The efficacy of proposed adjusted statin dosing schedules, such as intermittent dosing, should be studied with respect to both adherence and patient-oriented outcomes. Studies should verify the washout period that is frequently employed and prospectively evaluate the theoretical reduction in statin-induced myopathy with vitamin D supplementation. F. Prospective Comparative Study of Risk Prediction Strategies Among intermediate-risk populations for whom there is less certainty regarding the risk-benefit ratio of statins, some have advocated for tests that further refine risk. To date, the best candidate for such further risk stratification is CAC scoring using ultrafast computed tomography, which has been shown to improve the AUC for diagnosis by about 5% and result in a net reclassification of about 15 20% of patients. While more patients will be identified to be at risk for an event, CAC scoring will also falsely label seven patients at high risk for a coronary event for every true high risk patient identified. Only prospective studies that directly compare risk assessment strategies (conventional risk assessment and CAC scoring compared to conventional risk assessment only) as the basis for treatment decisions among primary prevention patients will truly answer this question. Such studies have been proposed and designed but involve very large populations (n=30,000) and a prohibitive cost.[148] G. Prospective Comparison of Risk Calculators in Varied Populations The use of electronic medical records (EMR) within large organizations (e.g., VHA, MHS) creates an opportunity to create large prospective data sets. One opportunity is for the EMR to calculate risk scores and longitudinally track patients. These large data sets would help determine the overall accuracy of risk calculators and the effect of gender, ethnicity, and other factors on these risk estimates. H. Pragmatic, Evidence-based Dietary Studies Studies of dietary interventions are problematic because of adherence and monitoring issues.


H. Pragmatic, Evidence-based Dietary Studies Studies of dietary interventions are problematic because of adherence and monitoring issues. The best study would be carefully monitored by a dietitian yet it would be impractical to have every patient pursue a dietitian-led plan. The other issue is the specific elements of the dietary program. This is seen primarily in the low saturated fat dietary intervention, where the replacement of saturated fat with polyunsaturated fat appears beneficial in men only. There is more evidence for the Mediterranean diet, which includes a high level of plant-based foods and low levels of saturated fats (replaced by monounsaturated and polyunsaturated fats). More study of the replacement of saturated fats with polyunsaturated fats alone and large, pragmatic dietary studies could help resolve the issues. There is also a need to study a whole- food, plant-based dietary strategy for CVD risk reduction in primary prevention. I. Comparative Studies of Cardiac Rehabilitation Programs While strong evidence supports the use of cardiac rehabilitation programs shortly after coronary events or revascularization procedures, there is little comparison of the elements of these programs. A comparison of different programs could help determine the most cost-effective form of rehabilitation. Appendix A: Evidence Review Methodology A. Developing the Key Questions The CPG Champions, along with the Work Group, were tasked with identifying KQs to guide the systematic evidence review on the management of dyslipidemia. These questions, which were developed in consultation with the Lewin Team, addressed clinical topics of the highest priority for the VA and DoD populations. The KQs follow the population, intervention, comparison, outcome, timing, and setting (PICOTS) framework for evidence questions, as established by the Agency for Healthcare Research and Quality (AHRQ). Table A-1 provides a brief overview of the PICOTS typology.


Table A-1 provides a brief overview of the PICOTS typology. PICOTS Elements Description Patients, Population, or Problem Describes the patients of interest. It includes the condition(s), populations or sub-populations, disease severity or stage, co-occurring conditions, and other patient characteristics or demographics. Intervention or Exposure Refers to the specific treatments or approaches used with the patient or population. It includes doses, frequency, methods of administering treatments, etc. Comparison Describes the interventions or care that is being compared with the intervention(s) of interest described above. It includes alternatives such as placebo, drugs, surgery, lifestyle changes, standard of care, etc. Outcome Describes the specific results of interest. Outcomes can include short, intermediate, and long-term outcomes, or specific results such as quality of life, complications, mortality, morbidity, etc. Timing, if applicable Describes the duration of time that is of interest for the particular patient intervention and outcome, benefit, or harm to occur (or not occur). Setting, if applicable Describes the setting or context of interest. Setting can be a location (such as primary, specialty, or inpatient care). Abbreviations: PICOTS: population, intervention, comparison, outcome, timing, and setting The Champions, Work Group, and evidence review team carried out several iterations of this process, each time narrowing the CPG s scope and literature review by prioritizing topics of interest. As a result of resource constraints, all developed KQs were not able to be included in the systematic evidence review. Thus, the Champions and Work Group determined which questions were of highest priority and those were included in the review. Table A-2 contains the final set of KQs used to guide this CPG s systematic evidence review. Once the KQs were finalized, the Work Group prioritized the outcomes they had defined for each KQ based on how important the Work Group judged each outcome to be.


