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. treatments: statins exp Hypolipidemic Agents/ or exp Ezetimibe, Simvastatin Drug Combination/ or exp Anticholesteremic Agents/ or exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/ or ((hydroxymethylglutaryl or hydroxy-methylglutaryl) ADJ5 (reductase ADJ inhibitor*)).ti. or "HMG CoA".ti. or (statin* or lovastatin or meglutol or pravastatin or atorvastatin or simvastatin).ti. treatments: non- statins Gemfibrozil/ or fenofibrate/ or niacin/ or exp Fatty Acids, Omega-3/ or exp Ezetimibe/ or exp Proprotein Convertase 9/tu or exp "Bile Acids and Salts"/tu OR (fibrate* or gemfibrozil or fenofibrate or bezafibrate or (nicotinic adj acid*) or niacin or (bile ADJ acid ADJ sequestrant*) or (bile ADJ acid ADJ resin*) or ezetimibe or (omega* ADJ3 fatty adj acid*) or "fish oil" or pcsk9 or pcsk-9 or "pcsk 9" or ((eicosapentaenoic or docosahexaenoic) ADJ acid*)).ti,ab. Question Set # Concept Strategy Questions Pertaining to pharmacologic treatment including cost (cont.) #5 Outcomes of interest Exp secondary prevention/ 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. OR ae.fs.OR to.fs. OR safety/ or exp patient harm/ OR ((side ADJ effect*) OR (adverse ADJ 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 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 ((high OR elevated OR low) ADJ5 (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 LDL-C or non-HDL-C goals (exp Cholesterol, HDL/bl OR exp Cholesterol, LDL/bl OR exp lipids/bl OR exp cholesterol/bl) AND (goal OR goals OR target* OR level OR levels).ti. OR ((exp Cholesterol, HDL/ OR exp Cholesterol, LDL/ OR exp lipids/ OR exp cholesterol/) AND exp goals/) 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 (goal OR goals OR target* OR level OR levels)).ti,ab. #4 Statins exp Hypolipidemic Agents/ or exp Ezetimibe, Simvastatin Drug Combination/ or exp Anticholesteremic Agents/ or exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/ or ((hydroxymethylglutaryl or hydroxy-methylglutaryl) ADJ5 (reductase ADJ inhibitor*)).ti. or "HMG CoA".ti. or (statin* or lovastatin or meglutol or pravastatin or atorvastatin or simvastatin).ti. #5 Non-statins Gemfibrozil/ or fenofibrate/ or niacin/ or exp Fatty Acids, Omega-3/ or exp Ezetimibe/ or exp Proprotein Convertase 9/tu or exp "Bile Acids and Salts"/tu OR (fibrate* or gemfibrozil or fenofibrate or bezafibrate or (nicotinic ADJ acid*) or niacin or (bile ADJ acid ADJ sequestrant*) or (bile ADJ acid ADJ resin*) or ezetimibe or (omega* ADJ3 fatty adj acid*) or "fish oil" or pcsk9 or pcsk-9 or "pcsk 9" or ((eicosapentaenoic or docosahexaenoic) ADJ acid*)).ti,ab. #6 Outcomes of interest Exp secondary prevention/ 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. OR ae.fs.OR to.fs. OR safety/ or exp patient harm/ OR ((side ADJ effect*) OR (adverse ADJ event*) OR safe OR safety).ti,ab. 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 Set # Concept Strategy Question Strategies to improve patient tolerance to statins #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. tolerance/adherenc e/ substitution (controlled terms) (exp Hypolipidemic Agents/ or exp Ezetimibe, Simvastatin Drug Combination/ or exp Anticholesteremic Agents/ or exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/) AND (exp Medication Adherence/ or exp "Treatment Adherence and Compliance"/ OR exp Drug Substitution/ OR exp Drug Administration Schedule/) tolerance/adherenc e/ substitution (keywords) (((hydroxymethylglutaryl or hydroxy-methylglutaryl) ADJ5 (reductase ADJ inhibitor*)) 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) ADJ3 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 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 CV risk (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.) AND (prevent* OR risk*).ti. supplements/ neutraceuticals exp dietary supplements/ OR exp herbal medicine/ OR exp plants, Medicinal/ OR vitamins/ OR exp plant extracts/ OR exp Fatty Acids, Omega-3/ or exp garlic/tu OR exp Dietary Fiber/tu OR exp psyllium/tu OR exp ginger/tu OR exp phytosterols/ OR exp