Evidence on Reducing Recurrent CVD Events with Moderate- or High-dose Statins Clinical Trial Intervention/Population (Maximize Statin or Add Non-statin) Results for Primary Composite Endpoint Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) [86] Alirocumab added to maximum-dose statin in patients 1 12 months after ACS over 2.8 years Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) Evolocumab added to maximum-dose statins with or without ezetimibe in patients with clinically evident ASCVD and one major risk factor or two minor risk factors IMProved Reduction of Outcomes: Vytorin Efficacy International Trial Ezetimibe added to moderate-dose statins in patients after ACS The Pravastatin or Atorvastatin Evaluation and Infection Therapy- Thrombolysis In Myocardial Infarction 22 Moderate-dose (pravastatin 40 mg) versus high-dose (atorvastatin 80 mg) statin in patients with ACS Treating to New Targets (TNT) [89] Moderate-dose (10 mg) versus high-dose (atorvastatin 80 mg) in patients with stable CAD over 4.9 years Abbreviations: ACS: acute coronary syndrome; ASCVD: atherosclerotic cardiovascular disease; CAD: coronary artery disease; mg: milligrams; NNT: number needed to treat; PCSK9: proprotein convertase subtilisin/kexin type 9; RRR: relative risk reduction Summary We recommend the combination of maximally tolerated statins and ezetimibe before PCSK9 inhibitors because high-dose statins and ezetimibe have evidence of long-term safety and reduction in CV events. Statins and ezetimibe are also administered orally and are widely available as generic products. In contrast, PCSK9 inhibitors have unknown long-term safety profiles, are administered as subcutaneous injections once or twice a month, are significantly more costly, and require education on proper use while achieving comparable or less relative risk reductions. In patients at higher risk (see Recommendation 12 for a definition) who are already receiving a maximally tolerated statin plus ezetimibe, addition of a PCSK9 inhibitor is suggested to reduce recurrent non-fatal events. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation [68,70,79,82-85] and considered the evidence put forth in the 2014 CPG.[88,89] The Work Group s confidence in the quality of the evidence was moderate. The benefits outweighed the harms and burden. There is likely to be high variation in patient and provider values and preferences because of various factors (e.g., long-term safety has not yet been established, CVD events are reduced but mortality is not impacted, route of administration issues, and high cost, feasibility of use for patients and healthcare systems). Because of these issues, the Work Group decided upon a Weak for recommendation centered on a patient s willingness to intensify drug therapy while already receiving a maximally tolerated statin plus ezetimibe. There is a need for continued investigation of the long-term safety of treatment with PCSK9 inhibitors combined with statins with or without ezetimibe, and the unknown safety of prolonged periods of very low LDL-C levels secondary to this treatment. More research on these topics would be useful: What is the optimal combination of lipid-lowering treatments or achieved LDL-C level that will result in the largest reduction in CV events (e.g., whether adding a PCSK9 inhibitor to maximum- dose statins plus ezetimibe versus moderate-dose statins plus ezetimibe results in an incremental benefit in CV risk)? What is the comparative effectiveness of a high-dose statin plus ezetimibe, a high-dose statin plus PCSK9 inhibitor, and a high-dose statin plus ezetimibe plus PCSK9 inhibitor (triple therapy) on important CV outcomes in higher risk patients? What is the optimal duration of more aggressive treatment in higher risk patients? For example, in a patient with ACS placed on high-dose statins, is the more aggressive treatment continued indefinitely or can some patients have their treatment titrated downward after a period of time? c. Other Medications, Supplements, and Nutraceuticals Recommendation 15. For primary or secondary prevention, we recommend against using niacin (i.e., supplements or prescriptions). (Strong against | Reviewed, New-replaced) Discussion Primary Prevention In a fair quality SR of five RCTs that evaluated niacin in primary prevention (n=30,310), Keene et al. (2014) noted no patient benefit from niacin. There was no difference in all-cause mortality, non-fatal MI, or stroke.[90] There was evidence of harm, manifested by an increase in infections, gastrointestinal (GI) complications, bleeding, new-onset DM, and DM complications. Primary and Secondary Prevention In a fair quality SR of five RCTs in a mix of primary and secondary prevention patients (n=32,966) who used supplements containing therapeutic doses of niacin (2 3 grams/day), Schandelmaier et al. (2017) noted no benefits and increased harms.[91] This systematic review noted no difference in CV mortality, all-cause mortality, non-fatal MI, or stroke. However, side effects resulted in significant flushing, pruritus, GI symptoms, new-onset DM, and more discontinuations. Secondary Prevention Finally, in a fair quality systematic review of two RCTs in patients in secondary prevention (n=1,726), Kaur et al. (2014) found no significant differences in CV mortality, all-cause mortality, non-fatal MI, or stroke. It did find significantly higher numbers of niacin discontinuations, dose reductions, and higher incidences of flushing and pruritus.[92] Summary The confidence in the quality of evidence was moderate. The evidence demonstrated in multiple populations that harms and burdens outweighed benefits. It is expected patients and providers will find niacin unacceptable and prefer against its use given the significant increase in adverse events (e.g., pruritus, flushing, DM, increased infections) and lack of benefit in clinical outcomes. Based on this data, the FDA removed the approval of combinations of statins with niacin in 2016.[93] As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation.[90-92] The Work Group s confidence in the quality of the evidence was moderate. Despite decades of niacin use based on the extrapolation that its effects on the lipid profile (i.e., lowering TC, LDL-C, and TGs, and raising HDL-C) would translate into a favorable impact on patient important outcomes, the Work Group determined that the clinical trial data clearly demonstrated in multiple populations that the harms of niacin use outweigh any benefit. Providers and patients are likely to view niacin as unacceptable given the adverse event profile and lack of benefit in clinically important outcomes. Thus, the Work Group decided upon a Strong against recommendation. However, the Work Group acknowledges there may be unique patient circumstances where niacin may be clinically appropriate after a shared decision making discussion between provider and patient. The Work Group had no research recommendations since further research is not likely to change the clinical landscape nor this recommendation. Recommendation 16. For primary or secondary prevention, we suggest against adding fibrates to statins. (Weak against | Reviewed, New-replaced) Discussion Primary Prevention (Fibrate Added to Statin versus Statin Alone) For primary prevention, fibrates added to statins have not been shown to be beneficial in patient-oriented clinical outcomes. In a fair quality systematic review with 3,502 primary prevention patients, Keene et al. (2014) showed no significant difference in CHD mortality (a subset of CVD mortality) with use of fibrates.[90] In another fair quality systematic review of 3,982 primary prevention patients, Jakob et al. (2016) noted no significant difference in all-cause mortality and major CVD events with fibrates.[94] The CVD benefits of fibrates added to statins remain unproven for primary prevention based on data from short-term clinical trials. In a systematic review of 12 studies in 5,398 primary prevention patients comparing fenofibrate plus a statin to a statin alone, Shao et al. (2016) found no increase in the important safety endpoints of any adverse event, including a CK at least five times the upper limit of normal (ULN).[95] However, evidence suggests there is some associated risk. Shao et al. (2016) also showed significant increases in LFT transaminases at least three times ULN and a renal safety endpoint of creatinine increase of >50%.[95] In an observational study of 1,538 primary prevention patients, Murray et al. (2017) noted no significant differences in cognitive test results between fenofibrate and a statin versus a statin alone.[96] Secondary Prevention (Fibrate Added to Statin versus Statin Alone) In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, 5,518 patients with DM who were receiving open-label simvastatin (80 mg) were randomized to receive fenofibrate or placebo for a mean of 4.7 years.[97] Approximately 36% of patients in each group had experienced a prior CVD event. The primary outcome of the first occurrence of non-fatal MI or stroke or death from CV causes was not different between groups and occurred in 2.2% of patients receiving fenofibrate versus 2.4% of those on placebo (HR: 0.92, 95% CI: 0.79 1.08, p=0.32). Underpowered prespecified subgroup analyses showed possible harm in women (increased CV events) while also showing some decrease in CV events for men with high TGs and low HDL-C.[97] Summary The Work Group determined the potential for harms outweighed potential benefits. Patient and provider values and preferences likely vary because some might use a statin/fenofibrate combination in the high TG, low HDL-C subgroup since benefits may be perceived to outweigh risks. Combination therapy entails a higher pill burden with associated decrements in adherence and additional cost for those with co-pays. Based on this data, the FDA removed the approval of combinations of statins with fenofibrate in 2016.[93] As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation [90,94-96] and considered the evidence put forth in the 2014 CPG.[97] The Work Group s confidence in the quality of the fibrate evidence was low for primary prevention and moderate for secondary prevention. Compared to the niacin data (see Recommendation 15), the fibrate data was less robust and lower quality. Patient and provider preferences likely vary because some patients with high TG may be interested in fibrates. However, the Work Group determined the potential for harm outweighed potential benefits given the adverse effects on LFTs, serum creatinine, and the possible increase in CV events in women. Given the lack of benefit in both primary and secondary prevention, the Work Group decided upon a Weak against recommendation. The Work Group had no research recommendations since further research is not likely to change the clinical landscape nor impact this recommendation. Recommendation 17. There is insufficient evidence to recommend for or against using bempedoic acid with or without statins for either primary or secondary prevention. (Neither for nor against | Reviewed, New-added) Discussion Bempedoic acid is a prodrug that is activated by very-long-chain acyl-CoA synthetase-1 to inhibit ATP- citrate lyase and works upstream of hydroxy methylglutaryl coenzyme A. Among patients at risk of CVD who are on statins, intensifying treatment by adding bempedoic acid has not been shown to reduce CVD mortality, all-cause mortality, non-fatal MI, non-fatal stroke, or MACE compared to the placebo group. There were no systematic reviews or meta-analyses that met the inclusion criteria for this CPG s systematic evidence review. Based on an RCT, Ray et al. (2019), treatment with bempedoic acid in addition to statins did not improve outcomes among patients with atherosclerotic CVD, HeFH, or both.[98] However, these findings were imprecise because of low event rates and the short follow-up (12 months), and the study was limited by high attrition. Evidence suggests a possibility of harm with bempedoic acid, with a non-significant trend toward higher CV (0.4% versus 0.1%) and all-cause mortality (0.9% versus 0.3%) in the treatment group compared to the placebo group. In Ray et al. (2019) there was no significant difference between placebo and bempedoic acid in CVD deaths and all-cause deaths. Adverse effects of bempedoic acid include potentially increased incidence of muscle pain (p=0.05) and gout (p <0.03), but with lower rates of new- onset or worsening DM (p=0.02).[98] Patient and provider values and preferences could not be determined since bempedoic acid was not on the market at the time of the systematic evidence review. Bempedoic acid received FDA approval in February 2020 and an ongoing clinical outcome trial will be completed in 2022. As a newly released drug, it has an uncertain safety profile and is expensive, compared to effective, safe, and low-priced statins. Given the adverse events and current lack of evidence in reducing CVD outcomes, patient and provider acceptability may be low. As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation.[98] However, there were no systematic reviews or meta-analyses that studied bempedoic acid and our major outcomes of interest. The Work Group s confidence in the quality of the evidence was low. This recommendation is based on one RCT, Ray et al. (2019), which was limited by a short 12-month follow-up and a small number of events. The Work Group also considered the potential harm of adverse events. Patient values and preferences could not be estimated. Finally, the drug will likely be expensive and patient/provider acceptability may be low if the adverse event rate continues to be high. Thus, the Work Group decided upon a Neither for nor against recommendation. There is a need for a larger secondary prevention study of bempedoic acid as an add-on to statins. The study should have longer follow-up and be appropriately powered for adverse events and important clinical outcomes (e.g., fatal and non-fatal stroke, MI, and mortality). Recommendation 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. (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. (Weak for | Reviewed, New-added) Discussion Icosapent ethyl is a purified ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). At the time of our systematic evidence review, the body of evidence examining the potential effects of icosapent ethyl on critical CV outcomes was limited to a single randomized trial. In this double-blinded, placebo-controlled trial by Bhatt et al. (2019), Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT), treatment with 4 grams of icosapent ethyl resulted in a 25% reduction in the primary endpoint defined as a combination of vascular death, non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina over 4.9 years (NNT=21).[99] The results from REDUCE-IT may not be generalizable to all patients represented in the spectrum of CV risk. Most of the study subjects were high-risk patients as evidenced by 70% of those enrolled having a history of CVD. Although patients without a history of atherosclerotic CVD were enrolled, primary prevention patients represented a minority of those studied. Further, a subgroup analysis of the primary prevention cohort did not find a difference in CV outcomes. Although beneficial effects in higher risk primary prevention populations might be demonstrated in contemporary studies not captured in this review or with future investigations, the Work Group determined the REDUCE-IT results alone are insufficient to suggest icosapent ethyl for CV risk reduction in patients without a history of CVD. The results from REDUCE-IT are applicable to many patients classified as high risk by virtue of a history of CVD. However, the inclusion criteria utilized limit its application to part of the secondary prevention population only. Subjects were restricted to those with elevated TG levels (median 216 mg/dL, 90% of patients >150 mg/dL), 90% of whom were on stable doses of moderate- to high-dose statins for at least four weeks before the intervention. As such, the reduction in CVD outcomes by 25% pertain to secondary prevention populations on statin therapy with hypertriglyceridemia. The composite outcome included coronary revascularization, which many deem as a less clinically valid outcome. For some, this might be a cause for concern that positive interpretations of the results are misleading and rendered by outcomes less important to patients. However, a statistically and clinically significant reduction was demonstrated in each of the component endpoints, including vascular death and other patient-important outcomes. Additionally, a similar 26% reduction in the secondary composite endpoint of CV death, non-fatal MI, and non-fatal stroke (MACE) was observed (NNT=28), further suggesting a potential benefit in patient-oriented outcomes. These beneficial results were balanced by an increased risk of hospitalization for atrial fibrillation (3.1% versus 2.1%; absolute risk increase [ARI]: 1%; NNH=100; p=0.004) and a higher rate of serious bleeding events (ARI: 0.6%; p=0.06) in the icosapent ethyl treatment arm.[99] The available evidence for icosapent ethyl has various significant limitations. First, the evidence base is limited to a single RCT without subsequent trials either corroborating or questioning the findings by Bhatt et al. (2019).[99] Further, Bhatt has numerous methodologic flaws that constrain interpretation, including the use of composite endpoints, lack of allocation concealment, conflict of interest concerns related to industry s heavy role, and the potential confounding related to the choice of placebo. In this latter limitation, the Work Group noted a 30% rise in hsCRP in the placebo group during the study period, while a 12% reduction was observed in the icosapent ethyl group. As hsCRP has been implicated in atherogenesis and plaque stability through inflammatory mechanisms, this imbalance in hsCRP could represent a loss of CV prognostic balance between groups by the study s conclusion, potentially confounding the results. One potential mechanism is the mineral oil used in the placebo, which could have reduced the adsorption of the statin therapy patients had been receiving before the trial period. The relatively stable level of LDL-C seen in the icosapent ethyl group and unexplained 10% rise in the placebo group might indicate a reduction in statin effect in the control arm. Although this relatively small proportional change in LDL might not reasonably explain the large differences in CV outcomes observed between treatment groups, loss of statin class effects independent of changes in LDL remain a possible explanation. Furthermore, subgroup analyses demonstrated similar effects on CV outcomes regardless of baseline TG level (including normal levels, defined as <150 mg/dL, for the secondary efficacy endpoint only) and whether TG levels were normalized to <150 mg/dL or not after treatment. This could suggest icosapent ethyl carries metabolic mechanisms other than TG lowering; however, a placebo-related elevation in the CV risk of the control arm unrelated to baseline or post-study TG levels remains a viable explanation. In addition to the evidence regarding potential beneficial effects and safety concerns with icosapent ethyl, the Work Group considered the drug s high cost and pill burden (i.e., two large pills twice daily) when crafting this recommendation. Both of these factors may be unacceptable for some patients. As these are Reviewed, New-added recommendations, the Work Group systematically reviewed evidence related to these recommendations.