Once the KQs were finalized, the Work Group prioritized the outcomes they had defined for each KQ based on how important the Work Group judged each outcome to be. Ranking outcomes by their relative importance can help focus attention on those outcomes that are considered most important for clinical decision making when making judgments regarding the overall quality of the evidence to support a Using GRADE methodology, the Work Group rated each outcome on a 1 9 scale (7 9, critical for decision making; 4 6, important, but not critical, for decision making; and 1 3, of limited importance for decision making). Critical and important outcomes were included in the evidence review (see Outcomes); however, only outcomes judged to be critical were used to determine the overall quality of evidence (see Grading Recommendations). a. Population(s) Key Question 1: Individuals previously screened for CVD risk and with risk score below 10 20% Key Question 2: All adults Key Question 3: All adults eligible for primary prevention Specific to adults who are at risk of CVD or already have dyslipidemia Key Question 8: Patients who have been taking a statin for 3 or more years for primary or secondary prevention b. Interventions Key Question 1: Repeat CVD risk assessment Key Question 2: Lipid lab test Key Question 3 CV risk stratification: Use of risk models (e.g., pooled cohort risk score versus FRS versus biology-based risk assessment).


, pooled cohort risk score versus FRS versus biology-based risk assessment). (1) Framingham score, (2) pooled cohort risk score, (3) novel markers Key Question 4 Pharmacotherapy: Statins Ezetimibe Bile acid sequestrants Niacin Fibrates Omega-3 fatty acids Bempedoic acid Key Question 5 Treating to goals with pharmacotherapy: LDL goal of <100 mg/dL or <70 mg/dL and non-HDL goal of <130 mg/dL or <100 mg/dL Low HDL or high TGs (150 499 mg/dL) Key Question 6 Pharmacotherapy: High dose/intensity statins or ezetimibe, PCSK9 inhibitors, bile acid sequestrant, niacin, fibrate, or fish oils added to statins LDL <70 or <100 and non-HDL <100 or 130 mg/dL Intensified treatment Lower LDL or non-HDL goals Key Question 7 Pharmacotherapy: Statin-Associated Muscle Symptom Clinical Index tool, measurement of CK levels assessment for myalgia and risk factors Alternative day statin therapy Switching to a different statin Lowering the dose Combination therapy after dose reduction or a change in drug Optimize vitamin D status using supplements Key Question 8: Stop statin use Key Question 9: Lipid interventions (pharmacologic and non-pharmacologic) Key Question 10 Dietary supplements: Red yeast rice Soluble fiber Garlic Ginger Plant sterols Green tea Niacin Key Question 11: Different dietary therapies (Mediterranean, vegetarian, vegan, low-fat, or DASH diet) Registered dietitian (RD) providing individualized counseling Key Question 12 Physical activity: Resistance training Aerobic exercise (no specification on duration, intensity) c. Comparators Key Question 1: No repeat testing Key Question 2: Previous lab test from same individual over varying time frames Key Question 3: Usual care No formal stratification Different stratification tool Key Question 4: Placebo Another medication class Another medication within the same class A different dose of the same medication Key Question 5: Treating without consideration of reaching lipid goal(s) but based on dosage Key Question 6: Control (less intense or no added therapy) Higher LDL or non-HDL goals Key Question 7: No intervention to improve statin tolerance Key Question 8: Continue statin use Key Question 9: Usual care (placebo, lower intensity statin; or high intensity statin if add-on comparison such as ezetimibe, PCSK9, fibrate, niacin, etc.)


Key Question 10: Placebo or different dietary supplement(s) Key Question 11: Different dietary therapy or no dietary therapy Different health professional other than an RD Key Question 12: No exercise No routine exercise Different type of exercise d. Outcomes Key Question 1: Critical outcomes CV mortality Important outcomes Composite CV outcomes (as defined as the a priori outcome by individual studies) that could include any of the following: unstable angina, AMI, revascularization, stroke, CV mortality, all-cause mortality AMI fatal or non-fatal Stroke fatal or non-fatal All-cause mortality Changing risk stratification, reclassification of CV risk Time to crossing to a different treatment threshold Key Question 2: Critical outcomes Change in lab value over time Key Question 3: Critical outcomes Test characteristics (AUC, specificity, sensitivity, positive predictive value, negative predictive value, etc.) Important outcomes Changing risk stratification, reclassification of CV risk Critical outcomes CV mortality Important outcomes Composite CV outcomes (as defined as the a priori outcome by individual studies) that could include any of the following: unstable angina, AMI, revascularization, stroke, CV mortality, all-cause mortality AMI fatal or non-fatal Stroke fatal or non-fatal All-cause mortality Key Question 7: Critical outcomes Adherence to lipid therapy medication >85% @ 1 year Important outcomes Changes in lipid levels (total-, LDL-, HDL-cholesterol, non-HDL cholesterol, TGs) Key Question 9: Critical outcomes Marginal cost-effectiveness Important outcomes Thresholds of cost-effectiveness for cost, effectiveness, utilities Sensitivity of cost-effectiveness to cost and effectiveness (ARR, RRR) e. Timing Key Question 1: 3 years follow-up No minimum follow-up Key Questions 4 6: 1 year follow-up Key Questions 8, 9: Lifetime horizon f. Settings Outpatient primary care (Key Question 2 also includes laboratory setting) B.


