The Work Group encourages shared decision making on the risks and benefits surrounding the use of CAC for enhancing CV risk assessment. Prospective studies of CAC screening do show improvement in the net reclassification index.[29] The use of CAC screening may result in overtreatment and unnecessary radiation exposure. No significant benefit in the incidence of MI, CVD, or overall mortality has been demonstrated with the addition of CAC scoring to a traditional risk score. Even in retrospective studies showing a favorable net reclassification index, many more patients were incorrectly reclassified to a higher risk category than were correctly The risk of radiation exposure from CAC scoring is not negligible. Although not included in our systematic evidence review and, thus, not considered in determining the strength of this recommendation, Kim et al. (2009) estimated a single CAC screening at the age of 40 would result in a lifetime excess cancer risk of 9 per 100,000 for males and 28 per 100,000 for females.[31] As this is a Reviewed, Not changed recommendation, the Work Group systematically reviewed evidence related to this recommendation.[29] The Work Group s confidence in the quality of the evidence was low. Other considerations regarding this recommendation include patient preference in understanding the risk and benefits of CAC. Patient values and preferences vary but often align with a desire for more testing. The Work Group encourages a patient-provider conversation regarding the risk of over-diagnosis, cost, and radiation exposure in relation to a very small potential net benefit associated with CAC testing. Thus, the Work Group decided upon a Weak against recommendation. In the absence of individual patient data, it is unclear which patients will benefit from CAC testing. The Work Group recommends prospective studies designed to assess the benefit of adding CAC to traditional risk scoring systems for the prediction of future atherosclerotic CVD endpoints. Recommendation 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 | Reviewed, New-replaced) Discussion Traditional CV risk assessment relies on the use of multivariate models that integrate data from known risk factors and biomarkers to predict the development of CVD in an individual patient. While numerous models exist, all tend to misestimate (i.e., under- or over-estimate) risk.[26,32]In addition, patients and providers remain interested in improving risk prediction for populations identified as intermediate risk by the currently used models. The use of non-traditional biomarkers to improve the estimation of CV risk assessment has been extensively studied. Non-traditional biomarkers include genetic, serologic, psychosocial, and physiologic markers (e.g., ankle-brachial index [ABI], electrocardiogram [ECG], apolipoproteins [Apo], high-sensitivity C-reactive protein [hsCRP], physical activity, and socioeconomic status). Numerous biomarkers and other variables were assessed in this review, including ABI, lipoprotein(a), Apo A1, Apo B, CAC score, ECG, fibrinogen, HDL-C, N-terminal-pro hormone brain natriuretic peptide (NT-proBNP), hsCRP, physical activity, socioeconomic status, and Apo C3.[29,33-35] Several biomarkers have demonstrated slight additive predictive risk (e.g., hsCRP, CAC, and ABI); however, the model performance studies that demonstrate these differences are hampered by low or very low quality evidence. Also, the potential clinical impact is unknown. For example, the addition of ABI to either the FRS or PCE improves model discrimination (change in AUC: -0.006 0.112 for FRS, 0.01 for PCE) but does not significantly improve calibration or risk reclassification.[29] The addition of hsCRP to either the FRS or PCE results in minimally improved discrimination (changes in AUC: 0 0.027).[29] Other than CAC scoring, none of the other risk markers reviewed demonstrated any additive predictive risk value to traditional risk assessment models. No prospective study has shown that incorporating any additional risk marker into CV risk assessment improves outcomes.[29,33-35] The only theoretical utility of these tests would be for intermediate risk situations where there is uncertainty about the benefit of treatment. There is no prospective evidence to validate any additional risk score method as a means of clarifying intermediate risk. Incorporating additional risk factors in CV risk assessment should occur in the context of a shared decision making framework with a clear discussion about the uncertainty in how lipid management decisions will be affected by the results. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation.[26,29,32-35] The Work Group s confidence in the quality of evidence was very low. The body of evidence had several limitations (i.e., short follow-up period, low number of outcome events per variable, and lack of adequate statistical reporting).[29,33] Some variation in patient and provider values and preferences is likely since some individuals prefer as much information as possible when determining CVD risk. Other factors influencing this recommendation included resource use (e.g., staffing, time burden), the limited benefit of additive predictive risk, and potential harms from overtreatment. Thus, the Work Group decided upon a Weak against recommendation. B. Pharmacotherapy, Supplements, and Nutraceuticals a. Primary Prevention Recommendation 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. (Strong for | Reviewed, New-replaced) 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 | Reviewed, New-replaced) Discussion Evidence suggests moderate-dose statins lower CV mortality, all-cause mortality, and CV events. The largest systematic review, Yebyo et al. (2019), included 40 primary prevention trials (n=94,283).[36] The summary effect size indicated a 20% relative risk reduction in all-cause mortality over one year (number needed to treat [NNT] = 908), an 11% relative risk reduction in CV mortality over one year (NNT=715), and a 26% relative risk reduction in major CV events over one year (NNT=833). A major limitation was the limited follow-up in many trials. This systematic review included a network meta-analysis that did not find a significant difference between statin drugs.