All feedback submitted during each review period was reviewed and discussed by the Work Group and appropriate revisions were made to the CPG. Draft 3 of the CPG was made available for peer review and comment. This process is described in the section titled Peer Review Process. After revisions were made based on the feedback received during the peer review and comment period, the Champions presented the CPG to the EBPWG for their approval. Changes were made based on feedback from the EBPWG and the guideline was finalized. The Work Group also produced a set of guideline toolkit materials which included a provider summary, pocket card, and patient summary. The final 2020 Dyslipidemia CPG was submitted to the EBPWG in April 2020. Appendix B: Cardiovascular Disease Risk Calculators Table B-1. Risk Calculators: Characteristics of Patient Population ACC/AHA pooled cohort PCE SRSRF VARS-CVD Framingham Sex Race Black/African American Age Abbreviations: ACA/AHA: American College of Cardiology/American Heart Association; PCE: Pooled Cohort Equations; SRSRF: Self- Reported Stroke Risk Function; VARS-CVD: Veterans Affairs Risk Score for Cardiovascular Disease Appendix C: Pharmacotherapy Table C-1. Summary of Statin and Non-statin Pharmacologic Agents* Drug Category Dose Major Drug Interactions Adverse Drug Reactions Notes Statins Atorvastatin once daily Since statins vary in their metabolic pathway, refer to product labeling for drug-drug interactions and statin dose limits Risk for myalgia, myopathy and, very rarely, rhabdomyolysis. Other risks include diabetes, LFT elevations, and asymptomatic CK elevations. First line therapy for primary or secondary prevention of CVD Rosuvastatin 5 40 mg once daily Simvastatin 5 40 mg once daily Lovastatin once daily Pravastatin once daily Fluvastatin 20 80 mg per day Pitavastatin 1 4 mg once daily Cholesterol absorption inhibitors Ezetimibe 10 mg once daily Increased incidence of transaminase elevation >3x ULN when combined with statins versus statins respectively) Generally well tolerated Benefit for reducing non- fatal CV events in secondary prevention patients in addition to statin inhibitors Alirocumab 75 mg once every 2 weeks OR 300 mg once every 4 weeks Max: 150 mg every 2 weeks No known significant interactions Injection site reactions (3 7%). Adverse reactions inhibitors reported in RCTs appear to be similar to placebo. Alirocumab had higher incidence of influenza, bronchitis, myalgia, muscle spasm, sinusitis, cough, and musculoskeletal pain compared to placebo Evolocumab had a higher incidence of cough, arthralgia, and fatigue Benefit for reducing non-fatal CV events in secondary prevention in addition to maximally tolerated statin +/- ezetimibe It is recommended that patients receive maximally tolerated statins plus ezetimibe prior to adding alirocumab or evolocumab Limited data on long- term safety Evolocumab 140 mg once every 2 weeks OR 420 mg once monthly Drug Category Dose Major Drug Interactions Adverse Drug Reactions Notes fatty acids Icosapent ethyl 2 gm twice daily with meals May enhance antiplatelet and anticoagulation effects. Caution with concomitant agents that increase risk of bleeding. oropharyngeal pain, peripheral edema, constipation, gout, and atrial fibrillation. Potential for allergic reactions in patients with fish allergy. Benefit for reduction of CV mortality and morbidity in patients treated for secondary prevention on statins with persistently elevated TG (>150 mg/dL); evidence is limited to one RCT Hospitalization for atrial fibrillation or flutter was statistically higher with icosapent and a non- significant trend towards a higher incidence of hospitalization for serious bleeding events was also observed * Refer to product prescribing insert for more information regarding use restrictions, dose modification, dosing in special populations (e.g., renal or liver impairment, advanced age, pregnancy, etc.), drug-drug interactions, and adverse events. Abbreviations: CK: creatine kinase; CV: cardiovascular; CVD: cardiovascular disease; dL: deciliter; gm: grams; LFT: liver function test; mg: milligrams; PCSK9: proprotein convertase subtilisin/kexin type 9; RCT: randomized controlled trial; TG: triglyceride; ULN: upper limit of the normal range Appendix D: Patient Education on the Mediterranean Diet Table D-1. Patient Education on the Mediterranean Diet [155] Eat More Eat Less Fruits and vegetables Whole grains Seafood (primarily fatty fish), skinless poultry Tree nuts, peanuts, nut butters Legumes Olive oil Low-fat milk and cheese Red wine* Red meat Processed meat Full-fat milk and cheese Butter or margarine Commercial bakery goods Avoid trans fat * Providers should consider the risk of recommending alcohol to individual patients. Appendix E: Patient Focus Group Methods and Findings A. Methods As part of the effort to update this CPG, the 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 of patients on a set of topics related to their dyslipidemia. The focus group considered a set of topics related to their dyslipidemia, including their treatment plan history, care delivery setting, medications, non-pharmacologic therapies, and the impact of therapy. VA and DoD Leadership recruited participants for the focus group. Patients were not incentivized for their participation or reimbursed for travel expenses. Three patients participated in the focus group. There were two men and one woman, ranging in age from 50 70. One participant receives care at the VA, while the other two receive care from the DoD. The Dyslipidemia CPG Work Group, with support from Lewin, developed a set of questions to help guide the focus group. The focus group facilitator led the discussion using the previously prepared questions as a general guide to elicit the patient s perspectives about their treatment and overall care. Given the limited time and the range of interests of the focus group participants, not all of the listed questions were addressed. B. Patient Focus Group Findings a. Patients stressed the importance of lifestyle changes and felt these were the most important ways to reduce cardiovascular risk and improve their health All three participants understood that eating a healthy diet would reduce their CV risk and, for that reason, several implemented comprehensive dietary changes. Two participants took supplements that were not recommended by their provider either in addition to, or instead of, pharmaceuticals. Two participants started exercising regularly after learning of their health issues, and they reported feeling better afterward. All three participants noted their risk of CVD has not impacted their quality of life. b. Participants stressed the importance of patient education, fully understanding their CV risk, and learning about the available treatment options. Participants were highly motivated to manage their CV risk. All three participants felt that learning of their health risks CV or otherwise motivated them to take personal responsibility for their health. Participants use various mediums to learn about lipids and CV risk, including websites, family and friends, and providers external to the VA/DoD health care systems. Two participants found visual aids that explain the benefits and harms of statins useful, but thought these aids would be confusing in the absence of a provider s explanation. All three participants stated they were more likely to adhere to prescribed regimens if they had a strong relationship with their provider. Also, they place a premium on patient-centered care. c. While all patients have used pharmacologic treatments, they noted various concerns with statins. In addition, they had a general preference for reducing their CV risk via non-pharmacologic treatments. All three participants generally did not experience issues regarding adherence to statins. However, some did struggle to take it at the proper time of day. Statin side effects varied for the three participants. One participant never had side effects. One participant experienced side effects, but the benefits outweighed the harms. Comparatively, two participants stopped taking statins because of side effects. All three participants had tried multiple statins and changed their course of treatment to reduce side effects. d. Patients had health concerns in