Important outcomes Changing risk stratification, reclassification of CV risk Critical outcomes CV mortality Important outcomes Composite CV outcomes (as defined as the a priori outcome by individual studies) that could include any of the following: unstable angina, AMI, revascularization, stroke, CV mortality, all-cause mortality AMI fatal or non-fatal Stroke fatal or non-fatal All-cause mortality Key Question 7: Critical outcomes Adherence to lipid therapy medication >85% @ 1 year Important outcomes Changes in lipid levels (total-, LDL-, HDL-cholesterol, non-HDL cholesterol, TGs) Key Question 9: Critical outcomes Marginal cost-effectiveness Important outcomes Thresholds of cost-effectiveness for cost, effectiveness, utilities Sensitivity of cost-effectiveness to cost and effectiveness (ARR, RRR) e. Timing Key Question 1: 3 years follow-up No minimum follow-up Key Questions 4 6: 1 year follow-up Key Questions 8, 9: Lifetime horizon f. Settings Outpatient primary care (Key Question 2 also includes laboratory setting) B. Conducting the Systematic Evidence Review Based on the decisions made by the Champions and Work Group members regarding the scope, the KQs, and the PICOTS statements, the Lewin Team produced a systematic evidence review protocol prior to conducting the review. The protocol was reviewed and approved by the Champions and Work Group members. It described in detail the final set of KQs, the methodology to be used during the systematic evidence review process, and the inclusion/exclusion criteria to be applied to each potential study, including, but not limited to, study type, sample size, and PICOTS criteria. Extensive literature searches identified 16,836 citations potentially addressing the KQs of interest to this evidence review. Of those, 4,831 were excluded upon title review for clearly not meeting inclusion criteria (e.g., not pertinent to the topic, not published in English, published prior to study inclusion publication date, or not a full-length article).


, not pertinent to the topic, not published in English, published prior to study inclusion publication date, or not a full-length article). Overall, 12,005 abstracts were reviewed with 11,142 of those being excluded for the following reasons: not a systematic review or an accepted study design (see the General Criteria for Inclusion in Systematic Review and Key Question Specific Criteria), did not address a KQ of interest to this review, did not report on an outcome of interest, or published outside cut-off publication dates. A total of 863 full-length articles were reviewed. Of those, 439 were excluded at a first pass review for the following: not addressing a KQ of interest, not enrolling the population of interest, not meeting inclusion criteria for study design, not meeting inclusion criteria for any KQ, or being a duplicate. A total of 424 full-length articles were thought to address one or more KQs and were further reviewed. Of these, 283 were ultimately excluded. Reasons for their exclusion are presented below in Figure A-1. Overall, 141 studies addressed one or more of the KQs and were considered as evidence in this review. Table A-2 indicates the number of studies that addressed each of the questions. Figure A-1. Study Flow Diagram Abbreviations: CS: clinical study; KQ: key question; SR: systematic review Alternative Text Description of Study Flow Diagram Figure A-1. Study Flow Diagram is a flow chart with nine labeled boxes linked by arrows that describe the literature review inclusion/exclusion process. Arrows point down to boxes that describe the next literature review step and arrows point right to boxes that describe the excluded citations at each step (including the reasons for exclusion and the numbers of excluded citations). 1. Box 1: 16,836 citations identified by searches a.


Arrows point down to boxes that describe the next literature review step and arrows point right to boxes that describe the excluded citations at each step (including the reasons for exclusion and the numbers of excluded citations). 1. Box 1: 16,836 citations identified by searches a. Right to Box 2: 4,831 citations excluded at the title level i. Citations excluded at this level were off-topic, not published in English, or published prior to inclusion date b. Down to Box 3 a. Right to Box 4: 11,142 citations excluded at the abstract level i. Citations excluded at this level were not an SR or clinical study, clearly did not address a KQ, did not report on an outcome of interest, or were outside cutoff publication dates b. Down to Box 5 a. Right to Box 6: 439 citations excluded at 1st pass full article level i. Articles excluded at this level did not: address a key question of interest, enroll the population of interest, meet inclusion criteria for clinical study or SR, meet inclusion criteria for any key question, or were a duplicate b. Down to Box 7 a. Right to Box 8: 283 citations excluded at 2nd pass KQ level i. 175 not a study design, setting, or population of interest ii. 71 superseded by more comprehensive review or included in an SR iii. 33 not a comparison of interest iv. 4 other (e.g., not published in English, not a clinical trial or SR, published outside date range) b. Down to Box 9 Table A-2.


