Severe Hypercholesterolemia (LDL-C 190 mg/dL [ 4.9 mmol/L]) Recommendations for Primary Severe Hypercholesterolemia (LDL-C 190 mg/dL [ 4.9 mmol/L]) Referenced studies that support recommendations are summarized in Online Data Supplements 9 and 10. COR LOE Recommendations I B-R In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher ( 4.9 mmol/L), maximally tolerated statin therapy IIa B-R In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher ( 4.9 mmol/L) who achieve less than a 50% reduction in LDL-C while receiving maximally tolerated statin therapy and/ or have an LDL-C level of 100 mg/dL or higher ( 2.6 mmol/L), ezetimibe therapy is IIb B-R In patients 20 to 75 years of age with a baseline LDL-C level of 190 mg/dL or higher ( 4.9 mmol/L), who achieve less than a 50% reduction in LDL-C levels and have fasting triglycerides 300 mg/dL or lower ( 3.4 mmol/L), while taking maximally tolerated statin and ezetimibe therapy, the addition of a bile acid sequestrant may be IIb B-R In patients 30 to 75 years of age with heterozygous FH and with an LDL-C level of 100 mg/dL or higher ( 2.6 mmol/L) while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered.S4.2-9,S4.2-13 S4.2-15 IIb C-LD In patients 40 to 75 years of age with a baseline LDL-C level of 220 mg/dL or higher ( 5.7 mmol/L) and who achieve an on-treatment LDL-C level of 130 mg/ dL or higher ( 3.4 mmol/L) while receiving maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered.S4.2-13 S4.2-17 Value Statement: Uncertain Value (B-NR) Among patients with FH without evidence of clinical ASCVD taking maximally tolerated statin and ezetimibe therapy, PCSK9 inhibitors provide uncertain value at mid- 2018 US list prices.


COR LOE Recommendations I B-R In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher ( 4.9 mmol/L), maximally tolerated statin therapy IIa B-R In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher ( 4.9 mmol/L) who achieve less than a 50% reduction in LDL-C while receiving maximally tolerated statin therapy and/ or have an LDL-C level of 100 mg/dL or higher ( 2.6 mmol/L), ezetimibe therapy is IIb B-R In patients 20 to 75 years of age with a baseline LDL-C level of 190 mg/dL or higher ( 4.9 mmol/L), who achieve less than a 50% reduction in LDL-C levels and have fasting triglycerides 300 mg/dL or lower ( 3.4 mmol/L), while taking maximally tolerated statin and ezetimibe therapy, the addition of a bile acid sequestrant may be IIb B-R In patients 30 to 75 years of age with heterozygous FH and with an LDL-C level of 100 mg/dL or higher ( 2.6 mmol/L) while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered.S4.2-9,S4.2-13 S4.2-15 IIb C-LD In patients 40 to 75 years of age with a baseline LDL-C level of 220 mg/dL or higher ( 5.7 mmol/L) and who achieve an on-treatment LDL-C level of 130 mg/ dL or higher ( 3.4 mmol/L) while receiving maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered.S4.2-13 S4.2-17 Value Statement: Uncertain Value (B-NR) Among patients with FH without evidence of clinical ASCVD taking maximally tolerated statin and ezetimibe therapy, PCSK9 inhibitors provide uncertain value at mid- 2018 US list prices. CLINICAL STATEMENTS AND GUIDELINES Synopsis Patients with severe hypercholesterolemia have a high lifetime risk, and decisions about statins in these pa- tients do not require ASCVD risk scoring.