addition to their cholesterol and stressed the importance that providers consider comorbidities when managing their cholesterol. Two participants are primarily concerned with cholesterol levels and heart health, while another was more concerned with chronic conditions or other diseases posing more immediate barriers to their life. Whether dyslipidemia was a patient s primary health care concern depended on their risk levels, comorbidities, and family history. e. Patients generally find mobile apps and smart devices useful for monitoring their health. Even though not all patients prefer telemedicine and other technology options, providers should be ready to offer these options. All three participants use devices (e.g., smartphone, smartwatch) for monitoring their health and some use this modality to share health information with providers. One participant communicated with a remote private provider via Skype and enjoys using this method of communication. f. Despite variability in patient preferences regarding learning their cholesterol levels, patients agreed it was important to hear about the available screening tests. In addition, patients believed it is important that they understand their lipid levels and lipid profile results. All three participants have their lipids tested every six months as recommended by their provider. All three participants did not feel that fasting lipid testing was burdensome. Patient knowledge about lipid profiles varied. One patient used and advocated for providing advanced lipoprotein testing, while two participants were only aware of cholesterol, LDL, and HDL testing. All three participants felt that knowing their lipid profile has not made them feel better or worse, or improved their understanding of risk. Appendix F: Evidence Table Table F-1. Evidence Tablea,b,c Recommendation 2014 Strength of Recommendation Evidence 2020 Strength of Recommendation Recommendation Category 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 for [20,21] 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. Not applicable [21-23] Weak against Reviewed, New- added 3. For cardiovascular risk assessment in primary prevention, we suggest using a 10-year risk calculator. Weak for [24-28] Weak for Reviewed, Amended 4. We suggest against the routine use of coronary artery calcium testing. Weak against [29] Additional references: 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 [26,29,32-35] Weak against Reviewed, New- replaced 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. Weak for, Weak for, Strong for Additional references: Strong for Reviewed, New- replaced a Evidence column: The first set of references listed in each row in the evidence column constitutes the evidence base for the recommendation. To be included in the evidence base for a recommendation, a reference needed to be identified through the 2019 evidence review or included in the evidence base for the 2014 VA/DoD Dyslipidemia CPG. The second set of references in the evidence column ( Additional References ) includes references that provide additional information related to the recommendation but which were not systematically identified through a literature review. These references were not included in the evidence base for the recommendation and, therefore, did not influence the strength and direction of the recommendation. b 2020 Strength of Recommendation column: Refer to the Grading Recommendations section for more information on how the strength of the recommendation was determined using GRADE methodology. c Recommendation Category column: Refer to the Recommendation Categorization section for more information on the description of the categorization process and the definition of each category. Recommendation 2014 Strength of Recommendation Evidence 2020 Strength of Recommendation Recommendation Category 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, Strong for Additional references: 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. Strong for [36,37,47,48,55- Additional references: Weak against Reviewed, New- replaced 9. For primary prevention, there is insufficient evidence to recommend for or against using ezetimibe with or without statins. Strong against [64] Additional references: 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. Not applicable [68,70-72] Additional references: Strong against Reviewed, New- added 11. For secondary prevention, we recommend using at least a moderate-dose statin. Strong for [49,56,74] Additional references: 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 [55-59,61,75-79] Additional references: Weak for Reviewed, New- replaced 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 [75,76,80,81] 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. Strong against [68,70,79,82-85,88,89] Additional references: Weak for Reviewed, New- replaced Recommendation 2014 Strength of Recommendation Evidence 2020 Strength of Recommendation Recommendation Category 15. For primary or secondary prevention, we recommend against using niacin (i.e., supplements or prescriptions). Strong against [90-92] Additional references: Strong against Reviewed, New- replaced 16. For primary or secondary prevention, we suggest against adding fibrates to statins. Strong against [90,94-97] Additional references: 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. Not applicable [98] 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. Not applicable [99] 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. Not applicable [99] 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. Not applicable [100] 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 risk. Not applicable [101-106] Additional references: Neither for nor against Reviewed, New- added 22. We suggest against the routine monitoring of lipid levels in patients taking statins. Strong against [109-113] Additional references: 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. Not applicable [56,114,116,119,120] Additional references: 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. Not applicable [121] Additional references: Weak for Reviewed, New- added Recommendation 2014 Strength of Recommendation Evidence 2020 Strength of Recommendation Recommendation Category 25. For primary and secondary prevention of cardiovascular disease, we suggest a dietitian-led Mediterranean diet. Weak for, Weak for [128,129] Additional references: 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. Not applicable [134-142] Additional references: 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. Not applicable [147] Additional references: Strong for Reviewed, New- added Appendix G: 2014 Recommendation Categorization Table Table G-1. 2014 Recommendation Categorization Tablea,b,c,d,e,f Recommendation Number Page 2014 Recommendation Text 2014 Strength of Recommendation Recommendation Category Recommendation We recommend CVD risk screening for men > age 35 and women > age 45, including a lipid profile and a risk calculation. Strong for Not reviewed, Deleted We recommend against routine screening for dyslipidemia outside of the context of a cardiovascular risk assessment. Strong against Not reviewed, Deleted 3 19 For risk calculation, we suggest a 10-year risk calculator. Weak for Reviewed, Amended a Recommendation Number column: This indicates the recommendation number of each recommendation within the 2014 VA/DoD Dyslipidemia CPG. b Page column: This indicates the page number of each recommendation within the 2014 VA/DoD Dyslipidemia CPG. c 2014 Recommendation Text column: This contains the wording of each recommendation from the 2014 VA/DoD Dyslipidemia CPG. d 2014 Strength of Recommendation column: The 2014 VA/DoD Dyslipidemia CPG used the GRADE evidence rating system. The strength of recommendations in the 2014 VA/DoD Dyslipidemia CPG were: Strong for, Weak for, Neither for nor against, Weak against, or Strong against. Refer to the Grading Recommendations section for more information. e Recommendation Category column: The Recommendation Category column indicates the way in which each 2014 VA/DoD Dyslipidemia CPG recommendation was updated. Refer to the Recommendation Categorization section for more information. f 2020 Recommendation column: For recommendations that were carried forward to the 2020 VA/DoD