[36] Although the absolute benefit of statin treatment for primary prevention is limited in the general population, the benefit becomes more substantial as time and risk levels increase. Another systematic review of primary prevention trials, Chou et al. (2016), included 19 studies (n=71,344) of adult patients with increased CVD risk and found the same effect of moderate-dose statins (i.e., reducing all-cause mortality, CV mortality and events) but with greater absolute benefits in patients at baseline higher risk.[37] For CV mortality over the 2 to 6 year treatment period of the trials, the NNT was 233; for all-cause mortality over 1 to 6 years, the NNT was 250; and for fatal and non-fatal MI over 2 to 6 years, the NNT was 123. Dedicated studies [38,39] and subgroup analyses show the benefit of statins for primary prevention does not vary with gender, age, race, baseline lipid levels, presence of DM, CKD, or hypertension.[37] Determining the cardiac risk cutoff to recommend statin treatment is a simplified strategy to most closely resemble the risk profiles of those included in the trials which demonstrated reduction in CV risk. While no studies used CV risk scores as part of the inclusion criteria, the studied populations had a high prevalence of CV risk factors, and some studies showed an increasing absolute benefit of statins with increased baseline CV risk. The 12% threshold we chose most closely resembles the lower limit of risk of populations in the clinical trials for which the benefits clearly outweighed the risks. The major primary prevention trials showed an event rate between 6 7.5%. Since these trials lasted 2 to 6 years (roughly equivalent to 12 15% ten-year event rate), the Work Group chose a 12% ten-year risk threshold to match the available data. There are no clinical trials that specifically address the <6% risk category, which would be represented by a control group event rate of approximately 3%. Using the same methodology, only two trials included patients with risks between 6 12%, although these trials did include nearly 30,000 patients.[40-43] The Work Group decided to retain the 12% ten-year CV risk score as a threshold for recommending initiation of treatment with statins in primary prevention along with shared decision making within the 6 12% risk range from the 2014 VA/DoD Dyslipidemia CPG. The addition of patients with an LDL-C level >190 mg/dL is intended to include patients with possible familial hypercholesterolemia. In an analysis of the 20-year follow-up of the West of Scotland primary prevention trial, Vallejo-Vaz et al. (2017) demonstrated that patients with LDL-C levels >190 mg/dL treated with moderate-dose statins had significant 20-year reductions in CV mortality (3%) and all-cause mortality (5%), more than double the reductions in the population with lower initial LDL-C levels.[44] Thus, this study provided the first prospective evidence on the long-term benefit of moderate-dose statins. Diabetes is similarly maintained as an indication for statin therapy because a systematic review by de Vries et al. (2012) showed a 3% reduction in CV events in diabetics with moderate-dose statins for primary prevention Moderate-dose Statin Safety While there are known risks associated with the use of moderate-dose statins, most feel these risks are low and that the benefits of statins outweigh these risks in patients at risk for CVD.[40-42,46] It should be noted, however, that most randomized controlled trials (RCTs) of statins did not systematically assess for adverse events routinely. In a systematic review by Chou et al. (2016) of primary prevention RCTs reporting statin-induced adverse events, there was no increased risk for new-onset DM in patients treated with moderate-dose statins versus placebo (relative risk [RR]: 1.05, 95% CI: 0.91 1.2).[37] However, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, used a high-dose statin for primary prevention and reported a higher risk for DM than placebo (RR: Another systematic review by Engeda et al. (2019) of statins for primary prevention demonstrated a borderline significant increase in DM risk in 78,039 patients from RCTs (RR: 1.11, 95% CI: 1.00 1.22) and a significant increase in DM incidence in nearly four million patients from observational studies (RR: 1.55, 95% CI: 1.39 1.74).[48] A systematic review by Macedo et al. (2014) of 90 observational studies of all statin doses for primary and secondary prevention showed a trend towards an increased risk for DM that did not reach significance (odds ratio [OR]: 1.31, 95% CI: 0.99 1.73).[49] While statins may increase the risk of DM, the risk has not been demonstrated in RCTs of moderate-dose statins. Observational studies suggest a low risk of DM attributable to moderate-dose statins. Other adverse effects of statins reported in clinical trials may include muscle-related complaints and elevation of liver transaminases. However, in the Chou et al. (2016) systematic review of primary prevention trials, there was no increase in serious adverse events, cancer or fatal cancer, myalgias or elevation of liver transaminases, or the risk for withdrawal because of adverse events.[37] Although there was no increased risk for rhabdomyolysis or myopathy, some trials reported these adverse events. This meta-analysis included all statin doses.[37] Macedo et al. (2014) reviewed observational studies of statins and found that statin use was not associated with an increased risk of neurologic or psychological effects, eye disorders, or renal impairment.[49] There was a higher incidence of reported myopathy (OR: 2.63, 95% CI: 1.5 4.61) and liver transaminase elevation (OR: 1.54, 95% CI: 1.47 1.62) with statins in these trials. The observational studies evaluated were heterogeneous in type and dose of statin, and the meta-analysis suffered from imprecision of the summary effects.[49] In a systematic review of primary prevention trials by Yebyo et al. (2019), discontinuation of statins for adverse effects was not different than placebo but there was a higher risk for myopathy, hepatic enzyme elevation, and renal dysfunction with statins.