In risk dis- cussion with intermediate-risk patients, the presence of CKD favors initiation of statin therapy. In adults with advanced kidney disease requiring dialysis treatment who are currently on pharmacological LDL-lowering therapy with a statin, it may be reasonable to continue In adults with CKD that requires dialysis treatment, initiation of a statin is not recommended on the basis of 2 large-scale RCTs.S4.5.4-3,S4.5.4-4 Recommendation-Specific Supportive Text not on dialy- sis) and presence of albuminuria (albumin-to- creatinine ratio 30 mcg/mg) are independently associated with elevated risk of ASCVD. Hence, in intermediate-risk patients, CKD counts as a risk- enhancing factor. According to some studies,S4.5.4-5 the cardiovascular risk for persons with reduced eGFR may be as high as that observed among patients with diabetes mellitus and no CKD. Presence of albuminuria with reduced eGFR multiplies this CVD risk. The risk is graded and increases with severity of eGFR impairment, with observed threshold of risk beginning around 75 , whereas the risk associated with albuminuria is linear.S4.5.4-6 Trials show abso- lute benefit from statin use, and this benefit is consistent across eGFR stages. However, the RRR per LDL-C lowering may be lower with more advanced CKD. Albuminuria is independently associated with CVD risk. However, the one trial done for primary prevention in persons with albu- minuria and preserved eGFR had too few events to be conclusive.S4.5.4-7 2. According to this recommendation, in patients with CKD who are currently taking a statin, it may be reasonable to continue the statin. In sup- port of this, in the SHARP trial (Study of Heart and Renal Protection) (simvastatin plus ezetimibe versus placebo), >30% of persons transitioned to After weighting for subgroup-spe- cific reductions in LDL-C was performed, the pro- portional effects on major atherosclerotic events were similar in patients on dialysis and those who were not on dialysis. 3. Although persons on dialysis have the high- est absolute risk of events (and thus poten- tial for higher ARR), the proportion of deaths thought to be due to atherosclerotic events is The lack of benefit in RCTs with statin initiation among persons on dialysis raises the question of competing risks. Unfortunately, there CLINICAL STATEMENTS AND GUIDELINES are not enough data to distinguish the potential for benefit from statin therapy between those on peritoneal dialysis and those on hemodialysis. 4.5.5. Adults With Chronic Inflammatory Disorders and HIV Recommendations for Adults With Chronic Inflammatory Disorders and HIV Referenced studies that support recommendations are summarized in Online Data Supplement 39. COR LOE Recommendations IIa B-NR In adults 40 to 75 years of age with LDL-C have a 10-year ASCVD risk of 7.5% or higher, chronic inflammatory disorders and HIV are risk-enhancing factors and in risk discussion favor moderate-intensity statin therapy or high-intensity statin IIa B-NR In patients with chronic inflammatory disorders or HIV, a fasting lipid profile and assessment of ASCVD risk factors can be useful as a) a guide to benefit of statin therapy and b) for monitoring or adjusting lipid-lowering drug therapy before and 4 to 12 weeks after starting inflammatory disease modifying therapy or antiretroviral IIa B-NR In adults with RA who undergo ASCVD risk assessment with measurement of a lipid profile, it can be useful to recheck lipid values and other major ASCVD risk factors 2 to 4 months after the patient s inflammatory disease has been Synopsis Chronic inflammatory disorders and HIV infection are conditions that often enhance risk. Clinicians should first focus on helping patients with these diagnoses to optimize their lifestyle habits. After a 3- to 6-month trial of lifestyle improvements, including cessation of cigarette smoking, the patient s 10-year ASCVD risk estimate should be reassessed. If the patient s ASCVD risk estimate is 5% over 10 years, it is reasonable to begin moderate-intensity statin therapy. If the pa- tient or clinician remains uncertain about the need for statin therapy or if the patient has had side effects with a statin in the past, a CAC scan can be used to improve risk assessment. The absence of CAC in a nonsmoking man 40 years of age or a nonsmoking woman 45 years of age would indicate that the pa- tient is likely at very low risk of an ASCVD event over the subsequent decade. Such patients can then focus on lifestyle habits and delay the decision about statin therapy for about 5 years. Similarly, a CAC score 75th percentile for a patient s age and sex or an ab- solute score 100 Agatston units would support the decision to use statin therapy and intensify lifestyle modifications. Recommendation-Specific Supportive Text 1. Inflammation promotes atherosclerosis and is a key feature of many chronic rheumatologic inflam- matory joint disorders, such systemic lupus ery- thematosus, RA, and psoriasis.S4.5.5-1 Inflammation mediates the progression of atherosclerosis, as well as instability, erosion, and rupture of vulnera- ble atherosclerotic plaques.S4.5.5-2 Among individu- als with