Dyslipidemia CPG, this column indicates the new corresponding recommendation(s). Recommendation Number Page 2014 Recommendation Text 2014 Strength of Recommendation Recommendation Category Recommendation We suggest that patients being considered for statin therapy be assessed for other CVD risk factors, including, but not limited to, the following: a. Age (males >35 and females >45) b. Family history of premature coronary artery disease (CAD); definite myocardial infarction (MI) or sudden death before age 55 in father or other male first-degree relative, or before age 65 in mother or other female first-degree relative c. Current tobacco use/cigarette smoking (or within the last one month) d. Hypertension (systolic blood pressure [SBP] >140 mmHg or diastolic blood pressure [DBP] >90 mmHg confirmed on more than one occasion, or current therapy with anti-hypertensive medications) e. Diabetes mellitus (DM) (See VA/DoD DM CPG, v4e.pdf). A diagnosis of DM is made if any of the following: a) Fasting plasma glucose (FPG) is 126 mg/dL on at least two occasions, or b) A single hemoglobin A1c (HbA1c) reading of 6.5%, confirmed with a FPG 126 mg/dL (these tests can be done on the same or different days); or c) HbA1c is 7% on two occasions using a clinical laboratory methodology standardized to the net splanchnic glucose production (NSGP) (not at the point of care); or d) Symptoms of hyperglycemia and a casual (random) glucose 200 mg/dL on two occasions. However, casual (random) plasma glucose is not recommended as a routine screening test. f. Level of high density lipoprotein cholesterol (HDL-C) (Less than 40 mg/dL confirmed on more than one occasion) Modified from the 2006 CPG without an updated systematic review of the evidence.* Weak for Not reviewed, Deleted We suggest against the routine use of high-sensitivity C-reactive protein (hsCRP) testing. Weak against Reviewed, New- replaced 6 21 We suggest against the routine use of coronary artery calcium (CAC) testing. Weak against Reviewed, Not Changed Recommendation Number Page 2014 Recommendation Text 2014 Strength of Recommendation Recommendation Category Recommendation We suggest shared decision making regarding pharmacologic treatment for patients with an estimated 10-year CVD risk of 12% or greater that takes into consideration the known minimal harms and substantial benefits of moderate- dose therapy in this group of patients. Weak for Reviewed, New- replaced We suggest initiation of a moderate-dose statin for patients with an estimated 10-year CVD risk of 12% or greater. Weak for Reviewed, New- replaced We suggest considering a moderate-dose statin for patients with a 10-year CVD risk between 6% and 12% following a discussion of the known minimal harms, benefits derived from limited evidence, and an exploration of the patient s values and preferences. Weak for Reviewed, New- replaced For primary prevention, we recommend a moderate dose statin as the agent of choice to reduce CVD risk if the patient chooses pharmacologic therapy. Strong for Reviewed, New- replaced Recommendations For primary prevention in patients who are unable to tolerate statins, we suggest reinforcing adherence to positive lifestyle changes. For patients who prefer to try pharmacotherapy, we suggest considering treatment with gemfibrozil or bile acid sequestrants (BAS), noting that these agents have been associated with only a small CVD risk reduction and studied in limited populations, e.g., males with low density lipoprotein cholesterol (LDL C) >190 mg/dL. Weak for Reviewed, Deleted We suggest establishing baseline liver function tests (LFTs) and creatinine kinase (CK) before initiation of drug therapy. Weak for Not reviewed, Deleted We recommend against routinely measuring LFTs or CK after a moderate dose statin is initiated. Strong against Not reviewed, Deleted In patients with established ASCVD, we recommend use of a moderate-dose statin following a discussion of the minimal harms, substantial benefits, and an exploration of the patient s values and preferences. Strong for Reviewed, New- replaced Recommendation In patients with ASCVD who are able to tolerate statins, we recommend against the routine use of non-statin lipid lowering drugs (e.g., fibrates, niacin, ezetimibe, omega-3 fatty acids, etc.) either alone as monotherapy or added to statins. Strong against Reviewed, New- replaced Recommendations Recommendation Number Page 2014 Recommendation Text 2014 Strength of Recommendation Recommendation Category Recommendation In patients with ASCVD who are unable to tolerate statins, we suggest reinforcing adherence to positive lifestyle changes and suggest offering niacin or gemfibrozil, noting that these agents have been associated with only a small CVD risk reduction and studied in limited populations (e.g., males with low HDL-C). Weak for Reviewed, Deleted We strongly recommend against the routine monitoring of LDL C and non- HDL C goals for the secondary prevention of ASCVD. Strong against Reviewed, New- replaced Recommendation We suggest offering a high-dose statin only in select patient populations (e.g., ACS, multiple uncontrolled risk factors or recurrent CVD events on moderate- dose statin) following a discussion of the added harms, small additional benefits, and an exploration of the patient s values and preferences. Weak for Reviewed, New- replaced Recommendations 19 29 We suggest measuring LFTs 4-12 weeks after the initiation of high-dose statin. Weak for Reviewed, Deleted We recommend all adults adopt healthy lifestyles to reduce CVD risk, including: a. Tobacco cessation for all smokers (See 2008 Tobacco Use CPG, http://www.healthquality.va.gov/guidelines/cd/mtu/index.asp) b. Therapeutic Lifestyle Changes (TLC) diet to optimize nutrition (For overweight and/or obese patients, see 2014 Obesity CPG, http://www.healthquality.va.gov/guidelines/CD/obesity/VADoDCPGMana c. Optimal physical activity (See 2008 Physical Activity Guidelines for Americans, http://www.health.gov/paguidelines/pdf/paguide.pdf) Modified from the 2006 CPG without an updated systematic review of the evidence. Strong for Reviewed, Deleted We suggest offering high-risk patients (see text for definition) a dietitian- monitored Mediterranean diet supplemented with either extra-virgin olive oil (roughly 1 liter per week) or 30 grams (g) of mixed nuts per day (15g of walnuts, 7.5g of hazelnuts, and 7.5g of almonds) for the reduction of CVD events. Weak for Reviewed, New- replaced Recommendation Recommendation Number Page 2014 Recommendation Text 2014 Strength of Recommendation Recommendation Category Recommendation We suggest that each patient s diet be individualized based on a nutrition assessment (preferably by a registered dietitian [RD]), other CVD risk factors, other disease conditions, and lifestyle. Modified from the 2006 CPG without an updated systematic review of the evidence. Weak for Reviewed, Deleted We recommend treating the common secondary causes of elevated triglycerides (TGs): dietary indiscretion (e.g., refined sugars), alcohol use, hypothyroidism, and hyperglycemia. Modified from the 2006 CPG without an updated systematic review of the evidence. Strong for Reviewed, Deleted We suggest for patients with TGs greater than 500 mg/dL a strict diet therapy including avoidance of alcohol, restriction of dietary fat, and avoidance of refined sugars. We suggest for patients with TGs greater than 1000 mg/dL a very low fat diet to reduce chylomicronemia and risk of acute pancreatitis. Weak for Reviewed, New- replaced Recommendation We suggest CVD risk assessment every five years for patients with low CVD risk and not on statin therapy. Weak for Reviewed, Amended We suggest CVD risk assessment every two years for patients with intermediate CVD risk or with appearance of a new CVD risk factor (e.g., new diagnosis of type 2 diabetes mellitus [DM] or hypertension) and not on statin therapy. Weak for Reviewed, Deleted Appendix H: Participant List CDR Michael J. Arnold, MD, FAAFP Assistant Professor, Family Medicine Uniformed Services University of the Health Services Bethesda, MD Jennifer Ballard-Hernandez, DNP, FNP-BC Cardiovascular Clinical Nurse Advisor Office of Nursing Services/VACO Cardiology Nurse Practitioner Tibor Rubin VA Medical Center Long Beach, CA Andrew Buelt, DO Internist