[99] The Work Group s confidence in the quality of the evidence was moderate. Limitations included a small evidence base (i.e., one clinical trial), unclear allocation concealment, and the potential for confounding related to the choice of placebo. Nonetheless, the study was a large RCT with results that demonstrated a favorable risk-benefit effect on patient outcomes. Given these positive results but significant limitations in the evidence, the Work Group decided upon a Weak for recommendation for Recommendation 19. Recommendation 19 is specific to those with a history of CVD, as the REDUCE-IT population primarily consisted of secondary prevention patients (70%). Furthermore, as this CPG s systematic evidence review did not capture primary evidence investigating only or mostly patients without a history of CVD, the Work Group decided upon a separate Neither for nor against recommendation for Recommendation 18, which pertains to primary prevention patients. Although a subgroup analysis of primary prevention patients in the REDUCE-IT trial showed no difference in the primary CV endpoint, the Work Group determined such analyses have limitations and should be used for hypothesis generation rather than clinical decision making. More RCT data is needed on the effectiveness and safety of icosapent ethyl in primary and secondary prevention populations. Use of placebo without mineral oil, and trials composed of mostly primary prevention populations, are needed to more accurately and comprehensively understand the potential effects of icosapent ethyl on CV outcomes. Recommendation 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. (Weak against | Reviewed, New-added) Discussion The systematic review by Abdelhamid et al. (2018) evaluated 79 RCTs for the effect of omega-3 supplements on primary and secondary prevention of CVD.[100] The evidence showed no statistically significant effect of omega-3 supplementation on CV mortality, composite CV events, MI, stroke, or all- cause mortality. The risk of bias was low for 25 RCTs and moderate-to-high in the remaining 54 RCTs.[100] In this systematic review, omega-3 supplementation ranged from 0.5 grams/day to greater than 5 grams/day.[100] Some studies used omega-3 enriched foods, or dietary advice to increase omega-3 consumption, compared to placebo or usual diet. Most studies assessed LCn3 supplementation with capsules, but some used LCn3- or alpha-linolenic acid-rich or enriched foods or dietary advice compared to placebo or usual diet.[100] Omega-3 enriched foods included margarine, juice, bread, walnuts, or other foods. Control groups received olive, corn, sunflower oils, or other types of fats. The duration of studies As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation.[100] The Work Group s confidence in the quality of the evidence was moderate. The evidence showed no effect of omega-3 supplements on CV mortality, composite CV events, MI, stroke, or all-cause mortality. There were inconclusive results for the risk of adverse effects, including bleeding and thrombosis, and risk of bias in the RCTs evaluated. Thus, the Work Group decided upon a Weak against recommendation. Future studies should measure the potential effects of omega-3 supplements on CVD risk factors. Recommendation 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 risks. (Neither for nor against | Reviewed, New-added) Discussion No studies evaluated the long-term effects of fiber, garlic, ginger, green tea, and red yeast rice supplements on CVD morbidity or mortality. Instead, these studies evaluated the safety of these interventions. Most of these studies evaluated these substances in their supplemental form not as they naturally occur in foods. In foods, these substances may have different effects. Fiber The systematic review by Hartley et al. (2016) reviewed 23 RCTs and found insufficient evidence of a patient-oriented benefit from fiber supplements.[101] Fourteen RCTs reported information on adverse events.[101] In seven studies, GI side effects including flatulence, constipation, nausea, bloating, and diarrhea were more common in the fiber intervention groups than in control groups, though rates were generally low. Few studies had an intervention duration exceeding 12 weeks. There was a wide variety of fiber sources used with little similarity between groups. The Work Group s confidence in the quality of evidence for fiber supplements was very low. Garlic A systematic review by Sahebkar et al. (2016) reviewed six RCTs and found insufficient evidence of a patient-oriented benefit from garlic supplements.[102] It found garlic supplements were well tolerated with no serious adverse events reported. An RCT by Ried et al. (2016) assessed the effect of aged garlic extract on central blood pressure and arterial stiffness in patients with uncontrolled hypertension.[103] There was no statistically significant difference in adverse events for the garlic or placebo group. The Work Group s confidence in the quality of evidence for garlic supplements was moderate.[102,103] Ginger There is no evidence of a patient-oriented benefit from ginger supplements. The systematic review by Zhu et al. (2018) reviewed 12 RCTs and assessed the effects of ginger supplements on Type 2 DM or components of the metabolic syndrome.[104] The evidence was inconclusive for increased adverse events. The Work Group s confidence in the quality of the evidence for ginger was very low.[104] Green Tea There is no evidence of a patient-oriented benefit from green tea supplements. The systematic review by Onakpoya et al. (2014) reviewed 20 RCTs and assessed the effectiveness of green tea supplements on blood pressure and lipid parameters.[105] The evidence demonstrated no increased adverse events. The Work Group s confidence in the quality of the evidence for green tea supplements was very low.[105] Red Yeast Rice There is no evidence of a patient-oriented benefit from red yeast rice supplements. A systematic review by Fogacci et al. (2019) reviewed 53 RCTs and assessed the safety of red yeast rice supplements.