, not published in English, not a clinical trial or SR, published outside date range) b. Down to Box 9 Table A-2. Evidence Base for KQs Question Number Question Number of Studies & Type of Studies What is the optimal time to repeat screening for cardiovascular risk, including lipid level and taking into consideration variability of lipid levels over time, on identification of individuals who would benefit from pharmacologic and non-pharmacologic dyslipidemia treatment and on cardiovascular outcomes? Does this vary by age group (20 to 39 years, 40 to 54/64 years, 55/65 to 79 years, 80 years and above), sex, or co-morbid conditions (e.g., diabetes, hypertension, CKD)? 2 cohort studies 2 What is the variability/stability of lipid levels over time? modeling study What is the optimal method to stratify cardiovascular risks, including a combination of classic (e.g., fasting and non-fasting lipid levels, age, sex, smoking history, diabetes, hypertension) and novel (e.g., CAC, IMT, hsCRP, particle size, ABI, coronary CT calcium score, apolipoprotein B, lipoprotein(a), hsCRP, NT proBNP, hs-TnI (high sensitivity troponin I), galectin-3) risk markers or risk calculators, in order to inform pharmacologic and non-pharmacologic treatment for dyslipidemia (e.g., initiating treatment, choice of treatment, or intensity/dosage)? 2 SRs and 11 model performance studies Among patients at risk of CVD, including patients with dyslipidemia, what is the effectiveness (vs. placebo), comparative effectiveness (vs. another medication class, another medication within the same class, a different dose of the same medication), and safety of pharmacotherapy (e.g., statins, PCSK9 inhibitors, ezetimibe, bile acid sequestrant, niacin, fibrate, omega-3, bempedoic acid) on cardiovascular outcomes? Does this vary by patients age, gender, co-morbid conditions (e.g., diabetes, hypertension, CKD), cardiovascular risk, intolerance to statins, or other patients characteristics, or for primary vs. secondary prevention?


, diabetes, hypertension, CKD), cardiovascular risk, intolerance to statins, or other patients characteristics, or for primary vs. secondary prevention? observational follow-ups of RCT cohorts What is the comparative effectiveness and safety of treating to reach specific LDL-C or non-HDL-C goals or based only on initial cardiovascular risk assessment? Does this vary by patients age, gender, co-morbid conditions (e.g., diabetes, hypertension, CKD, CHF), cardiovascular risk, intolerance to statins, or other patients characteristics, or for primary vs. secondary prevention? 4 SRs and 2 RCTs What is the effectiveness and safety of intensifying treatment by adding non-statins (i.e., ezetimibe, PCSK9 inhibitor, bile acid sequestrant, niacin, fibrate or fish oils) to statins, increasing statins dose, or using lower LDL-C or non-HDL-C goals to improve cardiovascular outcomes? Does this vary by patients age, gender, co-morbid conditions (e.g., diabetes, hypertension, CKD, CHF), cardiovascular risk, intolerance to statins, or other patients characteristics, or for primary vs. secondary prevention? label extensions of RCTs Among patients at risk of CVD, including patients with dyslipidemia on statin, but who do not tolerate statin well, what is the effectiveness of various strategies (e.g., education, switching statins, use of lower doses, alternate day dosing) to improve patients tolerance to statins, adherence, or to allow statin dose increase? studies What is the safety and efficacy of stopping statins for dyslipidemia among patients who have been on a statin? 2 SRs and 1 RCT What is the cost-effectiveness of various pharmacologic (PCSK9 inhibitors, statins) and non-pharmacologic treatment? 2 SRs and 3 cost- effectiveness studies Question Number Question Number of Studies & Type of Studies What is the effectiveness (vs. placebo), comparative effectiveness (vs. another dietary supplement/nutraceutical), and safety of dietary supplements/nutraceuticals (e.g., Omega-3, red yeast rice, soluble fiber, garlic, ginger, plant sterols, green tea, niacin) on cardiovascular outcomes?