Bay Pines VA Healthcare System Bay Pines, FL Mark Donahue, MD Associate Professor of Medicine Cardiology Duke University Medical Center Director of Coronary Intensive Care Unit Durham VA Medical Center Durham, NC John R. Rick Downs, MD, FACP Professor of Medicine University of Texas Long School of Medicine South Texas Veterans Health Care System San Antonio, TX Karen Grace, PharmD Pharmacy Analyst Cathy Kelley, PharmD National Clinical Pharmacy Program Manager VA Pharmacy Benefits Management Services Scottsdale, AZ Amanda Logan, MPS, RDN, LD Assistant Chief, NFS Cincinnati VA Medical Center Cincinnati, OH Sundar Natarajan, MD, MSc Associate Professor of Medicine New York University School of Medicine Internist VA New York Harbor Healthcare System New York, NY Lt Col Brian Neubauer, MD, MHPE, FACP Chief, General Internal Medicine Service Walter Reed National Military Medical Center Associate Professor of Medicine Uniformed Services University of the Health Sciences Bethesda, MD COL Patrick G. O Malley, MD, MPH, FACP Associate Dean, Clinical Affairs Division Director and Professor of Medicine, General Internal Medicine Uniformed Services University of the Health Sciences Bethesda, MD Joan Ritter, MD, FACP Assistant Service Chief, General Internal Medicine Walter Reed National Military Medical Center Bethesda, MD LTC Nikki Smith, DNP, FNP-BC USU DNP Phase II Site Director Deputy Chief Education William Beaumont Army Medical Center Fort Bliss, TX Lance Spacek, MD Assistant Professor of Medicine, Primary Care Sports Medicine University of Texas Long School of Medicine South Texas Veterans Health Care System San Antonio, TX Lauren Thomas, MS, RD, LD Registered Dietitian General Internal Medicine Walter Reed National Military Medical Center Bethesda, MD Elena Vagichev, PharmD, BCPS, BCACP Clinical Pharmacy Specialist Walter Reed National Military Medical Center Bethesda, MD Appendix I: Abbreviation List Abbreviation Definition AAA abdominal aortic aneurysm ABI ankle-brachial index ACS acute coronary syndrome AHRQ Agency for Healthcare Research and Quality Apo apolipoproteins ARR absolute risk reduction AUC area under the curve BID twice per day BMI body mass index BP blood pressure CABG coronary artery bypass grafting CAC coronary artery calcium CAD coronary artery disease CDC Centers for Disease Control and Prevention CHF congestive heart failure CI confidence intervals CK creatinine kinase CKD chronic kidney disease COR contracting officer s representative cPCE calibrated Pooled Cohort Equation CPGs clinical practice guidelines CTT Cholesterol Treatment Trialists CV cardiovascular CVA cerebrovascular accident CVD cardiovascular disease DASH Dietary Approaches to Stop Hypertension dL deciliter DM diabetes mellitus DoD Department of Defense EBPWG Evidence-Based Practice Work Group ECG electrocardiogram EF ejection fraction ESRD end-stage renal disease FDA U.S. Food and Drug Administration FH familial hypercholesterolemia FRS Framingham Risk Score g grams GI gastrointestinal Abbreviation Definition GRADE Grading of Recommendations Assessment, Development and Evaluation HDL-C high-density lipoprotein cholesterol HEC Health Executive Committee HF heart failure hsCRP high-sensitivity C-reactive protein IOM Institute of Medicine JUPITER Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin KQs key questions LDL-C low-density lipoprotein cholesterol LFT liver function tests MACE major adverse cardiac events mg milligrams MHS Military Health System MI myocardial infarction NAM National Academy of Medicine NICE National Institute for Health and Care Excellence NNH number needed to harm NNT number needed to treat OR odds ratio OTC over-the-counter PAD peripheral arterial disease PCE Pooled Cohort Equations PCI percutaneous coronary intervention PCSK9 proprotein convertase subtilisin/kexin type 9 PICOTS the population, intervention, comparison, outcome, timing and setting RCT randomized controlled trial RD registered dietitian RRR relative risk reduction SR systematic review TC total cholesterol TGs triglycerides TIA transient ischemic attack U.K. United Kingdom U.S. United States ULN upper limit of the normal range USPSTF U.S. Preventive Services Task Force VA Department of Veterans Affairs VHA Veterans Health Administration Appendix J: Literature Search Strategy A. EMBASE with EMBASE.com Syntax Question Set # Concept Strategy Question Time to repeat screening for CV risk (Note: this search builds upon the search for Questions and which include specific terms for CV risk) #1 Dyslipidemia dyslipidemia/exp OR 'hypercholesterolemia'/exp OR cholesterol/exp OR lipid/de OR (dyslipidemia* OR dyslipidaemia* OR dyslipidproteinemia* OR dyslipidproteinaemia* OR hyperlipidemia* OR hyperlipidaemia* OR hypercholesterolemia* OR hypercholesterolaemia* OR hyperlipoproteinemia* OR hyperlipoproteinaemia* OR hypertriglyceridemia* OR hypertriglyceridaemia* OR hyperlipemia OR hyperlipaemia):ti,ab OR ((high OR elevated OR low) NEAR/5 (cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C")):ti,ab assessment 'mass screening'/exp OR 'multiphasic screening'/exp OR 'screening test'/exp OR 'risk assessment'/exp OR ((risk or risks) NEAR/4 (stratify or stratifying or stratification or define or defining or predict or prediction or assess* OR classif* OR prioritiz* OR category* OR tier* OR calculat* OR index OR indices OR score OR scores OR marker* OR biomarker* OR profile* OR algorithm* OR factor* OR characteristic*)):ti,ab OR (cardiovascular NEAR/2 risk*) #3 Repeat screening/ monitoring 'time factor'/exp OR 'rescreening'/exp OR monitoring/exp OR (rescreen* OR re-screen* OR surveillance OR re-assess* OR monitor* OR ((repeat or repet* or replicat* or redo or "re-do" or rerun or "re-run" or subsequent* or redundant* or re- assess* or reassess* OR "follow up" OR "follow-up") NEAR/4 (test* or screen* OR assess*))):ti,ab #4 Outcomes of interest 'cardiovascular disease'/exp/mj/dm_pc OR 'primary prevention'/exp OR 'prevention and control'/exp OR 'treatment outcome'/exp OR 'morbidity'/exp OR 'mortality'/exp OR 'all cause mortality'/exp OR 'cerebrovascular accident'/exp OR 'heart infarction'/exp OR 'unstable angina pectoris'/exp OR (stroke* OR (cerebrovascular NEXT/1 accident*) OR morbidity OR mortality OR death OR (heart NEXT/1 attack*) OR (myocardial NEXT/1 infarct*) OR ((vascular OR cardiac OR coronary OR cerebrovascular) NEXT/2 event*) OR (heart NEXT/1 infarct*)):ti,ab OR (morbidity OR mortality OR prevent* OR outcome*):ti,ab OR (primary NEXT/1 prevention):ti,ab OR angina:ti,ab #6 Limit to RCTs/SRs/meta- analysis Randomized controlled trials/systematic review/meta-analysis hedge [see Search Limits at the end of this table] #7 Limit to additional study designs 'latin square design'/de OR 'controlled study'/exp OR 'clinical trial'/exp OR 'comparative study'/exp OR 'cohort analysis'/de OR 'follow up'/de OR 'intermethod comparison'/de OR 'parallel design'/de OR 'control group'/de OR 'prospective study'/de OR 'retrospective study'/de OR 'case control study'/exp OR 'major clinical study'/de OR 'evaluation study'/exp OR (cohort* OR longitudinal OR prospective OR retrospective OR "case control" OR compar* OR "control group" OR "controlled study" OR "controlled trial" OR "cross over" OR crossover OR "double blind" OR "double blinded" OR "matched controls" OR placebo* OR random* OR sham):ti,ab OR ((versus OR vs):ti) #9 Apply limits See Search Limits at the end of the table Question Set # Concept Strategy Question Stability of lipid levels over time #1 Dyslipidemia dyslipidemia/exp OR 'hypercholesterolemia'/exp OR cholesterol/exp OR lipid/de OR (dyslipidemia* OR dyslipidaemia* OR dyslipidproteinemia* OR dyslipidproteinaemia* OR hyperlipidemia* OR hyperlipidaemia* OR hypercholesterolemia* OR hypercholesterolaemia* OR hyperlipoproteinemia* OR hyperlipoproteinaemia* OR hypertriglyceridemia* OR hypertriglyceridaemia* OR hyperlipemia OR hyperlipaemia):ti,ab OR ((high OR elevated OR low) NEAR/5 (cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C")):ti,ab #2 CVD 'cardiovascular disease'/exp/mj/dm_pc OR 'cardiovascular disease'/de OR 'hypertension'/exp OR 'ischemic heart disease'/exp OR 'heart disease'/de OR 'coronary artery disease'/exp OR 'peripheral vascular disease'/exp OR 'cerebral artery disease'/exp OR 'brain ischemia'/exp OR 