[106] These supplements were compared to either a statin or placebo and the follow-up ranged from 1 month 4.5 years. The authors concluded red rice yeast supplements were safe for use but caution is recommended when used with other medications, especially other cholesterol-lowering agents, due to possible interactions.[107] The Work Group s confidence in the quality of the evidence for red yeast rice was low. Summary The National Institutes of Health s Office of Dietary Supplements states that dietary supplements are products intended to supplement the diet. They are not drugs and therefore are not intended to treat, diagnose, mitigate, prevent, or cure diseases. [108] Dietary supplements do not require FDA premarket review or approval. As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation.[101-106] The Work Group s confidence in the quality of the evidence was very low. The body of evidence did not yield results on the outcomes of CV mortality, all-cause mortality, or CV events. Most studies were short term (i.e., 1 6 months). Safety data for fiber, garlic, ginger, and green tea was inconclusive.[101-106] Patient and provider values and preferences likely vary based on personal beliefs about efficacy and safety and the ability to pay for supplements, which are generally not covered by health plans. Thus, the Work Group decided upon a Neither for nor against recommendation. d. Monitoring and Adherence Recommendation 22. We suggest against the routine monitoring of lipid levels in patients taking statins. (Weak against | Reviewed, New-replaced) Discussion Among dyslipidemic patients at high risk of CVD, we suggest against frequently monitoring lipid levels in patients taking statins, except for higher risk secondary prevention in patients for whom therapy could be intensified. No studies included in the systematic evidence review directly compared pharmacologic treatment of high lipid levels by titrating medications to reach target LDL-C or non-HDL-C goals versus fixed-dose treatment based on initial CV risk assessment and standard medication dosing. Therefore, the comparative effectiveness and safety of treating to reach specific LDL-C or non-HDL-C goals versus use of fixed statin doses based on initial CV risk assessment can only be determined indirectly at best. Several systematic reviews and meta-analyses have evaluated the association between more intensive LDL-C lowering and risk of stroke,[109] CVD,[110-112] and DM,[109,113] but all these reviews evaluated trials that modified treatment intensity instead of targeting LDL-C. They did find that a lower LDL-C level was associated with reduced CVD mortality and any stroke, ischemic stroke, hemorrhagic stroke, or CV event outcomes compared to those that had higher levels (i.e., received placebo or less intensive LDL- lowering treatment). Given that statins reduce LDL-C levels, these results indirectly demonstrate that treatment which reduces LDL levels is better than no treatment or less intensive LDL-lowering treatment (i.e., high intensity treatment is better). The main results are summarized in Table 2, which reports major systematic reviews/meta-analyses on the effect of more intensive lipid-lowering treatment on CVD and DM. Further, the Navarese et al. (2018) meta-analysis suggests that reduction in risk of total and CV mortality was primarily among patients with baseline (or before treatment intensification) LDL-C 100 mg/dL.[111] However, all of these analyses were conducted on trials looking at intensification of treatment (not lipid treatment goals) and, as designed, cannot be used to support lipid treatment targets due to indirectness. Evidence also shows a possibility of harm since more intensive LDL-lowering treatment was associated with a higher incidence of new-onset DM.[113] The 2014 VA/DoD Dyslipidemia CPG recommended against the routine frequent monitoring (i.e., every three or four months) of LDL-C and non-HDL-C goals for the secondary prevention of CVD. Since then, there is evidence supporting the benefits of even lower LDL levels achieved by PCSK9 inhibitors used in patients on statins at continually higher risk (ODYSSEY and FOURIER).[86,87] Yet, a specific LDL-C target or goal at which patients will benefit most from lipid-lowering treatment has not been identified. Since all primary and secondary prevention trials used treatment intensity as inputs, the Work Group determined that treatment intensity provides a more evidence-based input than LDL-C results. However, testing lipid levels is a simple and inexpensive measure of adherence and treatment efficacy. For this reason, the Work Group recommends that monitoring lipid levels in patients taking statins be individualized based on ongoing shared decision making between the patient and the provider rather than routine. Table 2. Effect of More Intense Lipid Lowering on CVD Outcomes and Diabetes: A Summary of Recent Meta-analyses Author Setting and Population Intervention/Comparator (either placebo or less intense LDL lowering) Primary Endpoint(s) Relative Risk Absolute Risk Meta- mmol/ L ) Shin et al. RCTs of subjects at risk for stroke LDL lowering by statins or non-statins (versus placebo or less intense LDL lowering) Stroke versus stroke risk CI: 0.7% LDL-C level: 1.3 mmoI/L (50 mg/dL) versus higher levels (control) versus LDL-C level: 1.3 mmoI/L (50 mg/dL) to 1.8 mmoI/L (70 mg/dL) versus higher levels (control) LDL-C level: achieved LDL-C level >1.8 mmoI/L (70 mg/ dL) versus control versus Silverman et al. RCTs of LDL lowering Different statin and non- statin therapies MI, CHD, or CVD death Statins Non-statins Navarese et al. LDL lowering trials with initial low LDL More intensive compared with less intensive LDL-C lowering, stratified by baseline LDL level Total and CVD death versus Sabatine et al. LDL lowering trials with initial low LDL Statins and non-statins CHD death, MI, ischemic CVA, or CABG/PTCA Statins Non-statins Cai et al. LDL lowering trials with statins LDL-C level: <1.8 mmol/L New-onset diabetes LDL-C level: 1.8 2.59 mmol/L (70 100 mg/dL) LDL-C level: >2.59 mmol/L Note: LDL levels were converted from mmol/L to mg/dL by multiplying by 38.6 Abbreviations: CABG: coronary artery bypass grafting; CHD: coronary heart disease; CI: confidence interval; CVA: cerebrovascular accident; CVD: cardiovascular disease; LDL-C: low-density lipoprotein cholesterol; mg/dL: milligrams per deciliter; MI: myocardial infarction; mmol/L: millimoles per liter; PTCA: percutaneous transluminal coronary angioplasty; RR: relative risk While the Work Group wishes to emphasize that regular monitoring of lipid levels is not required to monitor therapy effects, there are many reasons a provider may wish to obtain these values. Knowing the LDL level may provide objective data and facilitate shared decision making, identify medication non- adherence, help the provider motivate the patient to follow the treatment regimen, and tailor therapy for patients who are at high risk despite taking statins. Adherence can also be indirectly assessed (e.g., patient report and medication refill frequency). The Work Group acknowledges providers may measure lipid levels in patients of all ages for the reasons enumerated above, to emphasize the importance of lifestyle changes, or to quantify the effect of positive lifestyle changes. These measurements may also be useful in patients under age 40, for whom these guidelines do not make recommendations given the lack of evidence. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation.[109-113] The Work Group s confidence in the quality of the evidence was very low. While the evidence does not support setting an LDL-C target or goal for reducing CV events with statins, there is evidence showing that more intense LDL-lowering treatment reduces CV events in secondary prevention patients at higher risk. However, this may be achieved by using a statin dose target rather than an LDL target or by PCSK9 inhibitors. Patient values and preferences likely vary somewhat because patients may expect a cholesterol test and want to know their cholesterol levels. Finally, frequent lipid monitoring has an associated cost (i.e., resources for testing and patient and provider time). Thus, the Work Group decided upon a Weak against recommendation. A direct study evaluating the comparative effectiveness and safety of treating to reach specific LDL-C or non-HDL-C goals versus the use of a fixed-dose statin and based on initial CV risk assessment is needed. Recommendation 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. (Weak for | Reviewed, New-added) Discussion Retrospective studies have demonstrated that statins can usually be continued after documentation of a statin-related adverse event and that mortality is improved by continuing the treatment. A retrospective cohort study by Zhang et al. (2013) examined adherence to statins at one year following statin-related events.[114] Over 6,000 patients who discontinued statins were re-challenged, and over 90% were ultimately able to tolerate a statin. More than 40% were re-challenged with the same statin to which the adverse event was documented. At the 12-month follow-up, 37% of the patients re-challenged with the same statin were taking it at the same or a higher dose. On average, patients were re-challenged with 1.2 unique statins. While not included in the systematic evidence review and, thus, not considered in determining the strength of this recommendation, a second cohort study by Zhang et al. (2017) showed a lower incidence of death and CV events in patients who continued statins after an adverse reaction.[115] The authors examined 28,266 records of patients who had at least one presumed adverse reaction to a statin and found that patients who continued statins after a statin-related adverse event had a 0.9% absolute risk reduction (ARR) of CV events (95% CI: 0.1 1.7%) and 1.2% lower mortality over four years A retrospective cohort study of 1,605 patient records by Mampuya et al. (2013) evaluated the efficacy of intermittent statin dosing compared to daily dosing and statin discontinuation in patients with confirmed intolerance.[116] In this population, 63.2% of patients tolerated daily statin dosing, 9.3% tolerated intermittent dosing, and 27.5% discontinued statins. Intermittent dosing regimens ranged from once weekly to six days per week. Rosuvastatin was the most commonly used statin in the intermittent group, accounting for 75.2% of statin prescriptions. Both daily and intermittent dosing led to a significantly greater reduction in the surrogate endpoints of TC and LDL-C compared to statin discontinuation, with greater benefit from daily dosing. About 70% of studied patients were taking concomitant lipid-lowering prescription medications and supplements. The intermittent dosing group took a significantly higher rate of supplements compared to the daily dosing group and discontinuation group (52.3% versus 41.4% versus 46.2%, respectively), including red yeast rice, Metamucil , plant stanols/sterols, omega-3 fatty acids, and coenzyme Q10 (CoQ10). Also, both the intermittent dosing and discontinuation groups had higher rates of niacin and bile acid sequestrant use. There was a non-significant trend toward a decrease in all-cause mortality at eight years for intermittent statin dosing as compared to statin discontinuation, while mortality was similar in intermittent and daily dosing groups. The most common category of statin-related events is musculoskeletal symptoms, which can be misattributed to statins and may lead to statin discontinuation and a reluctance to restart treatment. A meta-analysis not included in this CPG s systematic evidence review, Riaz et al. (2017), included over 125,000 patients and concluded that rates of myopathy were similar between the statin and placebo group (OR: 1.2, 95% CI: 0.88 1.62).[117] The absolute incidence of serious muscle injury (e.g., rhabdomyolysis) is very low and estimated to be about 3.4 per 100,000 person-years.[118] Some risk factors may predispose patients to statin-induced muscle toxicity, including drug-drug interactions, impaired hepatic or renal function, hypothyroidism, advanced age, rheumatologic disorders, vitamin D deficiency, and alcoholism.[56,62,73] Those factors need to be considered when evaluating statin intolerance. A washout period (i.e., a short-term interruption of a statin), should be implemented to evaluate whether the perceived adverse event is related to a statin. The optimal duration of the washout period was not clear in the available evidence. Based on statin half-lives, an interruption of 2 4 weeks is reasonable. Statin treatment then can be reinitiated with the same statin (if symptoms were deemed non-statin related), or with a different statin at recommended intensity (if symptoms resolved after discontinuation). If intolerance persists, providers could consider decreases in dosage. Also, intermittent dosing is an acceptable option in patients with continued tolerance issues. Only in the rare case of a serious adverse event (e.g., rhabdomyolysis) should statins be discontinued. The Work Group systematically reviewed evidence on the role of vitamin D deficiency in statin-induced myopathy. The confidence in the quality of the two available cohort studies was very low based on a small number of patients and different protocols for vitamin D supplementation.