RA, the risk of an MI has been estimated to be similar to that of an adult with diabetes mel- litus or one who is about 10 years older without A large meta-analysis found that persons with RA had an approximately 50% increased risk of CVD death.S4.5.5-4 Individuals with systemic lupus erythematosus and advanced psoriasis have a similarly increased risk of CVD.S4.5.5-5 S4.5.5-7 HIV infection is associated with an increased risk of an ASCVD event even if viremia has been con- trolled by antiretroviral therapy.S4.5.5-8 There is an increased risk of MI in association with long-term use of antiretroviral therapy, and MI rates are increased in individuals with HIV.S4.5.5-9 Traditional ASCVD risk factors, long-term use of antiret- roviral therapy, prolonged immune activation, and inflammation are mediators of atheroscle- rosis progression and development.S4.5.5-9,S4.5.5-10 Coinfection with hepatitis C virus is frequently present in HIV-infected individuals and further increases ASCVD risk.S4.5.5-11,S4.5.5-12 2. The accuracy of the ASCVD risk estimator has not been well validated for adults with chronic inflam- matory disorders or HIV infection. Assessment of traditionalriskfactorsoftenhasresultedinunderesti- mationofactualriskandthepotentialforundertreat- ment with pharmacological therapy.S4.5.5-13,S4.5.5-14 Traditional risk factors should be assessed early in the disease process and then modified. Rates of smok- ing in HIV-infected adults have generally been 2 to 3 times that of the general population.S4.5.5-15,S4.5.5-16 Multiple studies have demonstrated underestima- tion of ASCVD risk in patients with chronic inflam- matory conditions or HIV.S4.5.5-15,S4.5.5-16 Antiretroviral therapy may adversely affect lipid levels, glycemic control, and endothelial functionS4.5.5-17 S4.5.5-19 and has been associated with adverse changes in body composition (lipodystrophy). However, use of newer agents may lessen the metabolic derange- ments of antiretroviral therapy. Similarly, the use of prednisone in chronic inflammatory diseases may worsen glycemic control and dyslipidemia.S4.5.5-20 The most common lipid abnormality phenotype in persons with HIV infection is an elevated triglycer- ide level with a low HDL-C. In HIV-infected adults, CLINICAL STATEMENTS AND GUIDELINES triglycerides should preferentially be measured in the fasting state. 3. Patients with RA who are untreated or who have high disease activity generally have decreased levels of TC, triglycerides, HDL-C, and LDL-C.S4.5.5-21 These lower lipid levels are likely attributable in part to increased inflammation and may lead to functional proatherogenic changes, such as decreased cho- lesterol efflux capacity of HDL-C.S4.5.5-22 Treatment with anti-inflammatory medications, such as tumor necrosis factor alpha inhibitors or methotrexate, is associated with an increase in and normalization of lipid levels and a reduction in the ratio of TC Thus, to produce a more accurate risk estimate, ASCVD risk estimation should be repeated when the patient has a stable and low disease activity with normalization of their lipid lev- els; lower lipid levels measured during high disease activity may lead to a significant underestimation of ASCVD risk for patients with RA. 5. STATIN SAFETY AND STATIN- ASSOCIATED SIDE EFFECTS Recommendations for Statin Safety and Statin-Associated Side Effects Referenced studies that support recommendations are summarized in Online Data Supplements 40 and 41. COR LOE Recommendations I A A clinician patient risk discussion is recommended before initiation of statin therapy to review net clinical benefit, weighing the potential for ASCVD risk reduction against the potential for statin-associated side effects, statin drug interactions, and safety, while emphasizing that side effects can be addressed I A In patients with statin-associated muscle symptoms (SAMS), a thorough assessment of symptoms is recommended, in addition to an evaluation for nonstatin causes and I B-R In patients with indication for statin therapy, identification of potential predisposing factors for statin-associated side effects, including new-onset diabetes mellitus and SAMS, is recommended before initiation of I B-R In patients with statin-associated side effects that are not severe, it is recommended to reassess and to rechallenge to achieve a maximal LDL-C lowering by modified dosing regimen, an alternate statin or in combination with nonstatin therapy.S5-3 S5-8 I B-R In patients with increased diabetes mellitus risk or new-onset diabetes mellitus, it is recommended to continue statin therapy, with added emphasis on adherence, net clinical benefit, and the core principles of regular moderate-intensity physical activity, maintaining a healthy dietary pattern, and sustaining modest weight loss.S5-8 S5-12 I C-LD In patients treated with statins, it is recommended to measure creatine kinase levels in individuals with severe statin- associated muscle symptoms, objective muscle weakness, and to measure liver transaminases (aspartate aminotransferase, alanine aminotransferase) as well as total bilirubin and alkaline phosphatase (hepatic panel) if there are symptoms