'cerebrovascular accident'/exp OR 'cerebrovascular disease'/exp OR 'heart infarction'/exp OR ((heart* OR cardio* OR cardiac* OR coronary OR vascular OR cerebrovascular OR artery OR arteries) NEAR/5 (disease* OR syndrome* OR event* OR ischem* OR ischaem* OR plaque*)):ti,de OR (hyperten* OR atherosclero* OR arteriosclero* OR angina OR (Heart NEXT/1 attack*) OR (myocardial NEXT/1 infarct*) OR stroke* OR (cerebrovascular #3 Monitoring of lipid levels over time 'lipid blood level'/exp AND (monitoring/exp OR 'time factor'/exp) OR ((cholesteryl* or cholesterol* or lipid* or lipoprotein* or tryglycer* or triaclyglycer* or "HDL-C" or "LDL-C" or "HDL C" or "LDL C" or "non HDL C" or "non-HDL C" or "non-HDL-C") NEAR/5 (level or levels or blood OR value*) NEAR/5 (monitor* OR surveillance OR stable OR stability OR variability OR variable OR "long term" OR "long-term" OR longitud* OR trend*)):ti,ab #5 Limit to RCTs/SRs/meta- analysis Randomized controlled trials/systematic review/meta-analysis hedge [see Search Limits at the end of this table] #6 Limit to additional study designs 'latin square design'/de OR 'controlled study'/exp OR 'clinical trial'/exp OR 'comparative study'/exp OR 'cohort analysis'/de OR 'follow up'/de OR 'intermethod comparison'/de OR 'parallel design'/de OR 'control group'/de OR 'prospective study'/de OR 'retrospective study'/de OR 'case control study'/exp OR 'major clinical study'/de OR 'evaluation study'/exp OR (cohort* OR longitudinal OR prospective OR retrospective OR "case control" OR compar* OR "control group" OR "controlled study" OR "controlled trial" OR "cross over" OR crossover OR "double blind" OR "double blinded" OR "matched controls" OR placebo* OR random* OR sham):ti,ab OR ((versus OR vs):ti) #8 Apply limits See Search Limits at the end of the table Question Set # Concept Strategy Question Methods for risk stratification #1 Dyslipidemia dyslipidemia/exp OR 'hypercholesterolemia'/exp OR cholesterol/exp OR lipid/de OR (dyslipidemia* OR dyslipidaemia* OR dyslipidproteinemia* OR dyslipidproteinaemia* OR hyperlipidemia* OR hyperlipidaemia* OR hypercholesterolemia* OR hypercholesterolaemia* OR hyperlipoproteinemia* OR hyperlipoproteinaemia* OR hypertriglyceridemia* OR hypertriglyceridaemia* OR hyperlipemia OR hyperlipaemia):ti,ab OR ((high OR elevated OR low) NEAR/5 (cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C")):ti,ab #2 CVD 'cardiovascular disease'/exp/mj OR 'hypertension'/exp/mj OR 'ischemic heart disease'/exp/mj OR 'heart disease'/mj OR 'coronary artery disease'/exp/mj OR 'peripheral vascular disease'/exp/mj OR 'cerebral artery disease'/exp/mj OR 'brain ischemia'/exp/mj OR 'cerebrovascular accident'/exp/mj OR 'cerebrovascular disease'/exp/mj OR 'heart infarction'/exp/mj OR ((heart* OR cardio* OR cardiac* OR coronary OR vascular OR cerebrovascular OR artery OR arteries) NEAR/5 (disease* OR syndrome* OR event* OR ischem* OR ischaem* OR plaque*)):ti OR (hyperten* OR atherosclero* OR arteriosclero* OR angina OR (Heart NEXT/1 attack*) OR (myocardial NEXT/1 infarct*) OR stroke* OR (cerebrovascular NEXT/1 accident*)):ti #3 Risk prediction/ stratification 'risk factor'/exp/mj OR 'risk assessment'/exp/mj OR 'cardiovascular risk'/exp/mj OR ((risk or risks) NEAR/4 (stratify or stratifying or stratification or define or defining or predict or prediction or assessment OR classif* OR prioritiz* OR category* OR tier* OR calculat* OR index OR indices OR score OR scores OR marker* OR biomarker* OR profile* OR algorithm* OR factor* OR characteristic*)):ti OR (cardiovascular NEAR/2 risk*):ti #4 Risk stratification tools lipid analysis /exp OR 'lipid blood level'/exp OR 'framingham risk score'/exp OR 'ankle brachial index'/exp OR 'coronary artery calcium score'/exp OR 'galectin 3'/exp OR 'c reactive protein'/exp OR 'apolipoprotein b'/exp OR 'lipoprotein a'/exp OR 'arterial wall thickness'/exp OR 'troponin I'/exp OR ((framingham NEXT/2 risk*) OR 'ankle brachial index' OR (coronary NEXT/4 calcium) OR ('c reactive' NEXT/2 protein*) OR 'hs-crp' OR 'hs crp' OR 'hscrp' OR 'ntprobnp' OR 'nt-probnp' OR 'hs- tnl' OR 'hs tnl' OR 'galecton 3' OR 'galecton-3' OR 'pooled cohort' OR (particle NEXT/2 size*) OR (high NEXT/1 sensitiv* NEXT/1 troponin*) OR apolipoprotein* OR lipoprotein* OR (carotid NEXT/1 intima* NEXT/3 thickness*)):ti,ab OR ((cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C" OR "non HDL C" OR "non-HDL C" OR "non-HDL-C") NEXT/5 (level OR levels)):ti #5 Outcomes of interest 'cardiovascular disease'/exp/mj/dm_pc OR 'primary prevention'/exp OR 'prevention and control'/exp OR 'treatment outcome'/exp OR 'morbidity'/exp OR 'mortality'/exp OR 'all cause mortality'/exp OR 'cerebrovascular accident'/exp OR 'heart infarction'/exp OR 'unstable angina pectoris'/exp OR (stroke* OR (cerebrovascular NEXT/1 accident*) OR morbidity OR mortality OR death OR (heart NEXT/1 attack*) OR (myocardial NEXT/1 infarct*) OR ((vascular OR cardiac OR coronary OR cerebrovascular) NEXT/2 event*) OR (heart NEXT/1 infarct*)):ti,ab OR (morbidity OR mortality OR prevent* OR outcome*):ti,ab OR (primary NEXT/1 prevention):ti,ab OR angina:ti,ab #6 Combine sets dyslipidemia terms plus CV outcomes #7 Combine sets CV terms without the outcomes string Question Set # Concept Strategy Question Methods for risk stratification (cont.) #9 Limit to RCTs/SRs/meta- analysis Randomized controlled trials/systematic review/meta-analysis hedge [see Search Limits at the end of this table] #10 Limit to additional study designs 'latin square design'/de OR 'controlled study'/exp OR 'clinical trial'/exp OR 'comparative study'/exp OR 'cohort analysis'/de OR 'follow up'/de OR 'intermethod comparison'/de OR 'parallel design'/de OR 'control group'/de OR 'prospective study'/de OR 'retrospective study'/de OR 'case control study'/exp OR 'major clinical study'/de OR 'evaluation study'/exp OR (cohort* OR longitudinal OR prospective OR retrospective OR "case control" OR compar* OR "control group" OR "controlled study" OR "controlled trial" OR "cross over" OR crossover OR "double blind" OR "double blinded" OR "matched controls" OR placebo* OR random* OR sham):ti,ab OR ((versus OR vs):ti) #11 Diagnostic test hedge 'diagnostic test accuracy':de OR 'diagnosis':lnk OR 'differential diagnosis'/exp OR 'receiver operating characteristic':de OR 'roc curve'/exp OR 'roc curve' OR 'sensitivity and specificity':de OR ('sensitivity' AND 'specficity') OR 'accuracy':de OR 'precision'/exp OR precision OR 'prediction and forecasting'/exp OR 'prediction and forecasting' OR 'diagnostic error'/exp OR 'diagnostic error' OR 'maximum likelihood method':de OR 'likelihood' OR 'predictive value'/exp OR 'predictive value' OR ppv OR ((false OR true) NEAR/1 (positive OR negative)) OR diagnos* or PPV OR "receiver operating characteristic" or (area NEXT/1 under NEXT/3 curve) OR AUC or "diagnostic accuracy" #13 Apply limits See Search Limits at the end of the table Questions Pertaining to pharmacologic treatment including cost #1 Dyslipidemia dyslipidemia/exp OR 'hypercholesterolemia'/exp OR cholesterol/exp OR lipid/de OR (dyslipidemia* OR dyslipidaemia* OR dyslipidproteinemia* OR dyslipidproteinaemia* OR hyperlipidemia* OR hyperlipidaemia* OR hypercholesterolemia* OR hypercholesterolaemia* OR hyperlipoproteinemia* OR hyperlipoproteinaemia* OR hypertriglyceridemia* OR hypertriglyceridaemia* OR hyperlipemia OR hyperlipaemia):ti,ab OR ((high OR elevated OR low) NEAR/5 (cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C")):ti,ab #2 CVD 'cardiovascular disease'/exp/mj/dm_pc OR 'cardiovascular disease'/de OR 'hypertension'/exp OR 'ischemic heart disease'/exp OR 'heart disease'/de OR 'coronary artery disease'/exp OR 'peripheral vascular disease'/exp OR 'cerebral artery disease'/exp OR 'brain ischemia'/exp OR 'cerebrovascular accident'/exp OR 'cerebrovascular disease'/exp OR 'heart infarction'/exp OR ((heart* OR cardio* OR cardiac* OR coronary OR vascular OR cerebrovascular OR artery OR arteries) NEAR/5 (disease* OR syndrome* OR event* OR ischem* OR ischaem* OR plaque*)):ti,de OR (hyperten* OR atherosclero* OR arteriosclero* OR angina OR (Heart NEXT/1 attack*) OR (myocardial NEXT/1 infarct*) OR stroke* OR (cerebrovascular treatments: statins 'hydroxymethylglutaryl coenzyme A reductase inhibitor'/exp OR 'hypocholesterolemic agent'/exp OR ((hydroxymethylglutaryl OR