CLINICAL STATEMENTS AND GUIDELINES Synopsis Patients with severe hypercholesterolemia have a high lifetime risk, and decisions about statins in these pa- tients do not require ASCVD risk scoring. These pa- tients derive net ASCVD risk reduction benefit from interventions that increase expression of LDL receptors. The strongest data have been derived from statin RCTs, which have demonstrated greater risk reduction with statins than with placebo and greater reduction from higher-intensity statin therapy than with moderate- intensity statin therapy. Ezetimibe plus a moderate-in- tensity statin is associated with greater LDL-C reduction than is statin monotherapy in patients with hetero- zygous FH, and the combination reduces ASCVD risk more than moderate-intensity statin monotherapy in patients who have had a recent ACS. In selected pa- tients with severe hypercholesterolemia whose LDL-C is inadequately controlled with drug therapy, LDL apher- esis is an option. Referral to a lipid specialist may be indicated. Recommendation-Specific Supportive Text 1. Patients with primary severe hypercholesterolemia (LDL-C levels 190 mg/dL [ 4.9 mmol/L]) have a high-risk of ASCVDS4.2-2,S4.2-4,S4.2-18 and premature and recurrent coronary events.S4.2-3 Although there have been no randomized, placebo-controlled tri- als of statin therapy done exclusively in subjects with LDL-C levels 190 mg/dL ( 4.9 mmol/L), a placebo-controlled primary prevention study performed in men with a mean baseline LDL-C level of 192 17 mg/dL (4.9 0.4 mmol/L) demon- strated a reduced incidence of MI and cardiovas- cular death in those receiving pravastatin 40 mg These findings were extended in a post hoc analysis of 2560 exclusively primary-preven- tion subjects in that RCT and in a 20-year observa- tional post-trial long-term follow-up study.S4.2-19 In addition, retrospective cohort studies have dem- onstrated that statin therapy reduces risk of inci- and of CHD and all-cause deathS4.2-1 in patients with phenotypic or genetically con- firmed FH.


Patients with primary severe hypercholesterolemia (LDL-C levels 190 mg/dL [ 4.9 mmol/L]) have a high-risk of ASCVDS4.2-2,S4.2-4,S4.2-18 and premature and recurrent coronary events.S4.2-3 Although there have been no randomized, placebo-controlled tri- als of statin therapy done exclusively in subjects with LDL-C levels 190 mg/dL ( 4.9 mmol/L), a placebo-controlled primary prevention study performed in men with a mean baseline LDL-C level of 192 17 mg/dL (4.9 0.4 mmol/L) demon- strated a reduced incidence of MI and cardiovas- cular death in those receiving pravastatin 40 mg These findings were extended in a post hoc analysis of 2560 exclusively primary-preven- tion subjects in that RCT and in a 20-year observa- tional post-trial long-term follow-up study.S4.2-19 In addition, retrospective cohort studies have dem- onstrated that statin therapy reduces risk of inci- and of CHD and all-cause deathS4.2-1 in patients with phenotypic or genetically con- firmed FH. Because moderate- or high-intensity statins have been shown to reduce ASCVD risk in both primary- and secondary-prevention trials and because high-intensity statins provide greater ASCVD risk reduction than moderate-intensity statins or placebo,S4.2-7 maximally tolerated statin therapy should be administered to patients with primary severe hypercholesterolemia. 2. A large placebo-controlled RCT examined the effect of simvastatin 80 mg daily, with or without ezetimibe 10 mg daily, on carotid intima-media thickness and plasma lipoproteins over 2 years. Mean LDL-C reduction was greater in the com- bined-therapy group, but there was no difference in carotid intima-media thickness between the 2 groups.


Mean LDL-C reduction was greater in the com- bined-therapy group, but there was no difference in carotid intima-media thickness between the 2 groups. The study was not powered to examine the risk of ASCVD events.S4.2-10 However, a very large placebo-controlled RCT examining ASCVD outcomes in post-ACS patients, performed over a period of 7 years, showed that the addition of ezetimibe 10 mg to simvastatin 40 mg daily resulted in greater ASCVD risk reduction than that produced by statin monotherapy.S4.2-8 Secondary- prevention patients with certain ASCVD risk indi- cators exhibit greater ASCVD risk reduction from ezetimibe therapy than do patients without these Patients with severe hyper- cholesterolemia who are adherent to statins, achieve <50% reduction in LDL-C levels with maximally tolerated statin therapy, and have an LDL-C level 100 mg/dL ( 2.6 mmol/L) are likely to derive additional ASCVD risk reduction from ezetimibe add-on therapy through additional 3. When administered to patients with severe hyper- cholesterolemia who are taking maximally toler- ated statins with or without ezetimibe, bile acid sequestrants have demonstrated LDL-C-lowering However, the clinical utility of bile acid sequestrants is limited by the absence of ASCVD outcomes data when used in combi- nation with statins, as well as by the issues of twice-daily dosing, high pill burden, the absence of well-tolerated generic formulations, drug inter- actions, and the potential for triglyceride eleva- tion. Nonetheless, in patients with very severe hypercholesterolemia, adding sequestrants to otherwise maximal cholesterol-lowering therapy in patients who are not eligible for a PCSK9 inhib- itor may be considered. 4.