suggesting I B-R In patients at increased ASCVD risk with chronic, stable liver disease (including non-alcoholic fatty liver disease) when appropriately indicated, it is reasonable to use statins after obtaining baseline measurements and determining a schedule of monitoring and safety checks.S5-16 S5-18 IIa B-R In patients at increased ASCVD risk with severe statin-associated muscle symptoms or recurrent statin-associated muscle symptoms despite appropriate statin rechallenge, it is reasonable to use RCT proven nonstatin therapy that is likely to provide net clinical III: No Benefit B-R Coenzyme Q10 is not recommended for routine use in patients treated with statins or for the treatment of SAMS.S5-20,S5-21 III: No Benefit C-LD In patients treated with statins, routine measurements of creatine kinase and transaminase levels are not useful.S5-13 S5-15 Synopsis Statin therapy is usually well tolerated and safe.S5-1,S5-14, As with other classes of medications, associ- ated side effects are seen. Instead of the label statin intolerance, the present guideline prefers statin-associ- ated side effects because the large majority of patients are able to tolerate statin rechallenge with an alterna- tive statin or alternative regimen, such as reduced dose or in combination with nonstatins. Although infrequent or rare in clinical trials, statin-associated side effects can be challenging to assess and manage.S5-25,S5-26 The most frequent are SAMS. SAMS usually are subjective myalgia, reported observationally in 5% to 20% of SAMS often result in nonadherence and can adversely impact ASCVD outcomes.S5-27 S5-29 Statins modestly increase risk of incident diabetes mel- litus in susceptible individuals,S5-8 S5-11 but this should not be cause for discontinuation (Table 11). The present guideline recommends a comprehensive approach to statin-associated symptoms. The clinician should reas- sess, rediscuss, and encourage rechallenge as the ini- tial approach unless side effects are severe. Ongoing communication is integral to patient care, as is regular monitoring to check for adherence, adequacy of re- sponse, new associated symptoms, and reaffirmation Recommendations for Statin Safety and Statin-Associated Side Effects (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES Recommendation-Specific Supportive Text 1. A clinician patient risk discussion focused on indi- cations, benefits, risks of statin-associated side effects, and patient concerns and preferences should precede initiation of statin treatment.S5-2 This dialogue is the foundation of a longitudinal care partnership that is based on informed deci- sion-making. Future encounters should address statin response, emphasize adherence, and reaf- firm benefit. Statin-associated symptoms should be comprehensively assessed, and because most can be well managed,S5-3 S5-7 the goal should be to optimize patient-centered strategies for ASCVD prevention. 2. The majority of SAMS are subjective myalgia (pain, aches) in the absence of other findings.S5-13,S5-25,S5-30 Myalgia is more likely to be statin associated if it is bilateral, involves proximal muscles, has its onset within weeks to months after initiation of statins, and resolves after discontinuation of statins.S5-13,S5-14 A thorough assessment of symptoms is recom- mended, in addition to evaluation for nonstatin etiologies, assessment of predisposing factors, and a physical exam. Objective muscle weakness Table 11. Statin-Associated Side Effects (SASE) Statin-Associated Side Effects Frequency Predisposing Factors Quality of Evidence Statin-associated muscle symptoms (SAMS) Myalgias (CK normal) Infrequent (1% to 5%) in RCTs; frequent (5% to 10%) in observational studies and clinical setting Age, female sex, low body mass index, high-risk medications (CYP3A4 inhibitors, OATP1B1 inhibitors), comorbidities (HIV, renal, liver, thyroid, preexisting myopathy), Asian ancestry, excess alcohol, high levels of physical activity, and trauma RCTs cohorts/ observational Myositis/myopathy (CK > ULN) with concerning symptoms or objective weakness Rare RCTs cohorts/ observational Rhabdomyolysis (CK >10 ULN + renal injury) Rare RCTs cohorts/ observational Statin-associated autoimmune myopathy (HMGCR antibodies, incomplete resolution) Rare Case reports New-onset diabetes mellitus Depends on population; more frequent if diabetes mellitus risk factors are present, such as body mass index 30, fasting blood glucose 100 mg/dL; metabolic syndrome, or A1c 6%. Diabetes mellitus risk factors/metabolic syndrome RCTs/meta-analyses High-intensity statin therapy Liver Transaminase elevation 3 ULN Infrequent RCTs/cohorts/ observational Case reports Hepatic failure Rare Central nervous system Memory/cognition Rare Case reports; no increase in memory/ cognition problems in 3 large-scale RCTs Cancer No definite association RCTs/meta-analyses Other Renal function Unfounded Cataracts Unfounded Tendon rupture Unfounded Hemorrhagic stroke Unfounded Interstitial lung disease Unfounded Low testosterone Unfounded CK indicates creatine kinase; HIV, human immunodeficiency virus; HMGCR, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; SAMS, statin-associated muscle symptoms; SAAM, statin-associated autoimmune myopathy; SASE, statin associated side effects; and ULN, upper limit of normal. CLINICAL STATEMENTS AND GUIDELINES (myopathy) and associated significant increase in CK (myositis) are rareS5-1,S5-22,S5-30 but require prompt statin cessation and evaluation for reversible causes. Rhabdomyolysis (CK >10 times upper limit of normal, with evidence of renal injury) is exceed- ingly rare and usually encountered in the setting of a patient with several predisposing comorbidities and concomitant high-risk medications.S5-1,S5-22,S5-30 It requires immediate medical attention. 