tea/ or exp teas, herbal/ OR exp niacin/tu OR (((diet OR dietary) ADJ5 supplement*) OR neutraceutical* OR (omega* ADJ3 fatty ADJ acid*) or "fish oil" or ((eicosapentaenoic or docosahexaenoic) ADJ acid*) OR ((diet* OR soluable) ADJ5 fiber) OR garlic OR ginger OR phytosterol* OR (plant ADJ2 sterol*) OR (green ADJ tea*) OR niacin* OR psyllium).ti. #4 Diet therapy exp Diet Therapy/ or ((Diet or diets or dietary or nutrition) and ("low sodium" or "low fat" or (gluten ADJ2 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".mp. or (dietary ADJ approaches ADJ1 stop ADJ hypertension).ti. or diet*.ti. #5 Exercise exp Exercise/ OR exp Resistance Training/ 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 walk* OR weight lifting OR yoga OR swim OR swimming OR run OR running OR weight training).ti. #6 Outcomes of interest exp *Cardiovascular Diseases/pc OR Exp secondary prevention/ 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 ((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. OR angina.ti,ab. OR ae.fs.OR to.fs. OR safety/ or exp patient harm/ OR ((side ADJ effect*) OR (adverse ADJ 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 '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 2014 CPG AND (english language and humans); limit 18 to ed=20131209-2019 Exclude conference publications, books, letters, editorials, case studies, etc. NOT ("column/opinion" OR "comment/reply" OR dissertation OR editorial OR letter OR book).dt. OR book.pt. OR letter/ or editorial/ or news/ or comment/ or case report or case reports/ or note/ or conference paper/ or (letter or editorial or news or comment or case reports or conference abstract*).pt. OR (child* or teen* or adolescen* or school* or baby or babies or infant* or neonat* or pediatric* or kid or kids or preschool*).ti. Limit to meta- analyses and SRs AND ('systematic review'/exp OR 'systematic review' OR 'meta analysis'/exp OR 'meta analysis') Limit to RCTs AND (Randomized controlled trials or random allocation or double-blind method or single-blind method or placebos or cross-over studies).de. or placebo*.mp. or random*.ti. or randomized controlled trial.pt. OR crossover*.mp. or cross over.mp. or ((singl* or doubl* or tripl* or trebl*) ADJ3 (blind* or mask* or sham*)).mp. or latin square.mp. or ISRTCN or ACTRN* or (NCT* not NCT) or (clinical trials/ and random*.ti.) Appendix K: Alternative Text Description of Algorithm The following outline narratively describes the Algorithm: Management of Dyslipidemia for Cardiovascular Risk Reduction. An explanation of the purpose of the algorithms and description of the various shapes used within the algorithms can be found in the Algorithm background section. The sidebars referenced within this outline can also be found in the Algorithm background section. Algorithm: Management of Dyslipidemia for Cardiovascular Risk Reduction 1. Module A begins with Box 1, in the shape of a rounded rectangle: Patient 40 years old (There are no evidence-based recommendations for patients under age 40 because there is no evidence for the benefit of lipid screening and treatment within this age group. In patients younger than 40 years old interested in pursuing lipid testing and management, shared decision making is recommended to discuss the risks and unknown benefit of pharmacotherapy, with therapeutic lifestyle changes being the primary focus of CVD primary prevention.) 2. Box 1 connects to Box 2, in the shape of a hexagon, asks the question: Does patient have HF with EF <35%, ESRD, or life expectancy <5 years? a. If the answer is Yes to Box 2, then Box 3, in the shape of an oval: Discuss lack of evidence demonstrating benefit and continue ongoing care b. If the answer is No to Box 2, then Box 4, in the shape of a hexagon, asks the question: Does patient have higher risk CVD? (see Sidebar 2) i. If the answer is Yes to Box 4, then Box 5, in the shape of a rectangle: Recommend stepped intensification: 1. Maximize statin or add ezetimibe 2. Consider PCSK9 inhibitor only after maximizing statin and adding ezetimibe 1) Box 5 connects to Box 10, in the shape of a