[36] Overall, there may be a risk of liver enzyme elevation and myopathy with statins, which appears inconsistent, even among large reviews. While the package inserts for statins continue to recommend baseline liver function testing (LFT), there is no recommendation for routine testing after initiation. Duration of Statin Therapy Any recommendation on the optimal duration of statin use beyond that of clinical trials (i.e., about six years) is unknown. Although many trials have studied the legacy effects of statins after completion of the trials, Nayak et al. (2018) demonstrated that after each trial, the proportion of patients taking statins after trial completion were nearly identical (within 4%) between the previous statin and control populations.[50] Instead of demonstrating the continued benefit of statin use during the trial period, these long-term follow-up studies simply demonstrate the continuing advantage of the initial study period for the treatment group. A systematic review by De Vera et al. (2014) found one cohort study that suggested a significant reduction in MI with two years of continuous statin use versus non-continuous use.[51] As outlined above in Scope of this Clinical Practice Guideline, the CPG applies to patients aged 40 years or older. The Work Group noted that evidence is limited to this population, which is why risk calculators require a minimum age of 40 years old. The Work Group understands there are conditions to consider for primary prevention treatment at younger ages, such as severely elevated LDL-C levels that may suggest a familial hyperlipidemic condition. These cases are challenging because there is no direct evidence to guide providers. Thus, shared decision making about the uncertain benefit and risks is the only recommended strategy for patients younger than age 40 who are interested in lipid testing and management. Several observational points can inform this decision but are not sufficient for an evidence-based recommendation. Cardiovascular events and mortality are very low in the under 40 age group, and even observational studies of FH do not suggest treatment is necessary. For example, a French registry of HeFH showed that only 7% had a lifetime history of MI, stroke, or peripheral arterial disease (PAD), which increased to 17% when revascularization was included.[52] Including revascularization, 4% of the registry had a CV event before age 40.[52] A Spanish registry showed that of the 15% of HeFH patients with CV event history, only 1.3% were age 40 or under when they had their first event.[53] While statin therapy is reasonable for patients under age 40, there are no randomized primary prevention trials to demonstrate or quantify benefit. The evidence of the risks of non-continuous statin treatment (see Recommendation 23) suggests the decision to start therapy should be considered lifelong. Because this is a personal decision, shared decision making is even more essential in the absence of direct evidence. Despite the consistent evidence supporting the use of statins for primary CV event prevention, the NNT is large overall and increases for patients at lower risk. Informing patients of the risks of moderate-dose statins, where the DM risk is questionable and other risks have not been consistently demonstrated in trials, may be helpful in shared decision making. The low cost of generic statins and convenience of oral daily dosing further support their use. As these are Reviewed, New-replaced recommendations, the Work Group systematically reviewed evidence related to this recommendation [36-39,44,48-51] and considered the evidence put forth in the 2014 CPG.[40,42,45,47] The Work Group s confidence in the quality of the evidence for both recommendations was moderate. The body of evidence was primarily limited by study populations with wide variability in CV risk and varied inclusion criteria, leading to the retention of the 12% threshold and 6 12% risk range from the 2014 VA/DoD Dyslipidemia CPG. Given the consistent evidence of improvement in CV and all-cause mortality and reduction in MACE with limited harms, the Work Group determined that the benefits of moderate-dose statins outweighed the harms of treatment, but with an absolute improvement that varies based on baseline risk. Thus, the Work Group decided upon a Strong for recommendation for Recommendation 6 and a Weak for for Recommendation 7. While the benefits of statins for primary prevention are well proven for higher risk populations (i.e., >12% 10-year risk), determining the risk reduction in lower risk populations is an important research priority. Recommendation 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. (Weak against | Reviewed, New-replaced) Discussion Despite consistent evidence supporting the use of statins for CVD, this CPG s systematic evidence review found no evidence that high-dose statins offer additional benefit over moderate-dose statins in the prevention of CV events or mortality for primary prevention.[36,37] The only major trial that evaluated a high-dose statin for primary prevention was the JUPITER trial, which compared rosuvastatin 20 mg daily to placebo.[47] The JUPITER trial showed comparable changes in patient-centered outcomes to other statins in primary prevention trials.[37] The ASTRONOMER and METEOR trials also included high-dose statins but were much smaller than JUPITER. There are no studies that directly compare high-dose to moderate-dose statins in a primary prevention population. High-dose Statin Safety Studies of both primary and secondary prevention suggest that higher statin doses increase the adverse event risk. The most common adverse events of statins are elevated liver enzymes without reports of liver failure and muscle symptoms with rare reports of rhabdomyolysis. A meta-analysis by Silva et al. (2007) showed high-dose simvastatin and atorvastatin are associated with more adverse events (OR: 1.44, 95% CI: 1.33 1.55) and more discontinuation due to adverse events (OR: 1.28, 95% CI: 1.18 1.39) than lower dosed statins.[54] Moreover, it showed more LFT and creatine kinase (CK) abnormalities in the higher dose group. A meta-analysis of 17 RCTs limited to high-dose atorvastatin, Li et al. (2016), showed a higher risk for liver transaminase elevation (RR: 4.59, 95% CI: 3.26 6.48) and discontinuation due to adverse events (RR: 1.29, 95% CI: 1.17 1.42) versus placebo or lower dose atorvastatin but no increases in CK, myalgia, or rhabdomyolysis.