Nonetheless, in patients with very severe hypercholesterolemia, adding sequestrants to otherwise maximal cholesterol-lowering therapy in patients who are not eligible for a PCSK9 inhib- itor may be considered. 4. PCSK9 inhibitors are promising drugs for treat- ment of FH.S4.2-9,S4.2-13 S4.2-15 Two placebo-con- trolled RCTs of the efficacy and safety of PCSK9 inhibitors in patients with heterozygous FH who were 18 years of age and taking stable, maxi- mally tolerated statin therapy demonstrated favorable safety profiles and an additional 50% reduction in LDL-C.S4.2-10,S4.2-15 There are no cur- rently available outcomes trials of PCSK9 inhibi- tors in patients with ASCVD heterozygous FH. In patients with LDL-C levels 190 mg/dL ( 4.9 mmol/L), advancing age is associated with pro- gressively increasing ASCVD risk,S4.2-4 and age- related risk would likely apply to those with heterozygous FH because of their higher lifetime exposure to increased LDL-C concentration.S4.2-18 A long-term prospective cohort registry study of CLINICAL STATEMENTS AND GUIDELINES 2404 patients with heterozygous FH (molecularly defined) taking contemporary statin with or with- out ezetimibe treatment regimens identified age >30 years, male sex, history of ASCVD, high blood pressure, increased waist circumference, active smoking, Lp(a) 50 mg/dL, and LDL-C levels 100 mg/dL ( 2.6 mmol/L) as independent predictors of incident ASCVD over a 5.5-year follow-up Because other medical interventions that lower LDL-C levels via increased expression of LDL receptors reduce ASCVD risk,S4.2-9 the use of PCSK9 inhibitors in selected maximally treated patients with heterozygous FH with persistently elevated LDL-C levels may be considered after a clinician patient discussion of the net benefits versus the cost of such therapy. 5.


In patients with LDL-C levels 190 mg/dL ( 4.9 mmol/L), advancing age is associated with pro- gressively increasing ASCVD risk,S4.2-4 and age- related risk would likely apply to those with heterozygous FH because of their higher lifetime exposure to increased LDL-C concentration.S4.2-18 A long-term prospective cohort registry study of CLINICAL STATEMENTS AND GUIDELINES 2404 patients with heterozygous FH (molecularly defined) taking contemporary statin with or with- out ezetimibe treatment regimens identified age >30 years, male sex, history of ASCVD, high blood pressure, increased waist circumference, active smoking, Lp(a) 50 mg/dL, and LDL-C levels 100 mg/dL ( 2.6 mmol/L) as independent predictors of incident ASCVD over a 5.5-year follow-up Because other medical interventions that lower LDL-C levels via increased expression of LDL receptors reduce ASCVD risk,S4.2-9 the use of PCSK9 inhibitors in selected maximally treated patients with heterozygous FH with persistently elevated LDL-C levels may be considered after a clinician patient discussion of the net benefits versus the cost of such therapy. 5. Regardless of whether a patient with LDL-C lev- els 190 mg/dL ( 4.9 mmol/L) is found to have a genetic mutation associated with FH, those with very high LDL-C values are most likely to achieve the greatest benefit from evidence-based LDL-C lowering therapy. Consequently, patients who have a baseline LDL-C level 220 mg/dL ( 5.7 mmol/L) and an on-treatment LDL-C level 130 mg/dL ( 3.4 mmol/L) despite maximally tolerated statin and ezetimibe therapy may be considered for treatment with a PCSK9 inhibitor after a clini- cian patient discussion of the net benefits versus the costs of such therapy. 6.