, Omega-3, red yeast rice, soluble fiber, garlic, ginger, plant sterols, green tea, niacin) on cardiovascular outcomes? 7 SRs and 1 RCT What is the effectiveness (vs. no intervention), comparative effectiveness (vs. a different dietary intervention), and safety of dietary therapy on cardiovascular outcomes? Does this vary by type of dietary therapy (e.g., Mediterranean, vegetarian, vegan, low-fat, or DASH diet), who is delivering the intervention (e.g., RD, or other health professionals), whether the intervention is standardized or individualized, patients age, gender, co-morbid conditions (e.g., diabetes, hypertension, CKD), cardiovascular risk, or for primary vs. secondary prevention? What is the efficacy and safety of various forms of physical activity, including both aerobic exercise and resistance training, for primary and secondary prevention in patients with dyslipidemia? 3 SRs and 24 cohort studies Total Evidence Base 141 studies (some studies addressed more than 1 KQ) Abbreviations: ABI: ankle-brachial index; CAC: coronary artery calcium; CHF: congestive heart failure; CKD: chronic kidney disease; CT: computerized tomography; CVD: cardiovascular disease; DASH: Dietary Approaches to Stop Hypertension; HDL-C: high-density lipoprotein cholesterol; hsCRP: high-sensitivity C-reactive protein; hs-TnI: high-sensitivity troponin; IMT: intima-media thickness; LDL-C: low-density lipoprotein cholesterol; NT proBNP: N-terminal pro b-type natriuretic peptide; PCSK9: proprotein convertase subtilisin/kexin type 9; RCT: randomized controlled trial; RD: registered dietitian; SR: systematic review; vs.: versus a. General Criteria for Inclusion in Systematic Review Clinical studies or SRs published on or after December 1, 2013, to May 16, 2019. If multiple SRs addressed a KQ, we selected the most recent and/or comprehensive review. SRs were supplemented with clinical studies published after the SR. Studies must be published in English. Publication must have been a full clinical study or SR; abstracts alone were not included. Similarly, letters, editorials, and other publications that are not full-length clinical studies were not accepted as evidence.


Similarly, letters, editorials, and other publications that are not full-length clinical studies were not accepted as evidence. SRs must have searched MEDLINE or EMBASE for eligible publications, performed a risk of bias assessment of included studies, and assessed the quality of evidence using a recognizable rating system, such as GRADE or something compatible (e.g., the one used by the AHRQ Evidence- based Practice Centers). If an existing review did not assess the overall quality of the evidence, evidence from the review must be reported in a manner that allowed us to judge the overall risk of bias, consistency, directness, and precision of evidence. We did not use an existing review as evidence if we were not able to assess the overall quality of the evidence in the review. Intervention studies must assess pharmacologic or non-pharmacologic treatment or evaluated the variability of lipid levels over time, effectiveness of CVD risk screening, timing of repeat screening for CVD risk assessment, or risk stratification methods. See Key Question Specific Criteria for additional study designs. Study must have enrolled at least 20 patients (10 per study group) unless otherwise noted (see Key Question Specific Criteria). Study must have enrolled at least 85% of patients who meet the study population criteria: adults aged 18 years or older at risk for CVD. Study must have reported on at least one outcome of interest. b. Key Question Specific Criteria For KQ 1, SRs of RCTs or comparative observational studies and individual RCTs or comparative observational studies not included in SRs were required. For KQ 2, SRs of clinical or lab-based observational repeated measures studies, or individual studies of these designs not included in SRs were required.


For KQ 2, SRs of clinical or lab-based observational repeated measures studies, or individual studies of these designs not included in SRs were required. For KQ 3, SRs of RCTs and/or prognostic cohort studies and individual RCTs and prognostic cohort studies not included in SRs were required. For KQs 4 and 6, SRs of RCTs (for efficacy or long-term safety) and/or observational cohort/case- control studies (for long-term safety) and individual RCTs (for efficacy or long-term safety) and observational cohort/case-control studies (for long-term safety) not included in SRs were required. For KQs 5, 7, 8, 10, and 11, SRs of RCTs and individual RCTs not included in SRs were required. For KQ 9, SRs of cost-effectiveness studies and individual cost-effectiveness studies not included in SRs were required. For KQ 12, SRs of RCTs and comparative prospective cohort studies and individual RCTs and comparative prospective cohort studies not included in SRs were required. Information regarding the bibliographic databases, date limits, and platform/provider can be found in Table A-3, below. Additional information on the search strategies, including topic-specific search terms and search strategies, can be found in Appendix J. Table A-3.


Additional information on the search strategies, including topic-specific search terms and search strategies, can be found in Appendix J. Table A-3. Bibliographic Database Information Name Date Limits Platform/Provider Cochrane Database of Systematic Reviews (Cochrane Reviews) Cochrane Central Register of Controlled Trials December 1, 2013, to May 16, 2019 Wiley Database of Abstracts of Reviews of Effects December 1, 2013, to May 16, 2019 Wiley EMBASE (Excerpta Medica) December 1, 2013, to May 16, 2019 Elsevier Health Technology Assessment Database (HTA) December 1, 2013, to May 16, 2019 Wiley PubMed (In-process and Publisher records) December 1, 2013, to May 16, 2019 National Library of Medicine C. Convening the Face-to-face Meeting In consultation with the COR, the Champions, and the Work Group, the Lewin Team convened a three and one-half day face-to-face meeting of the CPG Champions and Work Group members on August 6 9, 2019. These experts were developed and drafted the clinical recommendations for an update to the 2014 VA/DoD Dyslipidemia CPG. Lewin presented findings from the evidence review in order to facilitate and inform the process. Under the direction of the Champions, the Work Group members were charged with interpreting the results of the evidence review and asked to categorize and carry forward recommendations from the 2014 VA/DoD Dyslipidemia CPG, modifying the recommendations as necessary. The Work Grop also developed new clinical practice recommendations not presented in the 2014 VA/DoD Dyslipidemia CPG based on the 2019 evidence review. The subject matter experts were divided into three smaller subgroups. As the Work Group members drafted clinical practice recommendations, they also assigned a rating for each recommendation based on a modified GRADE and USPSTF methodology.