3. Before lipid-lowering therapy with a statin is initiated, a comprehensive evaluation of mus- culoskeletalsymptoms(withdocumentation)isrec- ommended because such symptoms are common at baseline in the general adult population.S5-3 S5-6 Beforetherapy,itisalsoimportanttoidentifypredis- posing factors for SAMS, including demographics, comorbid conditions, and use of medications that can adversely affect statin metabolismS5-3,S5-13,S5-14 (Table 11). Proactive and preemptive identification of patients at potential increased risk of statin- associated side effects should help guide informed clinical decision-making and is supportive of the goals of safe and effective therapy. 4. Several creatively designed randomized crossover trials in patients with SAMSS5-3 S5-7 support a man- agement strategy of statin discontinuation until symptoms improve, followed by rechallenge with a reduced dose, alternative agent, or alternative dosing regimen while monitoring for recurrent symptoms. If the approach of reassess, rediscuss (net clinical benefit), and rechallenge is used, a majority of patients will be able to be successfully treated with at least one or several statins.S5-29,S5-31 In patients at increased ASCVD risk, the goal should be to treat with the guideline-recommended max- imally tolerated statin dose. Patients who experi- ence rhabdomyolysis with statin therapy may need to discontinue statin use indefinitely, although reversible causes should be sought.S5-32 Clinicians should be aware of a rare disorder, statin-associ- ated autoimmune myopathy (muscle weakness, marked and persistent CK elevation, presence of HMG CoA reductase [HMGCR] antibodies, necrotizing myopathy, and lack of or incomplete resolution on statin discontinuation), that requires statin cessation and additional therapy directed at the autoimmune process.S5-32 Patients with statin- associated autoimmune myopathy may benefit from seeing a neurologist specializing in neuro- muscular disorders. 5. Evidence indicates that statins modestly increase the risk of incident or statin-associated new-onset diabetes mellitus in individuals with predisposing risk factors for diabetes mellitus, components of the metabolic syndrome, and higher-intensity statin The specific mechanisms leading to statin-associated diabetes mellitus remain unclear, although it is unlikely that statins directly cause diabetes mellitus. Rather, it appears that a small number of individuals with diabetic susceptibility cross the threshold to incident diabetes mellitus after statin therapy. is initiated It is important that patients are informed of the potential risk of new- onset diabetes mellitus before initiation of statin therapy. Because the benefits of statin therapy are shown to outweigh the risks of new-onset diabetes mellitus, the possibility of incident diabetes mellitus should not be a contraindication to statin therapy or indication for statin discontinuation.S5-8,S5-14,S5-33 In individuals at increased risk of both ASCVD and incident diabetes mellitus, it is recommended that counseling based on the ADA prevention approach be provided. This approach encourages regular moderate physical activity, maintaining a healthy dietary pattern, and sustaining modest weight loss (according to the core principles of the Diabetes 6. In patients with statin-associated side effects, it is recommended that CK be measured in the case of severe SAMS and in the presence of objective mus- cle weakness. After baseline liver transaminases, the FDA recommends measuring transaminases (aspar- tate aminotransferase [serum glutamic-oxaloacetic transaminase] and alanine aminotransferase [serum glutamic-pyruvic transaminase]) if there are signs or symptoms suggesting hepatotoxicity.S5-13 S5-15 upper limit of normal) is an infrequent statin-associ- ated side effect that often resolves with dose reduc- tion or rechallenge with alternative statins.S5-1,S5-22 Severe statin-associated hepatotoxicity is rare, and the incidence is not impacted by routine monitor- ing of transaminases.S5-34 A thorough evaluation for nonstatin etiologies is warranted when signifi- cant transaminase elevation persists. Importantly, statins are not contraindicated in patients with increased ASCVD risk with chronic, stable liver dis- ease (eg, nonalcoholic fatty liver), and limited data suggest potential benefit.S5-16 S5-18 8. Severe statin-associated side effects are rare, and recurrent SAMS are infrequent when a thorough reassessment and management strategy of