, many studies utilized self-reported physical activity levels), potential inaccuracies converting self-reported activity to accepted categories, imprecision in the evidence base, and heterogeneity in exercise interventions. Despite these limitations, the body of evidence on the CVD benefits of exercise indicates a positive association of high magnitude, which was consistently demonstrated across large studies. These positive effects were found on important patient outcomes (e.g., all-cause and CV mortality) in a dose-response relationship. Although the available evidence provides some support for physical activity to lower CV risk, large variability in patient preferences and resource limitations might limit feasibility. The behavioral change required to exercise can be challenging for many patients and motivation is often mixed. Furthermore, access to gyms or exercise equipment is variable. However, promoting physical activity of lower intensity and duration might mitigate some of these resource and feasibility limitations, especially in lower socioeconomic patients, patients with disabilities, and the elderly with poor physical function. As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation.[134-142] The Work Group s confidence in the quality of the evidence was very low. The body of evidence had significant methodologic limitations. The potential large benefit on mortality would appear to outweigh the risk of musculoskeletal injury. Although feasibility and resource requirements might be a concern with higher activity levels for some patients, this would not apply to lower intensity activities. Therefore, this recommendation broadens acceptability and feasibility to patients who are unable to achieve the traditional moderate to vigorous intensity physical activity recommendations. Thus, the Work Group decided upon a Weak for recommendation. Research utilizing randomization and more accurate methods of measuring physical activity levels are needed to improve confidence in the effect of physical activity on CV outcomes in both primary and secondary prevention populations. Recommendation 27. We recommend a structured, exercise-based cardiac rehabilitation program for patients with recent occurrence of coronary heart disease (i.e., myocardial infarction, diagnosis of coronary artery disease, coronary artery bypass grafting, or percutaneous coronary intervention) to reduce cardiovascular morbidity and mortality. (Strong for | Reviewed, New-added) Discussion Although the benefits of regular physical activity involve many health domains, its effects on CV risk reduction are commonly cited by providers when advocating for lifestyle change to patients. The biological plausibility that physical activity could improve CV outcomes by positively altering lipid profiles is well established. Although not included in this evidence review, cross-sectional and observational data have demonstrated an association between regular physical activity and reductions in TC and LDL.[143-146] A structured, exercise-based cardiac rehabilitation program in patients recently diagnosed with CHD has been found to improve CV mortality, all-cause mortality, and non-fatal MI. Based on the systematic review and meta-regression analysis of 69 RCTs by Abell et al. (2017), structured cardiac rehabilitation programs with detailed exercise prescription (i.e., frequency, duration, intensity) and follow-up assessments were associated with a 26% reduction (NNT=31) in CV mortality over an average follow-up period of 10 years (range 3 19 years).[147] This benefit does not apply to unstructured interventions, such as providing general exercise advice (e.g., exercise for 150 minutes per week, walk daily), which were excluded from Abell et al. (2017). As is typical for complex interventions, the formats of the 72 individual exercise programs were highly heterogeneous. There was variability in supervision (supervised versus unsupervised programs), setting (community based, residential, clinic), additional risk factor counseling, individual exercise components (i.e., frequency, intensity, type, duration), and adherence. The meta-regression analysis by Abell et al. (2017) found the abovementioned co-variates did not affect any of the CV outcomes with rare exception, such as high adherence.[147] Therefore, the Work Group determined the available evidence base does not support a specific cardiac rehabilitation program or exercise component type. Structured programs of variable format have been shown to reduce critical CV outcomes. Of note, reviewed studies included only patients with CHD (MI event, diagnosis of CAD, CABG, or PCI), most of whom began the exercise intervention between 2 8 weeks after the event. Therefore, the Work Group determined that the beneficial effects supported by the evidence are mostly limited to patients with a recent diagnosis or cardiac event. Safety outcomes were not reported in the body of evidence. Although the evidence base supports a structured cardiac rehabilitation program to lower mortality in patients with CHD, the Work Group would anticipate some variability in patient preference and limitations in feasibility related to resource requirements. The Work Group would anticipate some patients would be more accepting than others of the behavioral changes required to engage in an exercise program; in particular, cardiac rehabilitation programs tend to be of higher intensity. Additionally, the human resource (i.e., physiotherapists) and equipment requirements of many clinic and community-based programs might limit feasibility in some settings. However, the evidence demonstrated similar CV outcomes with home- based programs, which might have fewer fiscal costs and other resource demands compared to their clinic or community-based counterparts. As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation.[147] The Work Group s confidence in the quality of the evidence was moderate. The body of evidence had some limitations, including significant heterogeneity in exercise interventions and risk of bias in the primary studies. Most of the latter was detection bias because of the inherently problematic nature of blinding in exercise interventions and attrition bias from missing outcomes data. Other considerations regarding this recommendation included the benefits (e.g., improved CV mortality, all-cause mortality, and non-fatal MI). Although data on safety endpoints were not reported, the Work Group determined these benefits outweighed the risk of harm anticipated with exercise interventions, most of which would be minor musculoskeletal injuries. Although variation in patient preference and feasibility is a concern in some settings, the Work Group determined that given the highly favorable risk-benefit ratio for CV mortality, providers and healthcare systems should make strong efforts to motivate their patients and invest in the resources required to provide a cardiac rehabilitation program for their patients. Thus, the Work Group decided upon a Strong for recommendation. More research involving head-to-head comparisons between different exercise components is needed to better ascertain the optimal form of cardiac rehabilitation to improve CV outcomes in patients with CHD and other forms of CVD. VII. Knowledge Gaps and Recommended Research Despite the breadth of research on dyslipidemia and the prevention of CVD, the Work Group noted that many patient-oriented questions have not been specifically addressed. In looking towards the next iteration of these guidelines, the Work Group created a ranked list of research priorities. A. Comparison of Medical Therapies in Primary and Secondary Prevention a. Primary Prevention The pool of primary prevention studies using statins almost exclusively employed moderate-dose statins. The JUPITER trial was the only study that employed a high-dose statin.[47] The CV benefit of higher dose statins in JUPITER is consistent with benefits found in other primary prevention trials of moderate-dose statins. Prospective comparisons of different statin intensities might demonstrate an additional benefit of higher statin doses in patients treated for primary prevention. Similarly, studies of ezetimibe monotherapy and ezetimibe and statin combination therapy showing patient-oriented outcomes in primary prevention are lacking. While similar arguments can be made for bempedoic acid, icosapent ethyl, and PCSK9 inhibitors, their high cost and the large NNT for all therapies in primary prevention limit the potential cost-effectiveness of these medication classes in primary prevention at current prices. b. Secondary Prevention Patients with known CVD are at the highest risk of CV events. Since statins and ezetimibe are both generic and have proven benefit in this population when used in combination, the combination should be maximized and serve as the active control for evaluation of added efficacy and safety of newer therapies (bempedoic acid, icosapent ethyl, and PCSK9 inhibitors). Prospective studies evaluating the benefit of titrating lipid-lowering treatments to achieve specific LDL-C goals (e.g., <50, 70, 100 mg/dL) in patients at higher risk are lacking but would be helpful in determining the need for intensification of treatment to further reduce CV events. B. Effectiveness of Non-statin Monotherapy for Primary Prevention Most discontinuation of statin therapy is attributed to presumed statin myopathy. While many patients tolerate the same statin when re-challenged, some are reluctant to resume the same or different statin they presume caused the myalgias, leaving limited evidence-based medication options for primary prevention of CVD in patients who cannot take statins. There is a need for clinical trials of alternative lipid-lowering agents for CVD risk reduction in primary prevention populations. Current medications suitable for study would be ezetimibe, PCSK9 inhibitors, bempedoic acid, and icosapent ethyl. Because of the low cost of generic ezetimibe, studies of ezetimibe monotherapy for primary prevention would offer the highest potential benefit. C. Safety of Newer Therapies The long-term risks of PCSK9 inhibitors and bempedoic acid have not been established, warranting continued surveillance of post-marketing adverse event reports and the persistence of effect on CVD risk reduction in longer term