[55] Although a previous analysis by the Cholesterol Treatment Trialists (CTT) showed that high-dose statins slightly increase the risk of rhabdomyolysis, this increase was limited to simvastatin at 80 mg daily, which is no longer recommended by the FDA.[56] A meta-analysis by Engeda et al. (2019) shows that high-dose statins increase the risk of DM compared to placebo with a number needed to harm (NNH) of 208 over four years with no increased risk with lower statin doses.[48] In the JUPITER trial, the NNH for DM was nearly identical to the NNT to reduce all-cause mortality.[47] A meta-analysis by Wang et al. (2017) showed an increase in incident DM with any statin (OR: 1.11, 95% CI: 1.03 1.2) with high-dose statins conferring more risk (OR: 1.18, 95% CI: 1.10 1.28, NNH=130 over four years).[57] These findings are also supported by a meta-analysis, Preiss et al. (2011), that demonstrated more new-onset DM associated with high statin doses versus lower doses (OR: 1.12, The effect of high-dose statins on the risk for intracerebral hemorrhage (ICH) is uncertain. While a meta- analysis of seven RCTs by Pandit et al. (2016) showed increased ICH with high-dose statins versus placebo, studies comparing different statin doses were specifically excluded.[59] The results are contradicted by a more comprehensive meta-analysis by McKinney et al. (2012), which did not show an increased risk of ICH (OR: 1.08, 95% CI: 0.88 1.32).[60] McKinney et al. (2012) was not included in this CPG s systematic evidence review and, thus, did not impact the strength of this recommendation. A meta-analysis by Sun et al. (2015) suggested high-dose statins do not increase the risk of cancer.[61] Although not included in our systematic evidence review, a meta-analysis of 27 randomized trials from the CTT Collaborators, Emberson et al. (2012), also showed no increased risk of cancer or cancer mortality.[62] Summary The lack of evidence for increased benefit with high-dose statins in primary prevention populations led the Work Group to recommend against increasing statin intensity in primary prevention. Despite the low overall risks of higher statin doses, increased adverse events could lead to more statin discontinuation. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation [36,37,48,55,57,59,61,63] and considered the evidence put forth in the 2014 CPG.[47,56,58] The Work Group did not find direct comparisons of the benefit of high-dose statins compared with moderate-dose statins in a primary prevention population. The literature comparing high- and moderate-dose statins for secondary prevention suggests the increased harms of higher dose statins. Given the lack of evidence of added benefit with higher dose statins, the Work Group determined the increased risks outweigh unproven benefits, although patient preferences may vary significantly on this decision. Thus, the Work Group decided on a Weak against recommendation. More research is needed on the effectiveness of high-dose statins for primary prevention in comparison to moderate-dose statins. This research should consist of direct comparisons between moderate- and high- dose statins in similar populations. These populations should be stratified by CV risk scoring. Recommendation 9. For primary prevention, there is insufficient evidence to recommend for or against using ezetimibe with or without statins. (Neither for nor against | Reviewed, New-replaced) Discussion This CPG s systematic evidence review yielded insufficient evidence related to ezetimibe monotherapy for primary prevention. There was one relevant meta-analysis of 13 trials from the 2014 VA/DoD Dyslipidemia CPG systematic evidence review and a single subsequent trial not included in the meta-analysis.[64,65] All of this evidence compared the addition of ezetimibe to statins with increasing the statin dose in primary prevention patients. Outcomes were limited to patient safety and surrogate outcome measures (e.g., LDL- C lowering). The Study of Heart and Renal Protection (SHARP) by Baigent et al. (2011) was not included in either the current or previous systematic evidence review and, thus, was not considered in determining the strength of this recommendation.[66] This study evaluated ezetimibe for primary prevention by comparing an ezetimibe-simvastatin combination to placebo in patients with CKD. It found significant reductions in the primary composite outcome of major atherosclerotic events (e.g., non-fatal MI, coronary death, non- hemorrhagic stroke, and any arterial revascularization) in favor of the combination versus placebo (RR: 0.83, 95% CI: 0.74 0.94, NNT=48). However, the effect of ezetimibe on clinical outcomes could not be separated from that of statins. Thus, the benefit of ezetimibe alone could not be determined. The adverse effects of ezetimibe appear to be less than those associated with statins. The systematic review by Mikhailidis et al. (2011) that compared the combination of ezetimibe and a statin to increasing statin doses found that adverse effects were similar in the ezetimibe-statin combination group and the increased statin dose group.[65] However, the included trials were less than four months in length and reviewed outcomes that are neither patient centered nor within the scope of this guideline. In a separate trial evaluating ezetimibe in secondary prevention, Cannon et al. (2015), adverse events were significantly less with ezetimibe-statin combinations than high-dose statins.[67] As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation.[64] The systematic evidence review did not identify evidence in primary prevention populations for reducing CV events with ezetimibe monotherapy. With the strong evidence for the efficacy of statins for improving outcomes, providers should use statins whenever feasible. The evidence for ezetimibe in primary prevention is limited to surrogate outcomes, and even these are only available in combination with statins. Based on the lack of evidence for ezetimibe s effect on CV risk in primary prevention, either alone or in combination with statins, the Work Group decided upon a Neither for nor against recommendation. This recommendation highlights the research deficits for the use of ezetimibe for primary prevention. Since providers often consider the use of ezetimibe in patients who cannot tolerate statins, the lack of evidence for ezetimibe as monotherapy for primary prevention is a significant knowledge gap. Despite the lack of evidence for significant harm from statins, press coverage is replete with articles suggesting safety concerns with statins. This negative coverage contributes to patient apprehension toward statins, which was noted by patient focus group participants. If benefit with ezetimibe monotherapy in primary prevention could be proven, providers would have more options. Recommendation 10. For primary prevention, we recommend against offering PCSK9 inhibitors due to unknown long- term safety, inconclusive evidence for benefit, and high cost. (Strong against | Reviewed, New-added) Discussion The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been studied primarily for secondary prevention of CV events, but trials have included some primary prevention patients. A systematic review by Du et al. (2019) included 10,225 primary prevention patients from studies involving PCSK9 inhibitors with and without statins and failed to demonstrate significant improvements in CV events or mortality.[68] In fact, no important CV outcome showed significant improvement from PCSK9 inhibitors when used for primary prevention. The authors of this review reported they did not have individual trial data, so they could not separate trials that combined primary and secondary prevention. The FDA approved PCSK9 inhibitors for primary prevention in FH based solely on the effect of lipid parameters in this population. None of the studies were designed to measure CV outcomes. The ODYSSEY LONG TERM trial did perform a post hoc analysis of a combination of secondary prevention and FH patients that showed benefit but did not separate the primary and secondary prevention populations.[69] Because the systematic review of primary prevention patients showed no benefit in any outcome, the Work Group has no basis to recommend PCSK9 inhibitors in any primary prevention population. The high cost of these therapies and unknown long-term safety led the Work Group to recommend against this therapy until a patient-oriented outcome benefit is demonstrated. Although primary and secondary prevention studies show the short-term adverse effects of PCSK9 inhibitors are limited, the side effects beyond three years are unknown. The most common adverse event is injection site reactions, which occur at a higher rate compared to placebo. However, Schmidt et al. (2017) demonstrated a significant increase in the risk of adverse events, mainly myalgia and influenza, with PCSK9 inhibitors compared to placebo.[70] The primary limitation of studies exploring the safety of PCSK9 inhibitors for primary prevention is their limited follow-up. Unlike the evidence evaluating the effects of statins, which include trials with longer term safety outcomes in secondary prevention, the PCSK9 literature is limited to safety outcomes of up to three years. The possibility of long-term reactions, adverse events, or consequences of prolonged levels of very low LDL-C with these agents are unknown. PCSK9 inhibitors are extremely expensive and of questionable cost-effectiveness, even in populations where there is evidence of efficacy such as secondary prevention. A systematic review by Korman et al. (2018) included two cost-effectiveness analyses and even in secondary prevention found that PCSK9 inhibitors did not meet a willingness to pay (WTP) threshold of $100,000 per additional quality-adjusted life year (QALY).[71] This was reinforced by a later cost-effectiveness analysis by Kazi et al. (2019).[72] Because the evidence of benefit is lacking, the use of PCSK9 inhibitors in primary prevention cannot be justified, especially given the high current cost of these medications. Despite the dearth of evidence for primary prevention with PCSK9 inhibitors, there is heavy industry marketing and enthusiasm surrounding new therapies, which may influence some patients and providers to consider its use. We therefore felt it was important to make a clear statement against its use until there is more evidence about its risks and benefits. As this is a Reviewed, New-added recommendation, the Work Group systematically reviewed evidence related to this recommendation.[68,70-72] The Work Group s confidence in the quality of the evidence was low. The evidence s key limitation was the short duration of follow-up. Indeed, all but one study had a follow-up of fewer than two years. Per GRADE methodology, though, the Work Group determined a Strong against recommendation was warranted based on the lack of evidence for reducing CV risk, the unknown long-term adverse event/safety profile in a primary prevention population, and the treatment s prohibitive cost. Thus, the Work Group decided upon a Strong against recommendation. More research on the safety and effectiveness of PCSK9 inhibitors, specifically in the primary prevention populations, is needed. Similar to our recommendations for other primary prevention trials, these studies should use CV risk scores to select patients for treatment. These studies need to be larger and have longer follow-up periods given the lower baseline absolute CVD risk than the secondary prevention trials conducted to date, which will also allow the subgroup analysis that has been performed with statins. b. Secondary Prevention Recommendation 11. For secondary prevention, we recommend using at least a moderate-dose statin. (Strong for | Reviewed, New-replaced) Discussion Secondary prevention is intended to prevent subsequent CVD events in patients with an established clinical diagnosis of CVD. This includes patients with ACS, MI, coronary arteries bypass graft (CABG), percutaneous coronary interventions (PCI), stable obstructive coronary artery disease (CAD) including angina and equivalents, cerebrovascular accident (CVA)/stroke, transient ischemic attack (TIA), and atherosclerotic PAD including claudication or abdominal aortic aneurysm (AAA). Secondary prevention does not include patients with asymptomatic arteriosclerosis, as detected by incidentally reported or measurements of CAC, exercise test, intima-media thickness ultrasound measurement, ABI, or brachial reactivity because there is little evidence on how to best manage the detection of subclinical atherosclerosis. These entities were not specified within the inclusion criteria of clinical trials and the management of subclinical atherosclerosis is beyond the scope of this CPG. The Work Group conceded that revascularizations were not a clear outcome because the indications for these interventions are not well defined, may have regional variation, and their impact on mortality or other important outcomes (e.g., congestive heart failure [CHF]) is uncertain. This recommendation is supported by three meta-analyses by the CTT Collaborators.