reas- sess, rediscuss, and rechallenge is used. In patients at increased ASCVD risk with severe statin-asso- ciated side effects or recurrent SAMS, nonstatin therapy should be considered when there is net 9. The clinical diagnosis of SAMS remains chal- lenging, given that the majority of symptoms are subjective and definitive diagnostic criteria do not exist.S5-13 Multiple potential mechanisms have been suggested to contribute to SAMS, CLINICAL STATEMENTS AND GUIDELINES including depletion of ubiquinone or coenzyme Q10. Available evidence, however, does not sup- port the use of coenzyme Q10 supplementation for routine use in patients treated with statins or for the treatment of SAMS.S5-20,S5-21 10. The majority of SAMS are subjective myalgia in the absence of other findings,S5-3,S5-13,S5-14,S5-23,S5-30 and an asymptomatic increase in transaminases (>3 times upper limit of normal) is an infrequent statin-associated side effect.S5-1,S5-22,S5-24 Therefore, CK and transaminase levels should not be rou- tinely measured given the unlikely impact on clinical outcomes, and the lack of established cost Recommendations for Implementation Referenced studies that support recommendations are summarized in Online Data Supplements 42 to 46. COR LOE Recommendations I A Interventions focused on improving adherence to prescribed therapy are recommended for management of adults with elevated cholesterol levels, including telephone reminders, calendar reminders, integrated multidisciplinary educational activities, and pharmacist-led interventions, such as simplification of the drug regimen to I B-NR Clinicians, health systems, and health plans should identify patients who are not receiving guideline-directed medical therapy and should facilitate the initiation of appropriate guideline-directed medical therapy, using multifaceted strategies to improve guideline implementation.S6-5,S6-6 I B-NR Before therapy is prescribed, a patient- clinician discussion should take place to promote shared decision-making and should include the potential for ASCVD risk- reduction benefit, adverse effects, drug-drug interactions, and patient preferences.S6-7,S6-8 Synopsis Guideline publication does not guarantee guideline implementation. Healthcare delivery is complex, and barriers to guideline implementation can occur at the patient, clinician, health system, and health plan levels, leading to gaps in care. A more concerted effort, with multifaceted strategies aimed at the patient, clinician, health system, and health plan, is needed to overcome the barriers and achieve wider guideline implementa- tion (Table S7). The patient is a key player in success- ful guideline implementation, and the clinician patient discussion is crucial to the successful initiation and con- tinuation of guideline-directed management and thera- py (Table 7). As part of the clinician patient discussion, the patient should be encouraged to state what was heard, ask questions, express values and preferences, and state ability and willingness to adhere to lifestyle changes and medications. This is where a discussion of out-of-pocket costs can occur. Clinicians should use multiple interventions to promote adherence, including asking more specific questions about adherence, aim- ing for once-daily dosing, using automated reminders, participating in multidisciplinary educational activities, and using pharmacist-led interventions. Recommendation-Specific Supportive Text 1. Interventions focused on improving adherence to prescribed therapy are recommended for man- agement of adults with elevated cholesterol lev- els. A Cochrane systematic review demonstrated that intensification of patient care interventions improves both short- and long-term adherence to medication, as well as meaningful reduction in LDL-C levels. Interventions include telephone reminders, calendar reminders, integrated mul- tidisciplinary educational activities, simplification of the drug regimen to once-daily dosing, and Clinicians may wish to review Table S7 in the Web Supplement, Strategies to Improve Guideline Implementation by Setting and Target Audience Measures to Improve Lipid Medication Adherence. 2. Clinicians do not follow guidelines for many and cholesterol guideline implementation has not been optimal.S6-10 S6-13 Interventions aimed at the clinician may improve guideline implemen- tation. Educational outreach or academic detailing visits are generally effective for improving process- of-care, clinical, cost-reduction, and cost-effec- Audits of individual clinical performance and feedback are generally effective in improving process-of-care and clinical outcomes.S6-5 Reminders and individual pay-for-performance are generally effective for cost reduction.S6-5 Even if guideline-directed management and therapy are prescribed, patients may be nonadher- ent or not get the prescribed medication for a vari- ety of reasons.S6-14 Patients who are initially adherent to statin therapy may not demonstrate long-term Adherent patients, with and without clinical ASCVD, have improved outcomes and reduced costs.S6-15,S6-17 S6-20 Formulary restrictions and prior authorization requirements have been associated with care delays and nonadherence.S6-21 Interventions aimed at the patient may improve adherence and clinical outcomes. Guideline implementation strategies that are aimed at the patient, clinician, health system, and health plan are needed. Barriers to guideline CLINICAL STATEMENTS AND GUIDELINES implementation should be analyzed in advance, and implementation strategies should be tailored to the setting and target audience. Multiple strat- egies may be needed to effectively implement (Table S7 in the Web Supplement). 