-based recommendations for these populations, and suggests thatproviders consider basing treatment decisions on comorbidities, quality of life considerations, andpatient’s preferences, values, and culture.DiscussionAll but five trials excluded patients with systolic CHF (Ejection fraction [EF] 35%) or those onhemodialysis (HD). [8-12] In the Controlled rosuvastatin multinational study in heart failure (CORONA)(2007), 5011 patients with New York Heart Association (NYHA) functional class II, III or IV symptoms andischemic systolic heart failure (HF) (EF 35%) were randomized to rosuvastatin 10mg or placebo. [10]There was no reduction in the primary endpoint of cardiovascular death, nonfatal MI or nonfatal stroke.There was a 9% absolute risk reduction in the secondary endpoints of cardiovascular and CHFhospitalizations; however the study was powered only for the primary endpoints. The Gruppo Italianoper lo Studio della Sopravvivenza nell'Infarto Miocardico - Heart Failure (GISSI-HF) trial (2008) enrolledand randomized 4574 patients with CHF (EF 35%) from any etiology and NYHA functional class II, III orIV symptoms to rosuvastatin 10mg or placebo. [11] There was no difference in primary outcomes (i.e.,time to death or admission to hospital for cardiovascular evaluation). No safety concerns or increasedadverse events were noted in the treatment groups of either trial.Three trials examined patients on maintenance hemodialysis treated with either statin monotherapy(Randomized controlled trial on the efficacy and safety of atorvastatin in patients with type 2 diabeteson hemodialysis [4D], A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis:An Assessment of Survival and Cardiovascular Events [AURORA]) or a statin-ezetimibe combination(Study of Heart and Renal Protection [SHARP]). The 4D trial (2005) included diabetic patients, AURORA(2009) looked at patients with renal failure from any cause and SHARP (2011) included patients withCKD on HD or peritoneal dialysis and patients not receiving dialysis. [8,9,12,13] In 4D and AURORA, CVDevents were not reduced in any patients undergoing dialysis. [9,12] In SHARP, the primary outcome ofany major atherosclerotic event was reduced in favor of simvastatin/ezetimibe versus (vs.) placebo(11.3% vs. 13.4%, absolute risk reduction [ARR] 2.1%, risk ratio 0.83, 95% CI 0.74-0.94, p 0.0021,respectively) but nearly 70% of patients were not receiving dialysis at baseline. [8,13] The authors notedthat the trial was not powered to determine whether there were differences in outcomes betweenthose receiving dialysis and those who were not. The adverse event rates were high in both statin usersand placebo groups; study investigators identified no subgroups (among patients on dialysis) thatexperienced benefit from treatment. [8] Hou et al. (2013) assessed the efficacy of statin therapy vs.placebo or lower dose statin in patients with CKD with or without dialysis and with or without a historyDecember 2014Page 10 of 112
of CKD. [14] Statistically significant benefits were generally restricted to patients not on dialysis for allcause mortality, cardiovascular death and coronary events. There were non-significant effects on stroke,kidney failure and adverse events regardless of dialysis status.The American College of Cardiology and American Heart Association (ACC/AHA) Guideline (2013)concluded there is no evidence that statins confer a benefit in patients with heart failure or ESRD and ondialysis and suggest clinicians engage in patient-centered discussions acknowledging the limitedavailable evidence on harms and benefits for individual patients. [15] Given the lack of datademonstrating benefit, and the possibility of increased adverse events in the dialysis population, thecommittee concurred with this approach. [16] As the rest of the guideline does not apply to patientswith moderate-to-severe systolic HF or ESRD and on dialysis, these patient populations exit thealgorithm for patient-centered discussions of harms and benefits with their treating providers. Aspatients with CKD not yet on dialysis appeared to have improved outcomes, they continue on in thealgorithm.Reconciling 2006 CPG RecommendationsEvidence-based CPGs should be current, which typically requires revisions based on new evidence or asscheduled subject to time-based expirations. For example, the US Preventive Services Task Force(USPSTF) has a process for refining or otherwise updating its recommendations pertaining to preventiveservices. [17] Further, the inclusion criteria for the National Guideline Clearinghouse specify that aguideline must have been developed, reviewed or revised within the past five years.The Dyslipidemia Guideline Work Group focused largely on developing new and updatedrecommendations based on the evidence review conducted for the priority areas addressed by the keyquestions. In add
Guideline for Guidelines, [6] an internal document of the VA and DoD Evidence-based Practice Working Group (EBPWG). This document provides information regarding the process of developing guidelines, including the identification and assembly of the Guideline Champions (Champions) and other subject matter experts from within the VA
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This clinical practice guideline is based on the best available scientific evidence for the key questions as determined by the GDG. This means that our clinical practice guideline is not intended to replace the professional judgment of clinicians, but should help to inform clinical decision-making in particular clinical circumstances.
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VA/DoD Clinical Practice Guideline for the Management of Chronic Multisymptom Illness . May 2021 Page 2 of 117 . Prepared by: The Management of Chronic Multisymptom Illness Work Group . With support from: The Office of Quality and Patient Safety , VA, Washington, DC & Office of Evidence Based Practice, Defense Health Agency . Version 3.0 - 2021
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