follow-up. No negative health outcomes have been reported from very low LDL-C levels, including levels <50 mg/dL, caused by lipid-lowering drugs in observational studies or post hoc analyses of clinical trials to date. However, if future evidence supports that a minimum threshold LDL-C level is necessary, based upon safety risks, more frequent monitoring may be needed when high intensity treatments are employed. D. Stratifying Primary Prevention Benefits by Patient Risk Estimates Primary prevention studies include primarily patients with 10-year CV risk estimates of >12% with smaller numbers between 6 12% risk and very few <6%. No primary prevention study has used estimated CV risk as inclusion criteria or provided individual patient predicted cardiac risk data. Future primary prevention studies should include lower risk populations, measure predicted risk, and stratify the randomization procedure (using block randomization) by pretreatment CV risk estimate. We recognize that such a study may be impractical given the extremely large sample size and costs.[148] E. Prospective Studies to Improve Statin Adherence The high quality evidence for the benefit of statins for primary and secondary prevention makes adherence a key goal. The limited studies to date suggest that repeated trials of statins increase adherence, but the evidence base is sparse. Both clinic intervention strategies and alterations to prescribing patterns should be evaluated. 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. 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. 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. 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). (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. 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). 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. 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. 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? 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? 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. 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 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. 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. 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. 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. 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. 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.[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. 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. 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-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. 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 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. Appendix B: Cardiovascular Disease Risk Calculators Table B-1. Risk Calculators: Characteristics of Patient Population ACC/AHA pooled cohort PCE SRSRF VARS-CVD Framingham Sex Race Black/African American Age Abbreviations: ACA/AHA: American College of Cardiology/American Heart Association; PCE: Pooled Cohort Equations; SRSRF: Self- Reported Stroke Risk Function; VARS-CVD: Veterans Affairs Risk Score for Cardiovascular Disease Appendix C: Pharmacotherapy Table C-1. Summary of Statin and Non-statin Pharmacologic Agents* Drug Category Dose Major Drug Interactions Adverse Drug Reactions Notes Statins Atorvastatin once daily Since statins vary in their metabolic pathway, refer to product labeling for drug-drug interactions and statin dose limits Risk for myalgia, myopathy and, very rarely, rhabdomyolysis. Other risks include diabetes, LFT elevations, and asymptomatic CK elevations. First line therapy for primary or secondary prevention of CVD Rosuvastatin 5 40 mg once daily Simvastatin 5 40 mg once daily Lovastatin once daily Pravastatin once daily Fluvastatin 20 80 mg per day Pitavastatin 1 4 mg once daily Cholesterol absorption inhibitors Ezetimibe 10 mg once daily Increased incidence of transaminase elevation >3x ULN when combined with statins versus statins respectively) Generally well tolerated Benefit for reducing non- fatal CV events in secondary prevention patients in addition to statin inhibitors Alirocumab 75 mg once every 2 weeks OR 300 mg once every 4 weeks Max: 150 mg every 2 weeks No known significant interactions Injection site reactions (3 7%). Adverse reactions inhibitors reported in RCTs appear to be similar to placebo. Alirocumab had higher incidence of influenza, bronchitis, myalgia, muscle spasm, sinusitis, cough, and musculoskeletal pain compared to placebo Evolocumab had a higher incidence of cough, arthralgia, and fatigue Benefit for reducing non-fatal CV events in secondary prevention in addition to maximally tolerated statin +/- ezetimibe It is recommended that patients receive maximally tolerated statins plus ezetimibe prior to adding alirocumab or evolocumab Limited data on long- term safety Evolocumab 140 mg once every 2 weeks OR 420 mg once monthly Drug Category Dose Major Drug Interactions Adverse Drug Reactions Notes fatty acids Icosapent ethyl 2 gm twice daily with meals May enhance antiplatelet and anticoagulation effects. Caution with concomitant agents