Consequently, patients who have a baseline LDL-C level 220 mg/dL ( 5.7 mmol/L) and an on-treatment LDL-C level 130 mg/dL ( 3.4 mmol/L) despite maximally tolerated statin and ezetimibe therapy may be considered for treatment with a PCSK9 inhibitor after a clini- cian patient discussion of the net benefits versus the costs of such therapy. 6. The cost-effectiveness of PCSK9 inhibitors for primary prevention among patients with LDL-C levels >190 mg/dL ( 4.9 mmol/L), or with FH, has not been evaluated extensively, and their clinical effectiveness in reducing ASCVD events in these patients has also not been established. The 2 published cost-effectiveness models for pri- mary prevention (see Online Data Supplements 44 and 45 and Section 7.) report very different results, with one suggesting an incremental cost- effectiveness ratio of $503000 per QALY added, and the other reporting $75000 per QALY added. Because of the lack of consistent evidence, the use of PCSK9 inhibitors has uncertain value for the primary prevention of ASCVD in patients with severe hypercholesterolemia. 4.3. Diabetes Mellitus in Adults Recommendations for Patients With Diabetes Mellitus Referenced studies that support recommendations are summarized in Online Data Supplements 11 and 12.


Diabetes Mellitus in Adults Recommendations for Patients With Diabetes Mellitus Referenced studies that support recommendations are summarized in Online Data Supplements 11 and 12. COR LOE Recommendations I A In adults 40 to 75 years of age with diabetes mellitus, regardless of estimated 10-year ASCVD risk, moderate-intensity statin therapy is indicated.S4.3-1 S4.3-9 IIa B-NR In adults 40 to 75 years of age with diabetes mellitus and an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), it is reasonable to assess the 10-year risk of a first ASCVD event by using the race and sex-specific PCE to help stratify ASCVD risk.S4.3-10,S4.3-11 IIa B-R In adults with diabetes mellitus who have multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with the aim to reduce LDL-C levels by 50% IIa B-NR In adults older than 75 years of age with diabetes mellitus and who are already on statin therapy, it is reasonable to continue IIb C-LD In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more.S4.3-14,S4.3-15 IIb C-LD In adults older than 75 years with diabetes mellitus, it may be reasonable to initiate statin therapy after a clinician patient discussion of potential benefits and IIb C-LD In adults 20 to 39 years of age with diabetes mellitus that is either of long duration ( 10 years of type 2 diabetes mellitus, 20 years of type 1 diabetes mellitus), albuminuria ( 30 mcg of albumin/mg creatinine), estimated glomerular filtration rate (eGFR) , retinopathy, neuropathy, or ankle-brachial index (ABI; <0.9), it may be reasonable to initiate statin Synopsis Although most adults 40 to 75 years of age with dia- betes mellitus are at intermediate or high-risk of their first ASCVD event,S4.3-5,S4.3-6,S4.3-8,S4.3-9 evaluation of AS- CVD risk will help refine risk estimates and therapeu- tic decision-making.


COR LOE Recommendations I A In adults 40 to 75 years of age with diabetes mellitus, regardless of estimated 10-year ASCVD risk, moderate-intensity statin therapy is indicated.S4.3-1 S4.3-9 IIa B-NR In adults 40 to 75 years of age with diabetes mellitus and an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), it is reasonable to assess the 10-year risk of a first ASCVD event by using the race and sex-specific PCE to help stratify ASCVD risk.S4.3-10,S4.3-11 IIa B-R In adults with diabetes mellitus who have multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with the aim to reduce LDL-C levels by 50% IIa B-NR In adults older than 75 years of age with diabetes mellitus and who are already on statin therapy, it is reasonable to continue IIb C-LD In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more.S4.3-14,S4.3-15 IIb C-LD In adults older than 75 years with diabetes mellitus, it may be reasonable to initiate statin therapy after a clinician patient discussion of potential benefits and IIb C-LD In adults 20 to 39 years of age with diabetes mellitus that is either of long duration ( 10 years of type 2 diabetes mellitus, 20 years of type 1 diabetes mellitus), albuminuria ( 30 mcg of albumin/mg creatinine), estimated glomerular filtration rate (eGFR) , retinopathy, neuropathy, or ankle-brachial index (ABI; <0.9), it may be reasonable to initiate statin Synopsis Although most adults 40 to 75 years of age with dia- betes mellitus are at intermediate or high-risk of their first ASCVD event,S4.3-5,S4.3-6,S4.3-8,S4.3-9 evaluation of AS- CVD risk will help refine risk estimates and therapeu- tic decision-making. Because primary-prevention trials demonstrate that moderate-intensity statin therapy in large cohorts with diabetes mellitus provides significant this treatment is indicated in such individuals.