hydroxy-methylglutaryl) NEAR/5 reductase):ti OR (HMG NEXT/1 CoA):ti OR (statin* OR lovastatin OR meglutol OR pravastatin OR atorvastatin OR simvastatin):ti treatments: non- statins 'fibric acid derivative'/exp OR 'gemfibrozil'/exp OR 'hypocholesterolemic agent'/exp OR 'nicotinic acid'/exp OR 'bile acid sequestrant'/exp OR 'ezetimibe'/exp OR 'omega 3 fatty acid'/exp OR (fibrate* OR gemfibrozil OR fenofibrate OR bezafibrate OR (nicotinic NEXT/1 acid*) OR niacin OR ( bile acid NEXT/1 (sequestrant* OR resin*)) OR ezetimibe OR ((omega* OR marine) NEXT/3 fatty) OR pcsk9 OR pcsk-9 OR pcsk 9 OR ((eicosapentaenoic OR docosahexaenoic) NEXT/1 acid*) OR icosapent ethyl OR fish oil ):ti,ab Question Set # Concept Strategy Questions Pertaining to pharmacologic treatment including cost (cont.) #5 Outcomes of interest 'secondary prevention'/exp OR 'primary prevention'/exp OR 'prevention and control'/exp OR 'treatment outcome'/exp OR 'morbidity'/exp OR 'mortality'/exp OR 'all cause mortality'/exp OR 'cerebrovascular accident'/exp OR 'heart infarction'/exp OR 'unstable angina pectoris'/exp OR (stroke* OR (cerebrovascular NEXT/1 accident*) OR morbidity OR mortality OR death OR (heart NEXT/1 attack*) OR (myocardial NEXT/1 infarct*) OR ((vascular OR cardiac OR coronary OR cerebrovascular) NEXT/2 event*) OR (heart NEXT/1 infarct*)):ti,ab OR (morbidity OR mortality OR prevent* OR outcome*):ti,ab OR (secondary NEXT/1 prevention):ti,ab OR (primary NEXT/1 prevention):ti,ab OR angina:ti,ab OR 'adverse event'/exp OR 'side effect'/exp OR 'safety'/de OR ((side NEXT/1 effect*) OR (adverse NEXT/1 event*) OR safe OR safety):ti,ab Additional outcome of interest for KQ 8 [change in lipid levels] ((cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C") AND (level OR levels OR lower OR low OR reduce OR reduction OR profile* OR target*)).ti,ab #6 Combine sets including outcomes of interest #7 Combine sets without outcomes of interest #8 Limit to RCTs Randomized controlled trials hedge [see Search Limits at the end of this table] #9 Limit to SRs/meta- analyses systematic review/meta-analysis hedge [see Search Limits at the end of this table] #10 Limit to cost studies 'health care cost'/exp OR 'cost effectiveness analysis'/exp OR 'cost benefit analysis'/exp OR 'economic evaluation'/exp OR 'quality adjusted life year'/exp OR (cost OR costs OR costly OR costing OR price OR prices OR saving OR savings OR economi* OR financial OR finance* OR pharmacoeconomic* OR QALY or QALYs OR (quality NEXT/1 adjusted NEXT/1 life NEXT/1 year*) or (quality NEXT/1 adjusted life NEXT/1 expectanc*)):ti,ab #14 Apply limits See Search Limits at the end of the table Question Set # Concept Strategy Question Pharmacologic treatment to reach specific LDL-C or non-HDL-C goals #1 Dyslipidemia dyslipidemia/exp OR 'hypercholesterolemia'/exp OR cholesterol/exp OR lipid/de OR (dyslipidemia* OR dyslipidaemia* OR dyslipidproteinemia* OR dyslipidproteinaemia* OR hyperlipidemia* OR hyperlipidaemia* OR hypercholesterolemia* OR hypercholesterolaemia* OR hyperlipoproteinemia* OR hyperlipoproteinaemia* OR hypertriglyceridemia* OR hypertriglyceridaemia* OR hyperlipemia OR hyperlipaemia):ti,ab OR ((high OR elevated OR low) NEAR/5 (cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C")):ti,ab #2 CVD 'cardiovascular disease'/exp/mj/dm_pc OR 'cardiovascular disease'/de OR 'hypertension'/exp OR 'ischemic heart disease'/exp OR 'heart disease'/de OR 'coronary artery disease'/exp OR 'peripheral vascular disease'/exp OR 'cerebral artery disease'/exp OR 'brain ischemia'/exp OR 'cerebrovascular accident'/exp OR 'cerebrovascular disease'/exp OR 'heart infarction'/exp OR ((heart* OR cardio* OR cardiac* OR coronary OR vascular OR cerebrovascular OR artery OR arteries) NEAR/5 (disease* OR syndrome* OR event* OR ischem* OR ischaem* OR plaque*)):ti,de OR (hyperten* OR atherosclero* OR arteriosclero* OR angina OR (Heart NEXT/1 attack*) OR (myocardial NEXT/1 infarct*) OR stroke* OR (cerebrovascular #3 LDL-C or non-HDL- C goals (('low density lipoprotein cholesterol level'/exp OR 'high density lipoprotein cholesterol level'/exp) AND (goal OR goals OR target* OR level OR levels)).ti. OR (('high density lipoprotein cholesterol'/exp OR 'low density lipoprotein cholesterol'/exp) AND 'goal attainment'/exp) OR ((cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C" OR "non HDL C" OR "non-HDL C" OR "non-HDL-C") NEAR/5 (goal OR goals OR target* OR level OR levels)):ti,ab #4 Statins 'hydroxymethylglutaryl coenzyme A reductase inhibitor'/exp OR 'hypocholesterolemic agent'/exp OR ((hydroxymethylglutaryl OR hydroxy-methylglutaryl) NEAR/5 reductase):ti OR (HMG NEXT/1 CoA):ti OR (statin* OR lovastatin OR meglutol OR pravastatin OR atorvastatin OR simvastatin):ti #5 Non-statins 'fibric acid derivative'/exp OR 'gemfibrozil'/exp OR 'hypocholesterolemic agent'/exp OR 'nicotinic acid'/exp OR 'bile acid sequestrant'/exp OR 'ezetimibe'/exp OR 'omega 3 fatty acid'/exp OR (fibrate* OR gemfibrozil OR fenofibrate OR bezafibrate OR (nicotinic NEXT/1 acid*) OR niacin OR ( bile acid NEXT/1 (sequestrant* OR resin*)) OR ezetimibe OR ((omega* OR marine) NEXT/3 fatty) OR pcsk9 OR pcsk-9 OR pcsk 9 OR ((eicosapentaenoic OR docosahexaenoic) NEXT/1 acid*) OR icosapent ethyl OR fish oil ):ti,ab #6 Outcomes of interest 'secondary prevention'/exp OR 'primary prevention'/exp OR 'prevention and control'/exp OR 'treatment outcome'/exp OR 'morbidity'/exp OR 'mortality'/exp OR 'all cause mortality'/exp OR 'cerebrovascular accident'/exp OR 'heart infarction'/exp OR 'unstable angina pectoris'/exp OR (stroke* OR (cerebrovascular NEXT/1 accident*) OR morbidity OR mortality OR death OR (heart NEXT/1 attack*) OR (myocardial NEXT/1 infarct*) OR ((vascular OR cardiac OR coronary OR cerebrovascular) NEXT/2 event*) OR (heart NEXT/1 infarct*)):ti,ab OR (morbidity OR mortality OR prevent* OR outcome*):ti,ab OR (secondary NEXT/1 prevention):ti,ab OR (primary NEXT/1 prevention):ti,ab OR angina:ti,ab OR ('adverse event'/exp OR 'side effect'/exp OR 'safety'/de OR ((side NEXT/1 effect*) OR (adverse NEXT/1 event*) OR safe OR safety)):ti,ab Question Set # Concept Strategy Question Pharmacologic treatment to reach specific LDL-C or non-HDL-C goals (cont.) analyses Randomized controlled trials/systematic review/meta-analysis hedge [see Search Limits at the end of this table] #10 Apply limits See Search Limits at the end of the table Question Strategies to improve patient tolerance to statins Dyslipidemia dyslipidemia/exp OR 'hypercholesterolemia'/exp OR cholesterol/exp OR lipid/de OR (dyslipidemia* OR dyslipidaemia* OR dyslipidproteinemia* OR dyslipidproteinaemia* OR hyperlipidemia* OR hyperlipidaemia* OR hypercholesterolemia* OR hypercholesterolaemia* OR hyperlipoproteinemia* OR hyperlipoproteinaemia* OR hypertriglyceridemia* OR hypertriglyceridaemia* OR hyperlipemia OR hyperlipaemia):ti,ab OR ((high OR elevated OR low) NEAR/5 (cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C")):ti,ab #2 CVD 'cardiovascular disease'/exp/mj/dm_pc OR 'cardiovascular disease'/de OR 'hypertension'/exp OR 'ischemic heart disease'/exp OR 'heart disease'/de OR 'coronary artery disease'/exp OR 'peripheral vascular disease'/exp OR 'cerebral artery disease'/exp OR 'brain ischemia'/exp OR 'cerebrovascular accident'/exp OR 'cerebrovascular disease'/exp OR 'heart infarction'/exp OR ((heart* OR cardio* OR cardiac* OR coronary OR vascular OR cerebrovascular OR artery OR arteries) NEAR/5 (disease* OR syndrome* OR event* OR ischem* OR ischaem* OR plaque*)):ti,de OR (hyperten* OR atherosclero* OR arteriosclero* OR angina OR (Heart NEXT/1 attack*) OR (myocardial NEXT/1 infarct*) OR stroke* OR (cerebrovascular tolerance/adheren ce/ substitution (controlled terms) ('hydroxymethylglutaryl coenzyme A reductase inhibitor'/exp OR 'hypocholesterolemic agent'/exp) AND ('medication compliance'/exp OR 'patient compliance'/exp OR 'drug substitution'/exp OR 'drug dose intensification'/exp OR 'drug dose reduction'/exp) #4 Statin tolerance/ adherence/ substitution (keywords) ((hydroxymethylglutaryl or hydroxy-methylglutaryl) NEAR/5 reductase*) OR "HMG CoA" or statin* or lovastatin or meglutol or pravastatin or atorvastatin or simvastatin):ti,ab AND (tolerate* or tolerance or adher* or nonadherence* or non-adherence or ((alternat* or low or lower or high or higher or increase or decrease) NEXT/3 