[56,73,74] From the CTT meta-analyses, statin use led to a reduction in all-cause mortality, non-fatal MI, coronary death, and non-fatal stroke when compared to placebo control. The trials included in the meta-analyses used primarily fixed, moderate-dose statins (dosing that reduced LDL-C by 30 40% from baseline, including Moderate-dose Statin Safety There are known, limited harms associated with moderate-dose statins but the benefits of moderate-dose statins for both primary and secondary prevention significantly outweigh the risks.[46] A systematic review and meta-analysis of 90 observational studies in both primary and secondary prevention populations, Macedo et al. (2014), examined the adverse effects of statins and found statin use was not associated with an increased risk of neurologic or psychological effects, eye disorders, or renal impairment in the general population.[49] There was a higher incidence of reported myopathy (OR: 2.63, 95% CI: 1.5 4.61), liver transaminase elevation (OR: 1.54, 95% CI: 1.47 1.62), and a trend for DM (OR: 1.31, 95% CI: 0.99 1.73). The studies were observational in design and heterogeneous, and the meta-analysis suffered from imprecision of the summary effects. Additionally, dose range or mean statin dose was not reported.[49] As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation [49] and considered the evidence put forth in the 2014 CPG.[56,74] The Work Group s confidence in the quality of the evidence was moderate. Although some variation in patient and provider values and preferences is likely, the evidence base clearly demonstrated that the risks/harms were outweighed by the potential benefits (e.g., improved mortality, MI and stroke reduction). Thus, the Work Group decided upon a Strong for recommendation. Recommendation 12. For secondary prevention in higher risk patients who are willing to intensify treatment, we suggest offering high-dose statins for reducing non-fatal cardiovascular events after discussion of the risk of high-dose statins and an exploration of the patient s values and preferences. (Weak for | Reviewed, New-replaced) Discussion It is understood that the baseline risk for new CVD events is higher in patients treated for secondary prevention than patients treated for primary prevention. However, evidence suggests there are subgroups of patients with established CVD with features or risk factors that further increase their risk for future events. These subgroups include patients with (1) MI or ACS in past 12 months; (2) recurrent ACS, MI, or CVA; or (3) established CVD and with additional risk factors (e.g., currently smoking, DM, PAD, or CABG/PCI). These patients are more likely to benefit from intensified treatment (e.g., maximum dose statins, the addition of ezetimibe to statins, and then the addition of PCSK9 inhibitor to statins plus ezetimibe) to reduce their CV risk. Although there are no prospective studies comparing these higher risk groups to lower risk groups for secondary prevention, subgroup and post hoc analyses demonstrate a greater risk for CVD events in these patients who may benefit from more aggressive treatment.[75,76] The meta-analysis by de Vries et al. (2014) compared the incidence of major CV and cerebrovascular events between standard-dose statins and placebo (n=4,351) and standard-dose statins with intensive- dose statins (n=4,805) for secondary prevention in patients with DM.[77] There was a statistically significant reduction in major CV and cerebrovascular events in favor of the more intensive statin dose group versus standard dose (RR: 0.91, 95% CI: 0.84 0.98). Another meta-analysis, Koskinas et al. (2018), compared more intensive lipid-lowering therapy (n=76,678) to less intensive therapy.[78] It evaluated 19 clinical trials (n=75,829) conducted primarily in secondary prevention populations. Of the 15 statin trials, six compared a higher dose statin to a lower or moderate- dose statin. The primary outcome was a composite of major vascular events (e.g., CV death, MI or other ACS, coronary revascularization, and stroke). The high-dose statin therapy reduced events compared to less intensive statin therapy (RR: 0.88, 95% CI: 0.82 0.93). A meta-analysis included in the 2014 VA/DoD Dyslipidemia CPG s systematic evidence review, Preiss et al. (2011), analyzed five studies of moderate- versus high-dose statins.[58] Although its primary objective was to determine the risk for incident DM with high- versus moderate-dose statins, the authors also reported composite CV events, including all-cause mortality, CV death, non-fatal MI, non-fatal stroke and coronary revascularization. Cardiovascular events occurred less often in the high-dose statin group (OR: 0.84, 95% CI: 0.75 0.94, NNT=155), resulting in 6.5 fewer CVD events per 1,000 patient-years treated in the high- dose group over a mean follow-up period of 4.9 years. Of the individual CV events, only non-fatal MI (OR: were statistically different. The CTT meta-analysis by Baigent et al. (2010) analyzed five trials comparing a high- to moderate-dose statin and demonstrated a statistically significant reduction in any major vascular event (non-fatal MI, coronary heart disease [CHD] death, coronary revascularization, stroke) in favor of the higher dose (unweighted RR: 0.85, 95% CI: 0.82 0.89, NNT=125) versus the moderate statin dose.[56] In these meta-analyses, there was no statistically significant difference in CV or all-cause mortality when comparing high-dose statins to lower dose statins.