Because primary-prevention trials demonstrate that moderate-intensity statin therapy in large cohorts with diabetes mellitus provides significant this treatment is indicated in such individuals. However, given the increased morbidity and mortality associated with a first event in diabetes mellitus and the residual risk among the statin-treated groups in these trials, together with the evidence of benefit from high-intensity statin treatment in primary prevention among men >50 years of age and women high-intensity statin therapy to maximize risk reduction is preferred for patients with diabetes mellitus as they age or if they have risk modi- fiers. Adults 20 to 39 years of age are mostly at low 10-year risk, although moderate-intensity statin thera- py in those with long-standing diabetes mellitus or a concomitant higher-risk condition may be reasonable Adults >75 years of age with Recommendations for Patients With Diabetes Mellitus (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES diabetes mellitus are at high-riskS4.3-5,S4.3-8 and clinical suggests they are likely to benefit from continuing or initiating statin therapy, although this may be compromised by reduced longevity and in- creased adverse events. Recommendation-Specific Supportive Text 1. Most adults 40 to 75 years of age with diabetes mellitus are at intermediate or high-risk (PCE 7.5% 10-year risk) of ASCVD events.S4.3-5,S4.3-6,S4.3-8,S4.3-9 Three of 4 double-blinded primary-preven- tion RCTs of moderate statin therapy in large cohorts with diabetes mellitus in this age range showed significant reductions in ASCVD A meta-analysis of these trials found that moderate-intensity statin therapy is associated with a risk reduction of 25%,S4.3-3 resulting in a risk level similar to that of people without diabetes mellitus and with no apparent difference in benefit between type 1 and type 2 diabetes mellitus.


Most adults 40 to 75 years of age with diabetes mellitus are at intermediate or high-risk (PCE 7.5% 10-year risk) of ASCVD events.S4.3-5,S4.3-6,S4.3-8,S4.3-9 Three of 4 double-blinded primary-preven- tion RCTs of moderate statin therapy in large cohorts with diabetes mellitus in this age range showed significant reductions in ASCVD A meta-analysis of these trials found that moderate-intensity statin therapy is associated with a risk reduction of 25%,S4.3-3 resulting in a risk level similar to that of people without diabetes mellitus and with no apparent difference in benefit between type 1 and type 2 diabetes mellitus. Therefore, on the basis of a high level of evidence, moderate-intensity statin therapy is indicated in patients 40 to 75 years of age with diabetes mellitus for primary prevention. 2. Although it is well recognized that the frequency of a first ASCVD event in adults with diabetes mellitus is significantly increased compared with those without diabetes mellitus, there is a wide spectrum of risk among individuals with diabe- that varies with age, duration of diabetes mellitus, and the presence of traditional risk factors and risk modifiers com- mon to the general population, as well as those specific to the population with diabetes mellitus (Table 5). Because the decision to upgrade statin treatment from moderate to high intensity is influenced by the level of ASCVD risk, the PCE risk estimator in adults 40 to 75 years of age with diabetes mellitus has utility in refining treatment decisions in these patients.S4.3-10,S4.3-11 The ASCVD risk score, however, does not determine whether statin intensity should be increased.