dose or dosing or dosag*)):ti,ab analyses Randomized controlled trials/systematic review/meta-analysis hedge [see Search Limits at the end of this table] #8 Apply limits See Search Limits at the end of this table Question Set # Concept Strategy Questions Pertaining to non-pharmacologic treatment including cost #1 Dyslipidemia dyslipidemia/exp OR 'hypercholesterolemia'/exp OR cholesterol/exp OR lipid/de OR (dyslipidemia* OR dyslipidaemia* OR dyslipidproteinemia* OR dyslipidproteinaemia* OR hyperlipidemia* OR hyperlipidaemia* OR hypercholesterolemia* OR hypercholesterolaemia* OR hyperlipoproteinemia* OR hyperlipoproteinaemia* OR hypertriglyceridemia* OR hypertriglyceridaemia* OR hyperlipemia OR hyperlipaemia):ti,ab OR ((high OR elevated OR low) NEAR/5 (cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C")):ti,ab #2 CV risk ('cardiovascular disease'/exp/mj OR 'hypertension'/exp/mj OR 'ischemic heart disease'/exp/mj OR 'heart disease'/mj OR 'coronary artery disease'/exp/mj OR 'peripheral vascular disease'/exp/mj OR 'cerebral artery disease'/exp/mj OR 'brain ischemia'/exp/mj OR 'cerebrovascular accident'/exp/mj OR 'cerebrovascular disease'/exp/mj OR 'heart infarction'/exp/mj OR ((heart* OR cardio* OR cardiac* OR coronary OR vascular OR cerebrovascular OR artery OR arteries) NEAR/5 (disease* OR syndrome* OR event* OR ischem* OR ischaem* OR plaque*)):ti OR (hyperten* OR atherosclero* OR arteriosclero* OR angina OR (Heart NEXT/1 attack*) OR (myocardial NEXT/1 infarct*) OR stroke* OR (cerebrovascular NEXT/1 accident*)):ti) AND (risk* OR prevent*):ti supplements/ neutraceuticals 'dietary supplement'/exp OR 'plant medicinal product'/exp OR 'omega 3 fatty acid'/exp OR 'vitamin'/de OR garlic/exp OR 'dietary fiber'/exp OR 'ginger'/exp OR 'phytosterol'/exp OR 'ispagula'/exp OR 'tea'/exp OR (((diet OR dietary) NEAR/5 supplement*) OR neutraceutical* OR ((omega* OR marine) NEXT/3 fatty) or "fish oil" OR ((eicosapentaenoic OR docosahexaenoic) NEXT/1 acid*) OR icosapent ethyl OR ((diet* OR soluable) NEAR/5 fiber) OR garlic OR ginger OR phytosterol* OR (plant NEXT/2 sterol*) OR (green NEXT/1 tea*) OR niacin* OR psyllium):ti #4 Diet therapy 'diet therapy'/exp OR ((Diet or diets or dietary or nutrition) and ("low sodium" or "low fat" or (gluten next/2 free) or "low gluten" or "low carb" or "low carbohydrate" or "low calorie" or vegetarian or vegan or macrobiotic or Mediterranean or DASH)):ti or "diabetic diet":ti or (dietary next/1 approach* NEXT/1 stop NEXT/1 hypertension):ti or diet*:ti #5 Exercise 'exercise'/exp OR (aerobics OR dance OR dancing OR exercise* OR fitness OR kinesiotherapy OR "muscle strengthening" OR "physical activity" OR "physical conditioning" OR "plyometric training" OR "resistance training" OR "strength training" OR "tai chi" OR "tai-chi" OR walk* OR "weight lifting" OR yoga OR swim OR swimming OR run OR running OR "weight training"):ti #6 Outcomes of interest 'secondary prevention'/exp OR 'primary prevention'/exp OR 'prevention and control'/exp OR 'treatment outcome'/exp OR 'morbidity'/exp OR 'mortality'/exp OR 'all cause mortality'/exp OR 'cerebrovascular accident'/exp OR 'heart infarction'/exp OR 'unstable angina pectoris'/exp OR (stroke* OR (cerebrovascular NEXT/1 accident*) OR morbidity OR mortality OR death OR (heart NEXT/1 attack*) OR (myocardial NEXT/1 infarct*) OR ((vascular OR cardiac OR coronary OR cerebrovascular) NEXT/2 event*) OR (heart NEXT/1 infarct*)):ti,ab OR (morbidity OR mortality OR prevent* OR outcome*):ti,ab OR (secondary NEXT/1 prevention):ti,ab OR (primary NEXT/1 prevention):ti,ab OR angina:ti,ab OR ((cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C") AND (level OR levels OR lower OR low OR reduce OR reduction OR profile*)):ti,ab OR ('adverse event'/exp OR 'side effect'/exp OR 'safety'/de OR ((side NEXT/1 effect*) OR (adverse NEXT/1 event*) OR safe OR safety):ti,ab #7 Combine sets including outcomes of interest Question Set # Concept Strategy Questions Pertaining to non-pharmacologic treatment including cost (cont.) #8 Combine sets without outcomes of interest #9 Limit to RCTs Randomized controlled trials hedge [see Search Limits at the end of this table] #10 Limit to SRs/Meta- analysis Systematic review/meta-analysis hedge [see Search Limits at the end of this table] #11 Limit to cost studies (KQ 9) 'health care cost'/exp OR 'cost effectiveness analysis'/exp OR 'cost benefit analysis'/exp OR 'economic evaluation'/exp OR 'quality adjusted life year'/exp OR (cost OR costs OR costly OR costing OR price OR prices OR saving OR savings OR economi* OR financial OR finance* OR pharmacoeconomic* OR QALY or QALYs OR (quality NEXT/1 adjusted NEXT/1 life NEXT/1 year*) or (quality NEXT/1 adjusted life NEXT/1 expectanc*)):ti,ab #15 Apply limits See Search Limits at the end of this table Search Limits Applied to Each Search Limit to humans and items published since searches were conducted for AND [humans]/lim AND [english]/lim AND [9-12-2013]/sd NOT [2019]/sd Exclude conference publications, books, letters, editorials, case studies, etc. (abstract:nc OR annual:nc OR book/de OR 'case report'/de OR 'case study'/de OR conference:nc OR 'conference abstract':it OR 'conference paper'/de OR 'conference paper':it OR 'conference proceeding':pt OR 'conference review':it OR congress:nc OR editorial/de OR editorial:it OR erratum/de OR letter:it OR note/de OR note:it OR meeting:nc OR sessions:nc OR 'short survey'/de OR symposium:nc) Limit to meta- analyses and SRs AND ('systematic review'/exp OR 'systematic review' OR 'meta analysis'/exp OR 'meta analysis') Limit to RCTs ('randomized controlled trial'/exp OR 'randomization'/de OR 'double blind procedure'/de OR 'single blind procedure'/de OR 'placebo'/de OR 'crossover procedure'/de OR placebo* OR random*:ti,de OR crossover* OR 'cross over' OR ((singl* OR doubl* OR tripl* OR trebl*) AND (blind* OR mask* OR sham*)) OR 'latin square' OR isrtcn* OR actrn* OR (nct* NOT nct)) B. MEDLINE with Ovid Syntax Question Set # Concept Strategy Question Time to repeat screening for CV risk (Note: this search builds upon the search for Questions and which include specific terms for CV risk) #1 Dyslipidemia exp dyslipidemias/ OR exp cholesterol/ OR lipids/ OR (dyslipidemia* OR dyslipidaemia* OR dyslipidproteinemia* OR dyslipidproteinaemia* OR hyperlipidemia* OR hyperlipidaemia* OR hypercholesterolemia* OR hypercholesterolaemia* OR hyperlipoproteinemia* OR hyperlipoproteinaemia* OR hypertriglyceridemia* OR hypertriglyceridaemia* OR hyperlipemia OR hyperlipaemia OR cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C").ti,ab. assessment mass screening/ or exp multiphasic screening/ OR risk assessment/ OR ((risk or risks) ADJ4 (stratify or stratifying or stratification or define or defining or predict or prediction or assess* OR classif* OR prioritiz* OR category* OR tier* OR calculat* OR index OR indices OR score OR scores OR marker* OR biomarker* OR profile* OR algorithm* OR factor* OR characteristic*)).ti,ab. OR (cardiovascular ADJ2 risk*) #3 Repeat screening/ monitoring Exp time factors/ OR Monitoring, Physiologic/ OR (rescreen* OR re-screen* OR surveillance OR re-assess* OR monitor* OR ((repeat or repet* or replicat* or redo or "re-do" or rerun or "re-run" or subsequent* or redundant* or re-assess* or reassess*OR "follow up" OR "follow-up") ADJ4 (test* or screen* OR assess*))).ti,ab. #4 Outcomes exp *Cardiovascular Diseases/pc OR exp primary prevention/ OR exp mortality/ OR exp morbidity/ OR exp death/ OR exp myocardial infarction/ OR cerebrovascular accident/ OR stroke/ OR exp Angina, Unstable/ OR (stroke* OR (cerebrovascular ADJ accident*) OR morbidity OR mortality OR death OR (heart ADJ attack*) OR (myocardial ADJ infarct*) OR ((vascular OR cardiac OR coronary OR cerebrovascular) ADJ2 event*) OR (heart ADJ infarct*)).ti,ab. OR (morbidity OR mortality OR prevent* OR outcome*).ti,ab. OR (secondary ADJ prevention).ti,ab. OR (primary ADJ prevention).ti,ab. OR angina.ti,ab. #6 Limit to RCTs/SRs/ Meta-analysis Randomized controlled trials/systematic review/meta-analysis hedge [see Search Limits at the end of this table] #7 Limit to additional study designs exp cohort studies/ OR exp longitudinal studies/ OR exp retrospective studies/ OR exp prospective studies OR exp controlled study/ or exp clinical trial/ or exp comparative study/ OR