that increase risk of bleeding. oropharyngeal pain, peripheral edema, constipation, gout, and atrial fibrillation. Potential for allergic reactions in patients with fish allergy. Benefit for reduction of CV mortality and morbidity in patients treated for secondary prevention on statins with persistently elevated TG (>150 mg/dL); evidence is limited to one RCT Hospitalization for atrial fibrillation or flutter was statistically higher with icosapent and a non- significant trend towards a higher incidence of hospitalization for serious bleeding events was also observed * Refer to product prescribing insert for more information regarding use restrictions, dose modification, dosing in special populations (e.g., renal or liver impairment, advanced age, pregnancy, etc.), drug-drug interactions, and adverse events. Abbreviations: CK: creatine kinase; CV: cardiovascular; CVD: cardiovascular disease; dL: deciliter; gm: grams; LFT: liver function test; mg: milligrams; PCSK9: proprotein convertase subtilisin/kexin type 9; RCT: randomized controlled trial; TG: triglyceride; ULN: upper limit of the normal range Appendix D: Patient Education on the Mediterranean Diet Table D-1. Patient Education on the Mediterranean Diet [155] Eat More Eat Less Fruits and vegetables Whole grains Seafood (primarily fatty fish), skinless poultry Tree nuts, peanuts, nut butters Legumes Olive oil Low-fat milk and cheese Red wine* Red meat Processed meat Full-fat milk and cheese Butter or margarine Commercial bakery goods Avoid trans fat * Providers should consider the risk of recommending alcohol to individual patients. Appendix E: Patient Focus Group Methods and Findings A. Methods As part of the effort to update this CPG, the VA and DoD Leadership held a patient focus group on March 19, 2019, at the Walter Reed National Military Medical Center in Bethesda, MD. The aim of the focus group was to elicit patient perspectives of patients on a set of topics related to their dyslipidemia. The focus group considered a set of topics related to their dyslipidemia, including their treatment plan history, care delivery setting, medications, non-pharmacologic therapies, and the impact of therapy. VA and DoD Leadership recruited participants for the focus group. Patients were not incentivized for their participation or reimbursed for travel expenses. Three patients participated in the focus group. There were two men and one woman, ranging in age from 50 70. One participant receives care at the VA, while the other two receive care from the DoD. The Dyslipidemia CPG Work Group, with support from Lewin, developed a set of questions to help guide the focus group. The focus group facilitator led the discussion using the previously prepared questions as a general guide to elicit the patient s perspectives about their treatment and overall care. Given the limited time and the range of interests of the focus group participants, not all of the listed questions were addressed. B. Patient Focus Group Findings a. Patients stressed the importance of lifestyle changes and felt these were the most important ways to reduce cardiovascular risk and improve their health All three participants understood that eating a healthy diet would reduce their CV risk and, for that reason, several implemented comprehensive dietary changes. Two participants took supplements that were not recommended by their provider either in addition to, or instead of, pharmaceuticals. Two participants started exercising regularly after learning of their health issues, and they reported feeling better afterward. All three participants noted their risk of CVD has not impacted their quality of life. b. Participants stressed the importance of patient education, fully understanding their CV risk, and learning about the available treatment options. Participants were highly motivated to manage their CV risk. All three participants felt that learning of their health risks CV or otherwise motivated them to take personal responsibility for their health. Participants use various mediums to learn about lipids and CV risk, including websites, family and friends, and providers external to the VA/DoD health care systems. Two participants found visual aids that explain the benefits and harms of statins useful, but thought these aids would be confusing in the absence of a provider s explanation. All three participants stated they were more likely to adhere to prescribed regimens if they had a strong relationship with their provider. Also, they place a premium on patient-centered care. c. While all patients have used pharmacologic treatments, they noted various concerns with statins. In addition, they had a general preference for reducing their CV risk via non-pharmacologic treatments. All three participants generally did not experience issues regarding adherence to statins. However, some did struggle to take it at the proper time of day. Statin side effects varied for the three participants. One participant never had side effects. One participant experienced side effects, but the benefits outweighed the harms. Comparatively, two participants stopped taking statins because of side effects. All three participants had