Because the decision to upgrade statin treatment from moderate to high intensity is influenced by the level of ASCVD risk, the PCE risk estimator in adults 40 to 75 years of age with diabetes mellitus has utility in refining treatment decisions in these patients.S4.3-10,S4.3-11 The ASCVD risk score, however, does not determine whether statin intensity should be increased. Rather, it begins an evaluation that includes clinician judg- ment of the individual s global risk, the potential for benefit from a high-intensity statin versus the potential for adverse effects or drug-drug interac- tions and evaluation should also include patient preferences and values. 3. The occurrence of a first ASCVD event in patients 40 to 75 years of age with diabetes mellitus is associated with increased morbidity and mortality compared with those without diabetes mellitus, which places a particularly high premium on pri- mary prevention in those with diabetes mellitus in that age range. Although trials using moderate- intensity statin therapy demonstrate significant benefit in such individuals, the residual risk in the statin treatment groups in these trials remained high (eg, 8.5% had major cardiovascular events in Strong general evidence indicates that the benefit from statin therapy is related to both global risk and intensity of treatment,S4.3-12 and no RCTs of high-intensity statin therapy have been carried out in cohorts of patients exclusively with diabetes mellitus. On the basis of these con- siderations and the fact that patients with diabe- tes mellitus have a higher trajectory of lifetime risk than do those without diabetes mellitus, high- intensity statin therapy is preferred in patients with diabetes mellitus as they age or develop risk modifiers (Table 5). 4.


On the basis of these con- siderations and the fact that patients with diabe- tes mellitus have a higher trajectory of lifetime risk than do those without diabetes mellitus, high- intensity statin therapy is preferred in patients with diabetes mellitus as they age or develop risk modifiers (Table 5). 4. ASCVD risk increases incrementally with age in In one long-term cohort study of type 2 diabetes mellitus with- out ASCVD, incident rates of MI averaged 25.6 in those >75 years of age, while another in a type 1 diabetes mellitus cohort found the 10-year fatal CVD risk in those >75 years of age was 70% in men and 40% in Although no controlled statin tri- als in people >75 years of age are available, a meta-analysis of the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) and HOPE-3 (Heart Outcomes Prevention Evaluation) trials dem- onstrated similar benefits in ASCVD reduc- tion among those >70 of age versus <70 years Although that study included few patients with diabetes mellitus, it does support the continuation of moderate- or high-intensity statin therapy for primary prevention in those >75 years of age with diabetes mellitus, who comprise 21% of the population in this age category. The clinician should note that the benefit may be off- set by limited life span or increased susceptibility to adverse events in patients in this age group. Table 5. Diabetes-Specific Risk Enhancers That Are Independent of Other Risk Factors in Diabetes Mellitus Risk Enhancers Long duration ( 10 years for type 2 diabetes mellitusS4.3-20 or 20 years for type 1 diabetes mellitusS4.3-6 Albuminuria 30 mcg of albumin/mg creatinineS4.3-25 ABI indicates ankle-brachial index; and eGFR, estimated glomerular filtration rate. CLINICAL STATEMENTS AND GUIDELINES 5.


Diabetes-Specific Risk Enhancers That Are Independent of Other Risk Factors in Diabetes Mellitus Risk Enhancers Long duration ( 10 years for type 2 diabetes mellitusS4.3-20 or 20 years for type 1 diabetes mellitusS4.3-6 Albuminuria 30 mcg of albumin/mg creatinineS4.3-25 ABI indicates ankle-brachial index; and eGFR, estimated glomerular filtration rate. CLINICAL STATEMENTS AND GUIDELINES 5. According to a CTT analysis,S4.3-12 the higher the 10-year ASCVD risk, the greater is the ben- efit from increased LDL-C reduction. This is supported by the meta-analyses comparing high- intensity versus -low-intensity statin therapyS4.3-12 and those comparing the benefit of statins and nonstatin therapeutic agents (ie, ezetimibe, bile sequestrants, PCSK9 antagonists) that upregu- late LDL receptors.S4.3-27 Therefore, a risk discus- sion may be held on the benefits of achieving 50% LDL-C lowering in adults with diabetes mellitus who have 20% ASCVD risk. Addition of ezetimibe 10 mg/d to moderate-intensity statin therapy can achieve the same percent LDL-C low- ering as that achieved with high-intensity statin In this RCT, 27% of patients had Thus, ezetimibe added to a moderate-intensity statin can be considered if a high-intensity statin cannot be tolerated or does not lower LDL-C, as expected, by 50%. 6. Although the risk of ASCVD is high in adults >75 years of age with diabetes mellitusS4.3-5,S4.3-6,S4.3-8 who are not receiving statin therapy, particularly those with additional risk factors or risk modifi- ers, the benefit of initiating statin therapy in these individuals may be limited by their reduced life span or increased susceptibility to adverse effects of treatment. Among this group will also be indi- viduals with recent or newly diagnosed diabetes mellitus for whom the impact of diabetes mellitus on ASCVD risk is not well known.