rectangle: If MI, ACS, or CABG/PCI in past 6 weeks, refer for cardiac rehab 2) Box 10 connects to Box 11, in the shape of a rectangle: Recommend dietitian-led Mediterranean diet for risk >12% 3) Box 11 connects to Box 12, in the shape of a rectangle: Recommend regular aerobic exercise(Suggest regular aerobic activity of any intensity or duration. Although incremental benefit is associated with increased doses of physical activity, lower doses including leisure time activity [i.e., walking, landscaping, washing dishes] are associated with benefit when compared to mostly sedentary behavior. A provider s considerations when recommending physical activity might include a patient s motivation, functional capacity, and physical activity preferences.) and smoking cessation (if applicable) 4) Box 12 connects to Box 13, in the shape of a rectangle: Follow up evaluation: 1. Primary prevention, no statin: Lipids every 10 years, recommend non- fasting; Repeat risk evaluation at Box 1: Every 2 years if 6 12%, Every 5 years if <6%, If risk factors change. 2. Secondary prevention: lipids as needed only if higher risk and willing to intensify; 3. Once on optimal therapy, no need to recheck lipids routinely ii. If the answer is No to Box 4, then Box 6, in the shape of a hexagon, asks the question: Does patient have CVD per Sidebar 1, DM, or LDL 190 mg/dL? 1) If the answer is Yes to Box 6, then Box 7, in the shape of a rectangle: Recommend moderate-dose statin (see Sidebar 3) 2) If the answer is No to Box 6, then Box 8, in the shape of a hexagon, asks the question: Is patient s 10-year CVD risk >12%? a) If the answer is Yes to Box 8, then Box 7, in the shape of a rectangle: Recommend moderate-dose statin (see Sidebar 3) b) If the answer is No to Box 8, then Box 9, in the shape of a hexagon, asks the question: Is patient s 10-year risk 6 12% and does patient prefer statin treatment? i) If the answer is Yes to Box 9, then Box 7, in the shape of a rectangle: Recommend moderate-dose statin (see ii) If the answer is No to Box 9, then Box 12, in the shape of a rectangle: Recommend regular aerobic exercise (Suggest regular aerobic activity of any intensity or duration. Although incremental benefit is associated with increased doses of physical activity, lower doses including leisure time activity [i.e., walking, landscaping, washing dishes] are associated with benefit when compared to mostly sedentary behavior. A provider s considerations when recommending physical activity might include a patient s motivation, functional capacity, and physical activity preferences.) and smoking cessation (if applicable) (1) Box 12 connects to Box 13, in the shape of a rectangle: Follow up evaluation: 1. Primary prevention, no statin: Lipids every 10 years, recommend non-fasting; Repeat risk evaluation at If risk factors change. 2. Secondary prevention: lipids as needed only if higher risk and willing to intensify; 3. Once on optimal therapy, no need to recheck lipids routinely 3. Box 7 connects to Box 11, in the shape of a rectangle: Recommend dietitian-led Mediterranean diet for risk >12% 4. Box 11 connects to Box 12, in the shape of a rectangle: Recommend regular aerobic exercise (Suggest regular aerobic activity of any intensity or duration. Although incremental benefit is associated with increased doses of physical activity, lower doses including leisure time activity [i.e., walking, landscaping, washing dishes] are associated with benefit when compared to mostly sedentary behavior. A provider s considerations when recommending physical activity might include a patient s motivation, functional capacity, and physical activity preferences.) and smoking cessation (if applicable) 5. Box 12 connects to Box 13, in the shape of a rectangle: Follow up evaluation: 1. Primary prevention, no statin: Lipids every 10 years, recommend non-fasting; Repeat risk evaluation at Box 1: Every 2 years if 6 12%, Every 5 years if <6%, If risk factors change. 2. Secondary prevention: lipids as needed only if higher risk and willing to intensify; 3. 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