As the Work Group members drafted clinical practice recommendations, they also assigned a rating for each recommendation based on a modified GRADE and USPSTF methodology. Each recommendation was rated by assessing the quality of the overall evidence base, the associated benefits and harms, the variation in values and preferences, and other implications of the recommendation. In addition to developing recommendations, the Work Group also revised the 2014 VA/DoD Dyslipidemia CPG algorithm to reflect the new and amended recommendations. To update the algorithms, they discussed the available evidence and changes in clinical practice since 2014. D. Grading Recommendations This CPG uses the GRADE methodology to assess the quality of the evidence base and assign a strength for each recommendation. The GRADE system uses the following four domains to assess the strength of each Balance of desirable and undesirable outcomes Confidence in the quality of the evidence Values and preferences Other implications, as appropriate, e.g.,: Resource use Equity Acceptability Feasibility Subgroup considerations The following sections further describe each domain. Balance of desirable and undesirable outcomes refers to the size of anticipated benefits (e.g., increased longevity, reduction in morbid event, resolution of symptoms, improved quality of life, decreased resource use) and harms (e.g., decreased longevity, immediate serious complications, adverse event, impaired quality of life, increased resource use, inconvenience/hassle) relative to each other. This domain is based on the understanding that the majority of clinicians will offer patients therapeutic or preventive measures as long as the advantages of the intervention exceed the risks and adverse effects. The certainty or uncertainty of the clinician about the risk-benefit balance will greatly influence the strength of the recommendation.


The certainty or uncertainty of the clinician about the risk-benefit balance will greatly influence the strength of the recommendation. Some of the discussion questions that fall under this domain include: Given the best estimate of typical values and preferences, are you confident that the benefits outweigh the harms and burden or vice versa? Are the desirable anticipated effects large? Are the undesirable anticipated effects small? Are the desirable effects large relative to undesirable effects? Confidence in the quality of the evidence reflects the quality of the evidence base and the certainty in that evidence. This second domain reflects the methodological quality of the studies for each outcome variable. In general, the strength of recommendation follows the level of evidence, but not always, as other domains may increase or decrease the strength. The evidence review used for the development of recommendations, conducted by ECRI, assessed the confidence in the quality of the evidence base using GRADE methodology and assigned a rating of High, Moderate, Low, or Very Low. The outcomes judged to be critical were used to determine the overall quality of evidence. Per GRADE, if the quality of evidence differs across the critical outcomes, the lowest quality of evidence for any of the relevant critical outcomes determines the overall quality of the evidence for a recommendation; the overall confidence cannot be higher than the lowest confidence in effect estimates for any outcome that is determined to be critical for clinical decision making.[12,150] The elements that go into the confidence in the quality of the evidence include: Is there high or moderate quality evidence that answers this question? What is the overall certainty of this evidence? Values and preferences is an overarching term that includes patients perspectives, beliefs, expectations, and goals for health and life.


Values and preferences is an overarching term that includes patients perspectives, beliefs, expectations, and goals for health and life. More precisely, it refers to the processes that individuals use in considering the potential benefits, harms, costs, limitations, and inconvenience of the therapeutic or preventive measures in relation to one another. For some, the term values has the closest connotation to these processes. For others, the connotation of preferences best captures the notion of choice. In general, values and preferences increase the strength of the recommendation when there is high concordance and decrease it when there is great variability. In a situation in which the balance of benefits and risks are uncertain, eliciting the values and preferences of patients and empowering them and their surrogates to make decisions consistent with their goals of care becomes even more important. A recommendation can be described as having similar values, some variation, or large variation in typical values and preferences between patients and the larger populations of interest. Some of the discussion questions that fall under the purview of values and preferences include: Are you confident about the typical values and preferences and are they similar across the target population? What are the patient s values and preferences? Are the assumed or identified relative values similar across the target population? Other implications consider the practicality of the recommendation, including resource use, equity, acceptability, feasibility, and subgroup considerations. Resource use is related to the uncertainty around the cost-effectiveness of a therapeutic or preventive measure. For example, statin use in the frail elderly and others with multiple co-occurring conditions may not be effective and, depending on the societal benchmark for willingness to pay, may not be a good use of resources. Equity, acceptability, feasibility, and subgroup considerations require similar judgments around the practicality of the recommendation.