tried multiple statins and changed their course of treatment to reduce side effects. d. Patients had health concerns in addition to their cholesterol and stressed the importance that providers consider comorbidities when managing their cholesterol. Two participants are primarily concerned with cholesterol levels and heart health, while another was more concerned with chronic conditions or other diseases posing more immediate barriers to their life. Whether dyslipidemia was a patient s primary health care concern depended on their risk levels, comorbidities, and family history. e. Patients generally find mobile apps and smart devices useful for monitoring their health. Even though not all patients prefer telemedicine and other technology options, providers should be ready to offer these options. All three participants use devices (e.g., smartphone, smartwatch) for monitoring their health and some use this modality to share health information with providers. One participant communicated with a remote private provider via Skype and enjoys using this method of communication. f. Despite variability in patient preferences regarding learning their cholesterol levels, patients agreed it was important to hear about the available screening tests. In addition, patients believed it is important that they understand their lipid levels and lipid profile results. All three participants have their lipids tested every six months as recommended by their provider. All three participants did not feel that fasting lipid testing was burdensome. Patient knowledge about lipid profiles varied. One patient used and advocated for providing advanced lipoprotein testing, while two participants were only aware of cholesterol, LDL, and HDL testing. All three participants felt that knowing their lipid profile has not made them feel better or worse, or improved their understanding of risk. Appendix F: Evidence Table Table F-1. Evidence Tablea,b,c Recommendation 2014 Strength of Recommendation Evidence 2020 Strength of Recommendation Recommendation Category 1. For primary prevention in patients over age 40 and not on statin therapy who have not developed new cardiovascular risk factors (e.g., diabetes, hypertension, tobacco use), we suggest against offering a cardiovascular disease risk assessment more frequently than every five years. Weak for [20,21] Weak against Reviewed, Amended 2. For primary prevention in patients not on statin therapy, we suggest against routinely ordering a lipid panel more frequently than every 10 years. Not applicable [21-23] Weak against Reviewed, New- added 3. For cardiovascular risk assessment in primary prevention, we suggest using a 10-year risk calculator. Weak for [24-28] Weak for Reviewed, Amended 4. We suggest against the routine use of coronary artery calcium testing. Weak against [29] Additional references: Weak against Reviewed, Not changed 5. We suggest against the routine use of additional risk markers (e.g., high-sensitivity C-reactive protein, ankle-brachial index, coronary artery calcium) when assessing cardiovascular risk. Weak against [26,29,32-35] Weak against Reviewed, New- replaced 6. For primary prevention, we recommend offering a moderate- dose statin in patients with a >12% 10-year cardiovascular risk or low-density lipoprotein cholesterol >190 mg/dL or diabetes. Weak for, Weak for, Strong for Additional references: Strong for Reviewed, New- replaced a Evidence column: The first set of references listed in each row in the evidence column constitutes the evidence base for the recommendation. To be included in the evidence base for a recommendation, a reference needed to be identified through the 2019 evidence review or included in the evidence base for the 2014 VA/DoD Dyslipidemia CPG. The second set of references in the evidence column ( Additional References ) includes references that provide additional information related to the recommendation but which were not systematically identified through a literature review. These references were not included in the evidence base for the recommendation and, therefore, did not influence the strength and direction of the recommendation. b 2020 Strength of Recommendation column: Refer to the Grading Recommendations section for more information on how the strength of the recommendation was determined using GRADE methodology. c Recommendation Category column: Refer to the Recommendation Categorization section for more information on the description of the categorization process and the definition of each category. Recommendation 2014 Strength of Recommendation Evidence 2020 Strength of Recommendation Recommendation Category 7. For primary prevention, we suggest offering a moderate-dose statin for patients with a 10-year cardiovascular risk between 6% and 12% following a discussion of risks, limited benefit, and an exploration of the patient s values and preferences. Weak for, Strong for Additional references: Weak for Reviewed, New- replaced 8. For primary prevention in patients on moderate-dose statins, we suggest against maximizing the statin dose due to the lack of evidence proving added cardiovascular benefits and the risks of higher dose statins. 