3. Patients who participate in shared decision-making may have better health outcomes, better health- care experiences, and lower costs.S6-7,S6-8 During the clinician patient risk discussion with shared decision-making, the patient participates with the clinician in deciding lifestyle modifications, medica- tion treatment, and goals of therapy. The clinician should explain the patient s risk of clinical ASCVD and how the treatment recommendations reduce ASCVD risk. The patient should verbalize values, attitudes, abilities, concerns, and personal goals for making lifestyle changes and taking medications, including concerns about cost.S6-22 The clinician may use a checklist to facilitate shared decision-making with the patient (Table S8 in the Web Supplement). The clinician should use tools and techniques to support shared decision-making.S6-7,S6-22 S6-26 Decision aids may allow the patient to be more knowledgeable, have better risk perception, and have a clearer understanding of their values.S6-8,S6-27 Question prompt lists may increase knowledge by including questions about the purpose or goal of treatment, the risk with and without treatment, how the medication should be taken, potential side effects and how to manage them, when to notify the office, and monitoring and follow-up. Motivational and decision coaching may also promote patient knowledge and satisfaction. 7. COST AND VALUE CONSIDERATIONS 7.1. Economic Value Considerations: ACC/AHA clinical guidelines now recognize the im- portance of considering economic value in making recommendations, in accordance with the principles established by an expert group.S7.1-1 tors further reduce LDL-C when combined with other LDL-lowering drugs, and they reduced composite car- diovascular events in 2 RCTs of high-risk, secondary- prevention patients with clinical ASCVD.S7.1-2 The cost- effectiveness and economic value of PCSK9 inhibitors have been assessed by using simulation models (Online Data Supplements 47 and 48); the published models are based on different sets of assumptions. Compared with statin therapy for secondary prevention, PCSK9 inhibitors have incremental cost-effectiveness ratiosS7.1-3 from $141700 to $450000 per quality-adjusted life- year (QALY) added, at mid-2018 list prices. None of the published models report good value (<$50000 per QALY added; Table 12), and virtually all indicate low value ( $150000 per QALY added). All models pro- jected mortality benefit by assuming that mortality rate reductions either parallel LDL-C loweringS7.1-4 or parallel RRRs for nonfatal ASCVD events. All models project higher lifetime cost from use of PCSK9 inhibitors because the cost will exceed any sav- ings from prevention of cardiovascular events. To be cost-effective by conventional standards, the cost of PCSK9 inhibitors will have to be reduced on the order of 70% to 85% in the United States.S7.1-3 At any given price, the economic value of PCSK9 inhibitors will be improved by restricting their use to patients at very high-risk of ASCVD events, as recommended in the present guidelines. The inverse relationship between improved survival and the incremental cost-effective- ness ratio (Figure 3) indicates that the economic val- ue of PCSK9 inhibitors will be improved by selecting higher-risk patients. One simulation model suggested that restricting the use of PCSK9 inhibitor therapy to patients with baseline LDL-C levels 119 mg/dL ( 3 mmol/L), instead of 70 mg/dL ( 1.8 mmol/L), would improve their cost-effectiveness to $150000 per QALY added, instead of $268000.S7.1-5 Another study pro- jected a similar improvement in economic value.S7.1-6 Thus, raising the threshold for LDL-C on maximal statin therapy to initiate a PCSK9 inhibitor should im- prove its cost-effectiveness (Figure 3). Only 2 economic models have specifically examined the value provided by PCSK9 inhibitors for primary pre- vention in patients with heterozygous FH (Online Data found low value when PCSK9 inhibitors were used for FH ($503000 per QALY added), whereas the second modelS7.1-8 reported inter- mediate value (incremental cost-effectiveness ratio of $75900 per QALY added). Consequently, the value of PCSK9 inhibitor therapy in FH is uncertain. Table 12. Proposed Integration of Level of Value Into Clinical Guideline Recommendations* Level of Value High value: Better outcomes at lower cost or ICER <$50000 per QALY gained Intermediate value: $50000 to <$150000 per QALY gained Low value: $150000 per QALY gained Uncertain value: Value examined, but data are insufficient to draw a conclusion because of absence of studies, low-quality