Equity, acceptability, feasibility, and subgroup considerations require similar judgments around the practicality of the recommendation. The Work Group used the framework below (Table A-4) to guide discussions on each domain. Table A-4. GRADE Evidence to Recommendation Framework Decision Domain Questions to Consider Judgment Balance of desirable and undesirable outcomes Given the best estimate of typical values and preferences, are you confident that the benefits outweigh the harms and burden or vice versa? Are the desirable anticipated effects large? Are the undesirable anticipated effects small? Are the desirable effects large relative to undesirable effects? Benefits outweigh harms/burden Benefits slightly outweigh harms/ burden Benefits and harms/burden are balanced Harms/burden slightly outweigh benefits Harms/burden outweigh benefits Confidence in the quality of the evidence Is there high or moderate quality evidence that answers this question? What is the overall certainty of this evidence? High Moderate Low Very low Values and preferences Are you confident about the typical values and preferences and are they similar across the target population? What are the patient s values and preferences? Are the assumed or identified relative values similar across the target population? Similar values Some variation Large variation Other implications (e.g., resource use, equity, acceptability, feasibility, subgroup considerations) Are the resources worth the expected net benefit from the recommendation? What are the costs per resource unit? Is this intervention generally available? Is this intervention and its effects worth withdrawing or not allocating resources from other interventions? Is there lots of variability in resource requirements across settings? Various considerations The strength of a recommendation is defined as the extent to which one can be confident that the desirable effects of an intervention outweigh its undesirable effects and is based on the framework above, which combines the four domains.


Various considerations The strength of a recommendation is defined as the extent to which one can be confident that the desirable effects of an intervention outweigh its undesirable effects and is based on the framework above, which combines the four domains.[151] GRADE methodology does not allow for recommendations to be made based on expert opinion alone. While strong recommendations are usually based on high or moderate confidence in the estimates of effect (quality of the evidence) there may be instances where strong recommendations are warranted even when the quality of evidence is low.[5] In these types of instances where the balance of desirable and undesirable outcomes and values and preferences played large roles in determining the strength of a recommendation, this is explained in the discussion section for the recommendation. The GRADE of a recommendation is based on the following elements: Four decision domains used to determine the strength and direction (described above) Relative strength ( Strong or Weak ) Direction ( For or Against ) The relative strength of the recommendation is based on a binary scale, Strong or Weak. A strong recommendation indicates that the Work Group is highly confident that desirable outcomes outweigh undesirable outcomes. If the Work Group is less confident in the balance between desirable and undesirable outcomes, they present a weak recommendation. Similarly, a recommendation for a therapy or preventive measure indicates that the desirable consequences outweigh the undesirable consequences. A recommendation against a therapy or preventive measure indicates that the undesirable consequences outweigh the desirable consequences. Occasionally, instances may occur when the Work Group feels there is insufficient evidence to make a recommendation for or against a particular therapy or preventive measure.


Occasionally, instances may occur when the Work Group feels there is insufficient evidence to make a recommendation for or against a particular therapy or preventive measure. This can occur when there is an absence of studies on a particular topic that met evidence review inclusion criteria, studies included in the evidence review report conflicting results, or studies included in the evidence review report inconclusive results regarding the desirable and undesirable outcomes. Using these elements, the grade of each recommendation is presented as part of a continuum: Strong for (or We recommend offering this option ) Weak for (or We suggest offering this option ) No recommendation for or against (or There is insufficient evidence ) Weak against (or We suggest against offering this option ) Strong against (or We recommend against offering this option ) Note that weak (For or Against) recommendations may also be termed Conditional, Discretionary, or Qualified. Recommendations may be conditional based upon patient values and preferences, the resources available, or the setting in which the intervention will be implemented. Recommendations may be at the discretion of the patient and clinician or they may be qualified with an explanation about the issues that would lead decisions to vary. E. Recommendation Categorization a. Recommendation Categories and Definitions A set of recommendation categories was adapted from those used by NICE.[8,9] These categories, along with their corresponding definitions, were used to account for the various ways in which recommendations could have been updated from the 2014 VA/DoD Dyslipidemia CPG. The categories and definitions can be found in Table A-5. Table A-5.