[56,77,78] The incremental benefit was only statistically significant for a reduction in non-fatal events (e.g., MI, stroke, and revascularization). High-dose Statin Safety Studies of both primary and secondary prevention suggest that higher statin doses increase the risk for statin-related adverse events. The most commonly reported adverse events of statins in RCTs are elevated liver enzymes without reports of liver failure and muscle symptoms with rare cases of rhabdomyolysis. A meta-analysis by Silva et al. (2007), which was not identified in the 2014 or 2019 systematic evidence review, showed that high-dose simvastatin and atorvastatin were associated with more adverse events (OR: 1.44, 95% CI: 1.33 1.55) and more discontinuation due to adverse events (OR: 1.28, 95% CI: 1.18 1.39) than lower dose statins.[54] These interventions were also associated with statistically more LFT and CK abnormalities. A meta-analysis of 17 RCTs limited to high-dose atorvastatin, Li et al. (2016), showed a higher risk for liver transaminase elevation (RR: 4.59, 95% CI: 3.26 6.48) and discontinuation due to adverse events (RR: 1.29, 95% CI: 1.17 1.42) versus placebo or lower dose atorvastatin but no significant increase in CK, myalgia, or rhabdomyolysis.[55] Although a previous analysis by the CTT showed that high-dose statins slightly increase the risk of rhabdomyolysis, this increase was limited to simvastatin a dose of 80 mg daily, which is no longer recommended by the FDA.[56] Diabetes Mellitus A meta-analysis by Wang et al. (2017) showed an increase in incident DM with any statin (OR: 1.11, 95% CI: 1.03 1.2), with high-dose statins conferring more risk (OR: 1.18, 95% CI: 1.10 1.28, NNH=130 over four years).[57] Another meta-analysis, Khan et al. (2019), analyzed the association of reducing LDL-C with lipid- lowering drugs and the risk for DM.[79] It included 33 RCTs (n=21 statins, n=12 PCSK9 inhibitors) that compared more intensive therapy (n=83,123) to less intensive therapy (n=80,565). More intensive therapy was associated with a higher risk for new-onset DM versus less intensive regimens (RR: 1.07, 95% CI: 1.03 1.11, p <0.001, no heterogeneity). The increased risk was largely due to a higher rate of new cases of DM with statins (RR: 1.10, 95% CI: 1.05 1.15). A meta-analysis by Preiss et al. (2011) also demonstrated more new-onset DM with high statin doses versus lower doses (OR: 1.12, 95% CI: 1.04 1.22, NNH=498 over five years).[58] However, the reduction in CV events with high-dose statins was greater (OR: 0.84, 95% CI: 0.75 0.94, NNT=155) than the risk for new-onset DM (OR: 1.12, 95% CI: 1.04 1.22, NNH=498 over five years). Intracranial Hemorrhage The effect of high-dose statins on the risk for ICH is uncertain. While a meta-analysis of seven RCTs, Pandit et al. (2016), showed increased ICH with high-dose statins versus control, relevant studies comparing different statin doses were excluded.[59] These findings are contradicted by a more comprehensive meta- analysis by McKinney et al. (2012), which did not show an increased risk of ICH (OR: 1.08, 95% CI: 0.88 1.32) regardless of the percent reduction in LDL-C or level of LDL-C achieved.[60] Cancer A meta-analysis by Sun et al. (2015) suggests high-dose statins do not increase the risk of cancer.[61] Although not included in our systematic evidence review, a meta-analysis of 27 randomized trials from the CTT Collaborators also showed no increased risk of cancer or cancer mortality.[62] Summary Patients should be provided an opportunity for a shared, informed decision regarding the harms and benefits of statin therapy; therefore, treatment should be individualized based on CV risk. Use of high-dose statins is associated with a reduction in non-fatal CVD events without demonstrated improvement in mortality, which should be balanced with an increased risk for some adverse events and a higher rate of discontinuation due to adverse events compared to use of moderate statin doses. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation [55,57,59,61,75-79] and considered the evidence put forth in the 2014 CPG.[56,58] The Work Group s confidence in the quality of the evidence was moderate. The Work Group determined the benefits, a reduction in non-fatal CV events and no improved mortality, outweighed the increase in harms, including the risk for new-onset DM. Variation in patient and provider values and preferences is likely since the risk/benefit ratio is not as favorable for high-dose versus moderate-dose statins. Thus, the Work Group decided upon a Weak for recommendation. More research is needed to identify the most effective, safe approach for lowering risk for recurrent CVD events, including a comparison between maximizing statin doses and other interventions for secondary prevention. Risk stratification should be prospectively evaluated to identify patients at sufficiently high risk who would most benefit from more aggressive lipid-modifying treatment (e.g., assigning higher weight to risks like DM and PAD versus advanced age or renal impairment). Recommendation 13. For secondary prevention in higher risk patients who are willing to intensify treatment, we suggest adding ezetimibe to either moderate- or high-dose statins for reducing non-fatal cardiovascular events following a discussion of the risks, additional benefits, and an exploration of the patient s values and preferences. (Weak for | Reviewed, New-replaced) Discussion The addition of ezetimibe to moderate-dose statins in higher risk patients for secondary prevention of CV events is supported by two fair quality meta-analyses by Hong et al. (2018) [80] and Zhan et al. (2018) [81] and two fair quality studies of CV risk stratification and benefit of adding ezetimibe to statins using data from the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).[75,76] Hong et al. (2018) included seven trials (n=28,191 [7,298 with DM]) comparing a statin plus ezetimibe versus a statin alone or placebo and stratified by the presence of DM.[80] The addition of ezetimibe to statins in patients with DM was associated with a greater reduction in CV events compared to those respectively). Zhan et al. (2018) found that ezetimibe added to statins reduced CV event risk versus a statin alone (RR: 0.94, 95% CI: 0.9 0.98).[81] Neither analysis showed a change in CV or all-cause mortality. Two secondary analyses suggest the benefit of ezetimibe is greater in high-risk patients for secondary prevention.