Among this group will also be indi- viduals with recent or newly diagnosed diabetes mellitus for whom the impact of diabetes mellitus on ASCVD risk is not well known. It may there- fore be reasonable to have a clinician patient dis- cussion in which the potential benefits and risks of initiating statin therapy in this age group are reviewed. 7. There is limited information on ASCVD rates among individuals 20 to 39 years of age with diabetes mellitus and no information on whether statin therapy is beneficial in these individuals. Available evidence indicates that although rates of ASCVD are low in those <30 years of age, they increase with timeS4.3-6,S4.3-17,S4.3-20,S4.3-23 and may reach intermediate-risk levels by 30 to 39 years of age, especially in individuals with long- standing type 2 diabetes mellitus,S4.3-17 who may have more advanced subclinical coronary athero- sclerosis than do nondiabetic subjects,S4.3-21 and in those with type 1 diabetes mellitus of >20 years ASCVD rates will also be influ- enced by hypertension and diabetic microvascu- lar complications that may be prevalent in these Thus, it may be reasonable to have a discussion about initiating moderate- intensity statin therapy with patients who have had type 2 diabetes mellitus for at least 10 years or type 1 diabetes mellitus for at least 20 years and with patients with 1 or more major CVD risk factors or complications, such as diabetic nephropathy or albuminuria 30 mcg albumin/mg creatinine),S4.3-25 or an ABI of (Table 5). 4.4. Primary Prevention Primary prevention of ASCVD over the life span requires attention to prevention or management of ASCVD risk factors beginning early in life (Figure 2). One major AS- CVD risk factor is elevated serum cholesterol, usually identified clinically as measured LDL-C. Screening can be performed with fasting or nonfasting measurement of lipids.


Screening can be performed with fasting or nonfasting measurement of lipids. In children, adolescents (10 to 19 years of age), and young adults (20 to 39 years of age), priority should be given to estimation of lifetime risk and promotion of lifestyle risk reduction. Drug therapy is needed only in se- lected patients with moderately high LDL-C levels ( 160 mg/dL [ 4.1 mmol/L]) or patients with very high LDL-C levels (190 mg/dL [4.9 mmol/L]). Three major higher-risk categories are patients with severe hypercholesterol- emia (LDL-C levels 190 mg/dL [ 4.9 mmol/L]), adults with diabetes mellitus, and adults 40 to 75 years of age. Patients with severe hypercholesterolemia and adults 40 to 75 years of age with diabetes mellitus are candidates for immediate statin therapy without further risk assess- ment. Adults with diabetes mellitus should start with a moderate-intensity statin, and as they accrue multiple risk factors, a high-intensity statin may be indicated. In other adults 40 to 75 years of age, 10-year ASCVD risk should guide therapeutic considerations. The higher the estimated ASCVD risk, the more likely the patient is to benefit from evidence-based statin treatment. The risk discussion should also consider several risk enhancers that can be used to favor initiation or intensification of statin therapy. When risk is uncertain or if statin ther- apy is problematic, it can be helpful to measure CAC to refine risk assessment. A CAC score predicts ASCVD events in a graded fashion and is independent of other risk factors, such as age, sex, and ethnicity.S4.4-1 A CAC score equal to zero is useful for reclassifying patients to a lower-risk group, often allowing statin therapy to be withheld or postponed unless higher risk conditions are present.