[119,120] Thus, the Work Group was unable to make a recommendation on vitamin D supplementation. As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation [114,116,119,120] and considered the evidence put forth in the 2014 CPG.[56] The Work Group s confidence in the quality of the evidence was very low. The evidence was limited by the observational nature of data and outcomes assessment. For almost all patients, there are no significant harms associated with the trial of a different statin or implementation of intermittent dosing, and there is a potential benefit of continuing treatment. Because most agents in the class are available in generic formulations, it is unlikely that switching statins will add a substantial financial burden. With proper education, it is expected that most patients will be amenable to a change in statin or an intermittent dosing schedule. Since statins have the most robust safety and clinical outcome databases of any treatment for dyslipidemia, the Work Group determined any measures that continue statin therapy were preferred over other, less robust interventions. There appeared to be no harms to re-challenging nor intermittent nondaily dosing and statins are associated with improved clinical outcomes. Thus, the Work Group decided upon a Weak for recommendation. Randomized clinical trials that evaluate the relationship between vitamin D replacement or supplementation and statin-induced myopathy are needed. Recommendation 24. We suggest offering intensified patient care (e.g., phone calls, emails, patient education, drug regimen simplification) to improve adherence to lipid-lowering medications. (Weak for | Reviewed, New-added) Discussion In a systematic review of 35 RCTs (n=925,171), Van Driel et al. (2016) examined strategies to improve patient adherence to lipid-lowering medications.[121] The systematic review found adherence to lipid- lowering medication was improved after intensified patient care. When compared to standard care, these interventions demonstrated significantly better adherence rates and a decrease in cholesterol levels in both the short term (<6 months) and long term (>6 months). Overall, patients in the intensified care group were twice as likely to be adherent to statin treatment short term, and almost three times as likely to continue treatment long term. Intensified care included drug regimen simplification, patient education and information, intensified patient follow-up with reminders via mail, telephone, and hand-held pill devices, complex behavioral approaches, group sessions, decision support systems, administrative improvements, or large-scale pharmacy-led automated telephone sessions. Intensified care was delivered by different healthcare providers, including pharmacists, nurses, and physicians. Not all interventions among studies included in Van Driel et al. (2016) resulted in positive outcomes. The effect on adherence appeared to depend on the type and quality of the intervention. For instance, Fischer et al. (2014) showed that automated pharmacy-led phone reminders to patients who failed to pick up their prescriptions in eight days after a fill date did not affect the number of abandoned prescriptions.[122] On the other hand, Vollmer et al. (2014) noted increased adherence after automated phone call reminders to patients who were due or overdue for a refill.[123] According to the Centers for Disease Control and Prevention (CDC), improving medication adherence is a public health priority and could reduce the economic and health burdens of chronic conditions.[124] The following studies were not included in the systematic evidence review and, thus, were not considered in determining the strength of this recommendation. Rodriguez et al. (2019) estimated adherence to statin therapy is <50% at one year with further decline to <30% after two years.[125] Several sociodemographic characteristics (e.g., patients aged <50 years or >70 years, African American and Hispanic patients, females, patients with low health literacy, and low income) have been associated with lower statin adherence rates.[126] A retrospective cohort analysis of 304,104 patients with prior CVD being treated at the VA showed the risk of mortality was increased by 30% in those with estimated adherence of <50% based on refill history.[125] Conversely, a 10% increase in adherence was found to be associated with a 5% decreased risk of CV-related hospitalizations.[127] Medication adherence is a complex, multifactorial issue that involves the entire healthcare system. Patient factors negatively impacting adherence may include inadequate understanding of their medical condition, lack of perceived benefit, adverse effects, pill burden, and time lag to benefit. The patient focus group emphasized the need for stronger provider-patient communication and additional education to improve their understanding of treatment. As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation.[121] The Work Group s confidence in the quality of the evidence was low. The body of evidence had some limitations, including lack of blinding given the nature of the interventions, significant heterogeneity for short-term adherence, and outcome assessment. There were no harms identified in the systematic review, and there is a significant benefit of improved adherence. Other considerations regarding this recommendation are the cost and availability of resources, such as labor and time commitment. Patient values and preferences were somewhat varied. Because there were no harms identified and given the potential benefits of medication adherence, the Work Group decided upon a Weak for recommendation. C. Lifestyle Interventions Recommendation 25. For primary and secondary prevention of cardiovascular disease, we suggest a dietitian-led Mediterranean diet. (Weak for | Reviewed, New-replaced) Discussion A systematic review by Hooper et al. (2015) reviewed 15 RCTs that reduced dietary saturated fat and replaced it with carbohydrate, monounsaturated, or polyunsaturated fat to determine the effect on CVD morbidity and mortality.