studies, conflicting studies, or prior studies that are no longer relevant Not assessed: Value not assessed by the writing committee Proposed abbreviations for each value recommendation:Level of value: H to indicate high value; I, intermediate value; L, low value; U, uncertain value; and NA, value not assessed. *Dollar amounts used in this table are based on US GDP data from 2012 and were obtained from WHO-CHOICE Cost-Effectiveness Thresholds.S7.1-9 Reproduced from Anderson et al.S7.1-1 GDP indicates gross domestic product; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-years; and WHO-CHOICE, World Health Organization Choosing Interventions that are Cost-Effective. CLINICAL STATEMENTS AND GUIDELINES 8. LIMITATIONS AND KNOWLEDGE GAPS 8.1. Randomized Controlled Trials ACC/AHA guidelines are based largely on the outcomes of RCTs. Cholesterol guidelines have fortunately benefited from a large number of RCTs of cholesterol-lowering thera- pies. They have established that greater reductions of LDL- C are accompanied by greater reductions in risk of ASCVD. Robust RCTs exist for both primary and secondary preven- tion. Most of the data from RCTs have been obtained with statin therapy. Important limited data have also been ob- tained with nonstatins as add-on drugs to statin therapy. Nevertheless, more data are needed to determine the full scope of the benefit of nonstatin drugs. Several important questions need to be addressed by additional RCTs. 1. In secondary prevention, does a lower limit for LDL-C attainment exist, beyond which the incre- mental benefit attained is worth neither the risks nor the cost of additional therapy? 2. In secondary prevention, what are the indications for adding PCSK9 inhibitors to maximal statin therapy? 3. In patients with ASCVD who have statin-associ- ated side effects, are PCSK9 inhibitors an effective and safe substitute for high-intensity statins? 4. In primary prevention for adults 45 to 75 years of age (LDL-C <90 mg/dL [<2.3 mmol/L]) with or without diabetes mellitus, what is the incremental risk reduction imparted by high-intensity statins as compared with moderate-intensity statins? 5. In primary prevention for adults 45 to 75 years of age (LDL-C <190 mg/dL [<4.9 mmol/L]) with or without diabetes mellitus, what is the incremen- tal risk reduction imparted by moderate-intensity statins plus ezetimibe as compared with moder- ate-intensity statins alone? 6. Is statin therapy efficacious and safe in older patients (>75 years of age)? If so, what is a net benefit of statin therapy in this age group? 7. In patients with severe hypercholesterolemia, what are the efficacy and net benefit of PCSK9 inhibitors as add-on treatment to maximal statin therapy? 8. What is the efficacy of moderate-intensity and high-intensity statin therapy in patients with risk- enhancing factors (eg, chronic inflammatory dis- ease, CKD, metabolic syndrome)? 8.2. Risk Assessment In primary prevention, the appropriate selection of pa- tients for cholesterol-lowering drug therapy is highly de- pendent on risk assessment. Previous guidelines made Figure 3. Cost-effectiveness analysis for PCSK9 inhibitors. Conceptual relationship between the clinical effectiveness of PCSK9 inhibitor therapy, measured in QALYs added compared with statin therapy, on the horizontal axis, and their clinical value, measured in dollars per QALY added, on the vertical axis. The top curve indicates the relationship at full U.S list price of PCSK9 inhibi- tor therapy ($14000/y), the middle curve indicates the relationship if the price were reduced by 50% (ie, to $7000/y), and the bottom curve indicates the relation- ship if the price were reduced by 75% (ie, to $3500/y). Reproduced from Hlatky et al.S7.1-3 CV indicates cardiovascular; and QALY, quality-adjusted life-years. CLINICAL STATEMENTS AND GUIDELINES use of risk-assessment algorithms (eg, Framingham risk scoring or PCE) to estimate risk. Although these equa- tions are useful, they may overestimate or underesti- mate risk for individual patients. For this reason, the introduced the clinician patient risk discussion to facilitate clinical decisions about appropriate therapy. In the present guidelines, the clinician patient risk discussion has been amplified and made an integral part of the clinical decision. In addition, in cases in which uncertainty exists, the mea- surement of CAC has been proposed as a third step in making a treatment decision. Each of these steps could be improved for future guidelines. 8.2.1. Continuing Refinement of PCE Because the population baseline risk may be continually declining in the US population, ongoing epidemiological study is needed to assess and update population risk. An example is the development of QRISK in the U.K. popula- tion, which is continually expanding its scope. 8.2.2. Improvement in Lifetime Risk Estimate The present guidelines include a lifetime ASCVD risk al- gorithm for those 20 to 59 years of age, but it is based on an insufficient database. Along with a risk algorithm for short-term risk of ASCVD (eg, 10 years), a more robust lifetime risk algorithm would facilitate the clini- cian patient risk discussion for treatment decisions. 