major clinical study/ OR cross-over studies/ or crossover procedure/ or cross over studies/ OR observational study/ OR validation studies/ OR exp case-control studies/ OR follow-up studies/ #9 Apply limits See Search Limits at the end of the table Question Set # Concept Strategy Question Stability of lipid levels over time #1 Dyslipidemia exp dyslipidemias/ OR exp cholesterol/ OR lipids/ OR (dyslipidemia* OR dyslipidaemia* OR dyslipidproteinemia* OR dyslipidproteinaemia* OR hyperlipidemia* OR hyperlipidaemia* OR hypercholesterolemia* OR hypercholesterolaemia* OR hyperlipoproteinemia* OR hyperlipoproteinaemia* OR hypertriglyceridemia* OR hypertriglyceridaemia* OR hyperlipemia OR hyperlipaemia OR cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C").ti,ab. #2 CVD exp *Cardiovascular Diseases/pc or cardiovascular diseases/ or heart diseases/ or vascular diseases/ or exp arterial occlusive diseases/ or cerebrovascular disorders/ or exp brain ischemia/ or exp stroke/ or exp myocardial ischemia/ or exp myocardial Infarction/ or exp heart arrest/ or exp hypertension/ or exp peripheral vascular diseases/ or ((heart* or cardio* or cardiac* or coronary or vascular or cerebrovascular or artery or arteries) ADJ5 (disease* or syndrome* or event* or ischem* or ischaem* or plaque*)).ti,ab. or (hyperten* or atherosclero* or arteriosclero* or angina or (Heart ADJ attack*) or (myocardial ADJ infarct*) or stroke* or (cerebrovascular ADJ accident*)).ti,ab. #3 Monitoring of lipid levels over time (Lipids/an,bl,td OR exp Cholesterol/an,bl,td) AND (Exp Monitoring, physiologic/ OR exp lipid analysis/ OR exp lipid metabolism/ OR Exp time factors/) OR ((cholesteryl* or cholesterol* or lipid* or lipoprotein* or tryglycer* or triaclyglycer* or "HDL-C" or "LDL-C" or "HDL C" or "LDL C" or "non HDL C" or "non-HDL C" or "non-HDL-C") ADJ5 (level or levels or blood OR value*) ADJ5 (monitor* OR surveillance OR stable OR stability OR variability OR variable OR "long term" OR "long- term" OR longitud* OR trend*)).ti,ab. #5 Limit to RCTs/SRs/ Meta-analysis Randomized controlled trials/systematic review/meta-analysis hedge [see Search Limits at the end of this table] #6 Limit to additional study designs exp cohort studies/ OR exp longitudinal studies/ OR exp retrospective studies/ OR exp prospective studies OR exp controlled study/ or exp clinical trial/ or exp comparative study/ OR major clinical study/ OR cross-over studies/ or crossover procedure/ or cross over studies/ OR observational study/ OR validation studies/ OR exp case-control studies/ #8 Apply limits See Search Limits at the end of the table Question Set # Concept Strategy Question Methods for risk stratification #1 Dyslipidemia exp dyslipidemias/ OR exp cholesterol/ OR lipids/ OR (dyslipidemia* OR dyslipidaemia* OR dyslipidproteinemia* OR dyslipidproteinaemia* OR hyperlipidemia* OR hyperlipidaemia* OR hypercholesterolemia* OR hypercholesterolaemia* OR hyperlipoproteinemia* OR hyperlipoproteinaemia* OR hypertriglyceridemia* OR hypertriglyceridaemia* OR hyperlipemia OR hyperlipaemia OR cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C").ti,ab. #2 CVD exp *Cardiovascular Diseases/ OR *heart diseases/ or *vascular diseases/ or exp *arterial occlusive diseases/ or *cerebrovascular disorders/ OR exp *brain ischemia/ or exp *stroke/ or exp *myocardial ischemia/ OR exp *myocardial Infarction/ OR exp *heart arrest/ OR exp *hypertension/ OR exp *peripheral vascular diseases/ OR ((heart* OR cardio* OR cardiac* OR coronary OR vascular OR cerebrovascular OR artery OR arteries) ADJ5 (disease* OR syndrome* OR event* OR ischem* OR ischaem* OR plaque*)).ti. OR (hyperten* OR atherosclero* OR arteriosclero* OR angina OR (Heart ADJ attack*) OR (myocardial ADJ infarct*) OR stroke* OR (cerebrovascular ADJ accident*)).ti. prediction/stratifica tion exp *risk factors/ OR exp*risk assessment/ OR ((risk or risks) ADJ4 (stratify or stratifying or stratification or define or defining or predict or prediction or assessment OR classif* OR prioritiz* OR category* OR tier* OR calculat* OR index OR indices OR score OR scores OR marker* OR biomarker* OR profile* OR algorithm* OR factor* OR characteristic*)).ti. OR (cardiovascular ADJ2 risk*).ti. #4 Risk stratification tools Lipids/an,bl OR exp Cholesterol/an,bl OR exp Ankle Brachial Index/ OR exp Galectin 3/ OR C-Reactive Protein/ OR exp Apolipoproteins B/ OR exp Carotid Intima-Media Thickness/ OR c-reactive protein/ or exp Troponin I/ OR ((framingham ADJ2 risk*) OR 'ankle brachial index' OR (coronary ADJ2 calcium) OR ('c reactive' ADJ2 protein*) OR 'hs-crp' OR 'hs crp' OR 'hscrp' OR 'ntprobnp' OR 'nt-probnp' OR 'hs-tnl' OR 'hs tnl' OR 'galecton 3' OR 'galecton-3' OR 'pooled cohort' OR (particle ADJ2 size*) OR (high ADJ sensitiv* ADJ troponin*) OR apolipoprotein* OR lipoprotein* OR (carotid ADJ1 intima* ADJ3 thickness*)).ti,ab. OR ((cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C" OR "non HDL C" OR "non-HDL C" OR "non-HDL-C") ADJ5 (level OR levels)).ti. #5 Outcomes of interest exp *Cardiovascular Diseases/pc OR exp primary prevention/ OR exp mortality/ OR exp morbidity/ OR exp death/ OR exp myocardial infarction/ OR cerebrovascular accident/ OR stroke/ OR exp Angina, Unstable/ OR (stroke* OR (cerebrovascular ADJ accident*) OR morbidity OR mortality OR death OR (heart ADJ attack*) OR (myocardial ADJ infarct*) OR ((vascular OR cardiac OR coronary OR cerebrovascular) ADJ2 event*) OR (heart ADJ infarct*)).ti,ab. OR (morbidity OR mortality OR prevent* OR outcome*).ti,ab. OR (secondary ADJ prevention).ti,ab. OR (primary ADJ prevention).ti,ab. OR angina.ti,ab. #6 Combine sets dyslipidemia terms plus CV outcomes #7 Combine sets CV terms without the outcomes string #9 Limit to RCTs/SRs/Meta- analysis Randomized controlled trials/systematic review/meta-analysis hedge [see Search Limits at the end of this table] Question Set # Concept Strategy Question Methods for risk stratification (cont.) #10 Limit to additional study designs exp cohort studies/ OR exp longitudinal studies/ OR exp retrospective studies/ OR exp prospective studies OR exp controlled study/ or exp clinical trial/ or exp comparative study/ OR major clinical study/ OR cross-over studies/ or crossover procedure/ or cross over studies/ OR observational study/ OR validation studies/ OR exp case-control studies/ti #11 Diagnostic test hedge exp diagnosis/ or di.fs. or receiver operating characteristic/ or ROC curve/ or (sensitivity/ and specificity/) or accuracy/ or diagnostic accuracy/ or precision or (prediction and forecasting) or likelihood or ((false or true) ADJ (positive or negative)) or predictive value of tests/ or exp diagnostic errors/ or exp diagnostic error/ or diagnostic accuracy/ or positive predictive value or PPV OR (predictive value of tests or receiver operating characteristic or ROC curve or (sensitivity and specificity) or accuracy or diagnostic accuracy or precision or likelihood).de. OR ((false or true) ADJ (positive or negative)).mp. #13 Apply limits See Search Limits at the end of the table Questions Pertaining to pharmacologic treatment including cost #1 Dyslipidemia exp dyslipidemias/ OR exp cholesterol/ OR exp lipids/ OR (dyslipidemia* OR dyslipidaemia* OR dyslipidproteinemia* OR dyslipidproteinaemia* OR hyperlipidemia* OR hyperlipidaemia* OR hypercholesterolemia* OR hypercholesterolaemia* OR hyperlipoproteinemia* OR hyperlipoproteinaemia* OR hypertriglyceridemia* OR hypertriglyceridaemia* OR hyperlipemia OR hyperlipaemia OR cholesteryl* OR cholesterol* OR lipid* OR lipoprotein* OR tryglycer* OR triaclyglycer* OR "HDL-C" OR "LDL-C" OR "HDL C" OR "LDL C").ti,ab. #2 CVD exp *Cardiovascular Diseases/pc OR cardiovascular diseases/ or heart diseases/ or vascular diseases/ or exp arterial occlusive diseases/ or cerebrovascular disorders/ OR exp brain ischemia/ or exp stroke/ or exp myocardial ischemia/ OR exp myocardial Infarction/ OR exp heart arrest/ OR exp hypertension/ OR exp peripheral vascular diseases/ OR ((heart* OR cardio* OR cardiac* OR coronary OR vascular OR cerebrovascular OR artery OR arteries) ADJ5 (disease* OR syndrome* OR event* OR ischem* OR ischaem* OR plaque*)).ti,ab. OR (hyperten* OR atherosclero* OR arteriosclero* OR angina OR (Heart ADJ attack*) OR (myocardial ADJ infarct*) OR stroke* OR (cerebrovascular ADJ accident*)).ti,ab. 