[75,76] In Bohula et al. (2017), the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS) Tool was applied to data from IMPROVE-IT to predict which patients may benefit most from the addition of ezetimibe to statins.[75] The TIMI TRS is a nine-point risk stratification tool developed from a large population of patients with atherothrombosis to predict CV death, MI, and ischemic stroke. The nine risk indicators include: CHF, hypertension, aged 75 years and older, DM, prior stroke, prior CABG, PAD, estimated glomerular filtration rate <60 mL/min, and smoking. Based upon number of risk indicators, 45% of patients (n=8,032) were low risk, 30% (n=5,292) were intermediate risk, and 25% (n=4,393) were high risk. Using the risk prediction tool, patients at high risk (>3 risk indicators) had a statistically lower incidence of the composite endpoint of CV death, MI, or ischemic stroke in the simvastatin 40 mg plus ezetimibe group versus simvastatin 40 mg alone (33.9% versus 40.2%, respectively, hazard ratio [HR]: 0.81, 95% CI: 0.73 0.9, NNT=16) and individual components of the primary endpoint.[75] Patients at intermediate risk (i.e., two risk indicators) and low risk (i.e., 0 1 risk indicator) did not show a statistically significant benefit of combination treatment versus statins alone over a period of seven years in IMPROVE-IT.[75] In another analysis of IMPROVE-IT, Giugliano et al. (2018), examined outcomes based upon the presence of DM.[76] Patients with DM were generally older and women. There were 4,933 patients with DM in IMPROVE-IT, representing 27% of the intervention and control group. In patients with DM, statin plus ezetimibe reduced the seven-year Kaplan-Meier (KM) event rate in the composite endpoint more than statins alone (HR: 0.85, 95% CI: 0.78 0.94, NNT=18). In patients without DM, the absolute difference in the primary composite outcome was 0.7% and not statistically different over a seven-year period (HR: 0.98, 95% CI: 0.91 1.04). When the authors applied the TRS tool, all patients with DM had a statistically significant benefit regardless of risk. However, in patients without DM and determined to be at low to intermediate risk based upon the TRS tool, no benefit was observed with combination therapy. There were no differences in CV or all-cause mortality regardless of CV risk.[76] Safety The addition of ezetimibe to statins is not associated with a greater risk for hepatic toxicity, cancer, or gallbladder-related conditions, but it is unclear if the risk of myopathy or rhabdomyolysis is increased because of imprecision in the data and low event rates.[76,81] Summary The addition of ezetimibe to statins (e.g., simvastatin) reduces CV event endpoints without changing mortality, similar to maximizing the statin dose.[75,76,80,81] The greatest reduction in CV events occurred in patients with DM or in those with three or more risk factors. There is no evidence for an increased risk of cancer, hepatotoxicity, or gallbladder-related diagnoses with the addition of ezetimibe to statins, but the effect on muscle-related complaints is less clear. As this is a Reviewed, New-replaced recommendation, the Work Group systematically reviewed evidence related to this recommendation.[75,76,80,81] The Work Group s confidence in the quality of the evidence was moderate. Based on secondary analyses of the available evidence, the Work Group determined the benefit of adding ezetimibe to statins in patients with DM or in those at higher risk outweighed the risk of harms. Some variation in patient and provider preferences is likely but because of the reduction in non- fatal events, limited harms, ease of use, and generic availability, the Work Group decided upon a Weak for recommendation. More research is needed to identify the most effective, safe approach for lowering risk for recurrent CVD events including a comparison between maximizing statin doses and adding ezetimibe to moderate- and high-dose statins for secondary prevention. Risk stratification should be prospectively evaluated to identify patients at sufficiently high risk who would most benefit from more aggressive lipid-modifying treatment (e.g., assigning higher weight to risks like DM and PAD versus advanced age or renal impairment). Recommendation 14. For secondary prevention in higher risk patients who are willing to intensify treatment, we suggest offering a PCSK9 inhibitor in addition to a maximally tolerated statin dose with ezetimibe for reducing non-fatal cardiovascular events following a discussion of their uncertain long-term safety, additional benefits, and an exploration of the patient s values and preferences. (Weak for | Reviewed, New-replaced) Discussion In the systematic review of eight trials by Schmidt et al. (2017), PCSK9 inhibitors reduced the risk of CVD events in high-risk patients (OR: 0.86, 95% CI: 0.8 0.92) without effecting CV or all-cause mortality. Control treatments varied, including placebo and a statin with or without ezetimibe.[70] The more recent systematic review by Du et al. (2019) found that PCSK9 inhibitors reduced the risk of CV events (RR: 0.84, 95% CI: 0.79 0.89), non-fatal MI (RR: 0.83, 95% CI: 0.74 0.93), and any type of stroke (RR: 0.75, 95% CI: 0.65 0.85), with no effect on mortality.[68] Short-term (<3 years) safety data for PCSK9 inhibitors suggest no increased risk for new-onset DM,[79,82] no effect on neurocognitive function,[83] and no difference in serious adverse events. The only significant treatment-emergent adverse effect was injection site reactions, which were statistically higher for evolocumab and alirocumab versus control.[82,84,85] The long-term safety of these agents and the effect of prolonged levels of very low LDL-C is unknown. Thus, additional research is needed. In higher risk patients, there are several approaches that have been proven to reduce non-fatal CVD events compared to moderate-dose statins (see Table 1). However, there is no direct evidence to support the superiority of a single approach for intensification of lipid-lowering therapy between: a) maximizing statin dose; b) adding ezetimibe to moderate- or high-dose statin (in patients already on high-dose statins); or c) adding PCSK9 inhibitors to maximum-dose statin with or without ezetimibe Table 1. 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. 