8.2.3. Refinement of Clinician Patient Risk Discussion An ongoing study of how a clinician can best interact with a patient to arrive at an informed decision must be done, taking multiple factors into consideration. This is particularly important because cholesterol-lowering therapy is meant to be a lifetime therapy. 8.2.4. Monitoring and Adjustment of Treatment The clinician patient risk discussion will likely prove in- adequate unless an ongoing interaction between the patient and clinician occurs. This involves monitoring the effectiveness of therapy and adherence to therapy. Thus, the clinician patient risk discussion should in- clude more than the initial treatment decision. Ongoing research on how to improve the entire process of initial decision-making and long-term follow-up is necessary. 8.2.5. Prognostic Significance of CAC The present guideline makes use of the available data to predict the risk associated with CAC. These data need to be amplified by new and ongoing studies to guide treatment decisions. Particular uncertainty exists about the predictive value of intermediate CAC scores. In addition, the predictive significance of a CAC score of zero must be further verified in follow-up studies. For patients with a CAC score of zero, it is currently uncer- tain when and if follow-up CAC measurements should be done to reassess risk status. ACC/AHA TASK FORCE MEMBERS Glenn N. Levine, MD, FACC, FAHA, Chair; Patrick T. O Gara, MD, MACC, FAHA, Chair-Elect; Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair*; Sana M. Al-Khatib, MD, MHS, FACC, FAHA; Joshua A. Beckman, MD, MS, FAHA; Kim K. Birtcher, PharmD, MS, AACC; Biykem Bozkurt, MD, PhD, FACC, FAHA*; Ralph G. Brindis, MD, MPH, MACC*; Joaquin E. Cigarroa, MD, FACC; Lesley H. Curtis, PhD, FAHA*; Anita Deswal, MD, MPH, FACC, FAHA; Lee A. Fleisher, MD, FACC, FAHA; Federico Gentile, MD, FACC; Samuel Gidding, MD, FAHA*; Zachary D. Goldberger, MD, MSc, FACC, FAHA; Mark A. Hlatky, MD, FACC, FAHA; John Ikonomidis, MD, PhD, FAHA*; Jos A. Joglar, MD, FACC, FAHA; Laura Mauri, MD, MSc, FAHA*; Mariann R. Piano, RN, PhD, FAHA; Susan J. Pressler, PhD, RN, FAHA*; Barbara Riegel, PhD, RN, FAHA*; Duminda N. Wijeysundera, MD, PhD PRESIDENTS AND STAFF American College of Cardiology C. Michael Valentine, MD, FACC, President Timothy W. Attebery, MBA, FACHE, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice Presi- dent, Science, Education, Quality, and Publishing MaryAnne Elma, MPH, Senior Director, Science, Educa- tion, Quality, and Publishing Amelia Scholtz, PhD, Publications Manager, Science, Education, Quality, and Publishing American College of Cardiology/ American Heart Association Katherine A. Sheehan, PhD, Director, Guideline Strat- egy and Operations Abdul R. Abdullah, MD, Senior Manager, Guideline Science Thomas S.D. Getchius, Manager, Guideline Operations American Heart Association Ivor Benjamin, MD, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medicine Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Prashant Nedungadi, PhD, Science and Medicine Advi- sor, Office of Science Operations Jody Hundley, Production and Operations Manager, Sci- entific Publications, Office of Science Operations *Former Task Force member; current member during the writing effort. CLINICAL STATEMENTS AND GUIDELINES ARTICLE INFORMATION This document was approved by the American College of Cardiology Clinical Policy Approval Committee, the American Heart Association Science Advisory and Coordinating Committee, American Association of Cardiovascular and Pulmonary Rehabilitation, American Academy of Physician Assistants, Associa- tion of Black Cardiologists, American College of Preventive Medicine, American Diabetes Association, American Geriatrics Society, American Pharmacists Asso- ciation, American Society for Preventive Cardiology, National Lipid Association, and Preventive Cardiovascular Nurses Association in October 2018, and the American Heart Association Executive Committee in October 2018. Supplemental materials are available with this article at https://www. ahajournals.org/doi/suppl/10.1161/CIR.0000000000000625. This article has been copublished in the Journal of the American College of Cardiology. Copies: This document is available on the websites of the American College of Cardiology (www.acc.org) and the American Heart Association (professional.heart.org). A copy of the document is also available at https:// professional.heart.org/statements by selecting the Guidelines & Statements button. To purchase additional reprints, call 843-216-2533 or e-mail kelle. ramsay@wolterskluwer.com. The expert peer review of AHA-commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guide- lines development, visit https://professional.heart.org/statements. Select the Guidelines & Statements drop-down menu near the top of the web page, then click Publication Development. Permissions: Multiple copies, modification, alteration, enhancement, and/ or distribution of this document are not permitted without the express permis- sion of the American Heart Association. 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