[128] In eight RCTs, reducing saturated fat did not reduce CVD mortality. A systematic review by Rees et al. (2019) found that a Mediterranean diet reduced composite CV events, stroke, incidence of Type 2 DM, MI, and CV and all-cause mortality and improved the management of dyslipidemia.[129] Wu et al. (2015) conducted a meta-analysis of 18 studies that showed a significant dose-related response between dietary fiber intake and the risk of CHD and concluded that a higher intake of fiber, as in the Mediterranean diet, led to lower risk of CHD morbidity and mortality.[130] The Mediterranean diet includes a high unsaturated fat/saturated fat ratio, a substantial increase in fiber from plant-based foods (fruits, vegetables, nuts, legumes, and grains), an increased intake of fish, moderate intake of low-fat dairy products, and a low-to-moderate red wine intake for those who drink alcohol. Moreover, evidence suggests lipid outcomes were improved when a registered dietitian provided medical nutrition therapy for the management of dyslipidemia.[131] As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation.[128,129] The Work Group s confidence in the quality of the evidence was low. With respect to diet, patient values and preferences vary largely. Given the lack of risks and harm related to this diet and the evidence showing improved CV outcomes, the Work Group decided upon a Weak for recommendation. Well-controlled RCTs are needed to evaluate the effectiveness of replacing saturated fat with unsaturated fats to determine the effect on CVD mortality and morbidity. Recommendation 26. For primary and secondary prevention of cardiovascular disease, we suggest regular aerobic physical activity of any intensity and duration. (Weak 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 clinicians when advocating for lifestyle change to their patients. The biological plausibility that physical activity could improve CV outcomes by positively altering lipid profiles has been well established. Lipids and their various subtypes are established independent CV risk factors and observational data indicate associations between regular physical activity and the main components of lipids (i.e., reductions in TC and LDL, and increases in HDL).[132] Whether these changes in lipids are mediating the association between physical activity and lower CVD risk is unknown. However, a biological connection is plausible and although this evidence did not restrict inclusion to patients meeting the traditional definition of dyslipidemia based on lipid levels, we think it is reasonable to extrapolate these data to patients with dyslipidemia defined by CV risk, as we do with statins (see Dyslipidemia is Defined by Risk for Cardiovascular Disease). This broader definition of dyslipidemia and the biological plausibility connection warrant consideration of physical activity as a strategy in managing dyslipidemia. The Work Group recognized that both the 2008 Physical Activity Guidelines for Americans (PAGA) (referenced in the 2014 VA/DoD Dyslipidemia CPG) and the updated 2018 PAGA guideline recommend at least 150 minutes of moderate intensity or 75 minutes of vigorous intensity aerobic exercise per week.[133] Although randomized trial data are lacking, this CPG s systematic evidence review yielded an expansive body of observational data whose findings align with the established federal PAGA recommendations. These findings from systematic reviews and pooled analyses of observational data [134-136] and other prospective cohort studies [137-141] demonstrated an association between recommended physical activity levels and a reduction in CV mortality by 21 91% and all-cause mortality by 19 70%. These associations were found in both primary and secondary prevention populations. However, the body of evidence also suggests CV benefits at various doses of physical activity. Based on pooled analysis research of over 600,000 primary prevention patients by Arem et al. (2015), leisure time aerobic physical activity appears to have a dose-response relationship with CV and all-cause mortality.[136] Leisure time activity levels below federal recommendations were associated with a 20% reduction in CV and all-cause mortality compared to no leisure time activity, while activity three to five times the recommended level was associated with a 39% reduction in all-cause mortality and 42% reduction in CV mortality. The dose-response curve demonstrated an upper limit of benefit at three to five times recommended levels, suggesting a ceiling effect on leisure time physical activity benefits.[136] Evidence also indicates a possible benefit to activity levels much lower than federal recommendations. A systematic review and meta-analysis of prospective cohort studies by Chastin et al. (2017) showed a 29% reduction in all-cause mortality in primary prevention patients whose time spent daily in light-intensity physical activity (LIPA) (1.5 3 metabolic equivalent of task [METs]) (i.e., writing, walking 2 mph, slow ballroom dancing, golfing with a cart) was approximately twice that of their counterparts.[142] In the Copenhagen City Heart Study, Schnohr et al. (2017) prospectively followed over 12,000 primary prevention patients for over 30 years and found a 24% reduction in CV mortality in patients persistently at light leisure time physical activity (2 4 hours LIPA per week) compared to those persistently sedentary (<2 hours LIPA per week).[141] These findings suggest that in patients who are not able to achieve recommended moderate or vigorous activity levels, any movement in daily living during their leisure time might have beneficial effects on CV and all-cause mortality. Safety outcomes were not reported, though the Work Group recognizes musculoskeletal injuries are not uncommon during exercise. The Work Group determined the available body of evidence had significant methodologic limitations. No randomized studies were found and, although most were large prospective cohorts whose findings were maintained after multivariable adjustment, imbalance in unmeasured CV prognostic variables could have impacted outcomes. Additional limitations included reporting bias (i.e., 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. 