The categories and definitions can be found in Table A-5. Table A-5. Recommendation Categories and Definitions* Evidence Reviewed Recommendation Category Definition Reviewed New-added New recommendation following review of the evidence New-replaced Recommendation from previous CPG that has been carried over to the updated CPG that has been changed following review of the evidence Not changed Recommendation from previous CPG that has been carried forward to the updated CPG where the evidence has been reviewed but the recommendation was not changed Amended Recommendation from previous CPG that has been carried forward to the updated CPG where the evidence has been reviewed and a minor amendment was made Deleted Recommendation from previous CPG that has been removed based on review of the evidence Not reviewed Not changed Recommendation from previous CPG that has been carried forward to the updated CPG, but for which the evidence has not been reviewed Amended Recommendation from previous CPG that has been carried forward to the updated CPG where the evidence has not been reviewed and a minor amendment has been made Deleted Recommendation from previous CPG that has been removed because it was deemed out of scope for the updated CPG * Adapted from the NICE guideline manual (2012) [8] and Garcia et al. (2014) [9] Abbreviations: CPG: clinical practice guideline; NICE: National Institute for Health and Care Excellence b. Categorizing Recommendations with an Updated Review of the Evidence Recommendations were first categorized by whether or not they were based on an updated review of the evidence. If evidence had been reviewed, recommendations were categorized as New-added, New- replaced, Not changed, Amended, or Deleted. Reviewed, New-added recommendations were original, new recommendations that were not in the 2014 VA/DoD Dyslipidemia CPG.


Reviewed, New-added recommendations were original, new recommendations that were not in the 2014 VA/DoD Dyslipidemia CPG. Reviewed, New-replaced recommendations were in the previous version of the guideline but were modified to align with the updated review of the evidence. These recommendations could have also included clinically significant changes to the previous version. Recommendations categorized as Reviewed, Not changed were carried forward from the previous version of the CPG unchanged. For recommendations carried forward to the updated CPG with a review of the evidence and slightly modified wording, the Reviewed, Amended recommendation category was used. This allowed for the wording of the recommendation to reflect GRADE methodology as well as for any other non-substantive (i.e., not clinically meaningful) language changes deemed necessary. The evidence used to support these recommendations was carried forward from the previous version of the CPG and/or was identified in the evidence review for the update. Recommendations could have also been designated Reviewed, Deleted. These were recommendations from the previous version of the CPG that were not brought forward to the updated guideline after review of the evidence. This occurred if the evidence supporting the recommendations was out of date, to the extent that there was no longer any basis to recommend a particular course of care and/or new evidence suggests a shift in care, rendering recommendations in the previous version of the guideline obsolete. c. Categorizing Recommendations without an Updated Review of the Evidence There were also cases in which it was necessary to carry forward recommendations from the previous version of the CPG without an updated systematic evidence review.


c. Categorizing Recommendations without an Updated Review of the Evidence There were also cases in which it was necessary to carry forward recommendations from the previous version of the CPG without an updated systematic evidence review. Because of time and budget constraints, the update of the Dyslipidemia CPG could not review all available evidence on the management of dyslipidemia but instead focused its KQs on areas of new or updated scientific research or areas not previously covered in the CPG. For areas of research that have not changed and for which recommendations made in the previous version of the guideline were still relevant, recommendations could have been carried forward to the updated guideline without an updated systematic review of the evidence. The support for these recommendations in the updated CPG was thus also carried forward from the 2014 VA/DoD Dyslipidemia CPG. These recommendations were categorized as Not reviewed. If evidence had not been reviewed, recommendations could have been categorized as Not changed, Amended, or Deleted. Not reviewed, Not changed recommendations refer to recommendations from the previous version of the Dyslipidemia CPG that were carried forward unchanged to the updated version. The category of Not reviewed, Amended was used to designate recommendations that were modified from the 2014 VA/DoD Dyslipidemia CPG. Recommendations could also have been categorized as Not reviewed, Deleted if they were determined to be out of scope. A recommendation was out of scope if it pertained to a topic (e.g., population, care setting, treatment, and condition) outside of the scope for the updated CPG as defined by the Work Group. The categories for the recommendations included in the 2020 version of the guideline are noted in the Recommendations.


The categories for the recommendations included in the 2020 version of the guideline are noted in the Recommendations. The categories for the recommendations from the 2014 VA/DoD Dyslipidemia CPG are noted in Appendix G. F. Drafting and Submitting the Final Clinical Practice Guideline After the face-to-face meeting, the Champions and Work Group members were assigned to craft discussion sections to support the new recommendations and/or to update discussion sections from the 2014 VA/DoD Dyslipidemia CPG to support the amended carried forward recommendations. The Work Group also considered including in this CPG tables, appendices, and other sections from the 2014 VA/DoD Dyslipidemia CPG. During this time, the Champions and Work Group also revised the algorithm. After developing the initial draft of the updated CPG, an iterative review process was used to solicit feedback on and make revisions to the CPG. Once they were developed, the first two drafts of the CPG were posted on a wiki website for a period of 14 20 business days for internal review and comment by the Work Group. 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.


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.


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.


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 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.


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.


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.


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.


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 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 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.


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).


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.


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.


, 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, 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.


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.


, 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.