A CAC score predicts ASCVD events in a graded fashion and is independent of other risk factors, such as age, sex, and ethnicity.S4.4-1 A CAC score equal to zero is useful for reclassifying patients to a lower-risk group, often allowing statin therapy to be withheld or postponed unless higher risk conditions are present. For patients >75 years of age, RCT evidence for statin therapy is not strong, so clinical assessment of risk status in a clinician patient risk discussion is need- ed for deciding whether to continue or initiate statin 4.4.1. Evaluation and Risk Assessment 4.4.1.1. Essential Process of Risk Assessment Children and adolescents should be tested for lipid dis- orders as described in Section 4.4.4.3. Risk assessment in young adults 20 to 39 years of age is discussed in CLINICAL STATEMENTS AND GUIDELINES Section 4.4.4.2. In the young adult age group, mea- surement of risk factors allows for estimation of life- time risk of ASCVD. (See the risk calculators provided on the ACC and AHA websites.S4.4.1.1-1,S4.4.1-2 ) Young adults with moderate hypercholesterolemia (LDL-C levels 160 189 mg/dL [4.1 4.8 mmol/L]) may be can- didates for cholesterol-lowering drugs. After age 20 years, traditional risk factors should be assessed every In adults who are free from ASCVD, traditional ASCVD risk factors should be assessed every 4 to 6 Adults 40 to 75 years of age are po- tential candidates for statin therapy. Selection of pa- tients for statin therapy is a multistep process. The first step to determine individual risk of clinical ASCVD is to categorize patients into 4 categories of risk, from high to low.


The first step to determine individual risk of clinical ASCVD is to categorize patients into 4 categories of risk, from high to low. The categories with highest overall risk (secondary prevention and primary LDL-C levels 190 mg/dL [ 4.9 mmol/L]) require prompt treatment to lower ASCVD risk without using risk calculation by the PCE, which were introduced in 2013. Adults 40 to 75 years of age with diabetes mellitus merit initiation of a moderate-intensity statin without using risk calculation by the PCE; however, it is reasonable to use PCE to fur- ther stratify risk (Section 4.3. on diabetes mellitus). The fourth category includes adults 40 to 75 years of age whose 10-year ASCVD risk is estimated by the PCE. This leads to the clinician patient risk discussion to consider the pros and cons of statin therapy; factors to consider are PCE scoring, presence or absence of other risk-en- hancing factors, potential benefit of intensified lifestyle therapy, likelihood of statin-associated side effects or drug drug interactions, and patient choice. If risk sta- tus remains uncertain after these considerations, mea- surement of CAC can provide additional information to help make a decision with regard to statin therapy. 4.4.1.2. Pooled Cohort Equations Several algorithms have been proposed for estimation A useful one, and the most representative algorithm for the United States, is one derived from 5 prospective community-based studies representing a broad spectrum of the US population Figure 2. Primary prevention. Colors correspond to Class of Recommendation in Table 2. apoB indicates apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; HIV, human immunodeficiency virus; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; and Lp(a), lipoprotein (a).


Colors correspond to Class of Recommendation in Table 2. apoB indicates apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; HIV, human immunodeficiency virus; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; and Lp(a), lipoprotein (a). CLINICAL STATEMENTS AND GUIDELINES and validated in a similar natural his- The PCE estimate risk of hard ASCVD events (MI and stroke, both fatal and nonfatal). Esti- mates are readily applied in clinical practice. Their risk factors include age, cigarette smoking, blood pressure, serum TC, HDL-C, and presence or absence of diabetes mellitus. The race and sex-specific PCE are best validat- ed in non-Hispanic blacks and non-Hispanic whites 40 to 75 years of age.S4.4.1.2-1 S4.4.1,2-3,S4.4.1.2-7 S4.4.1.2-19 In other racial/ethnic groups, equations are less extensively stud- ied. Because the PCE are population equations, they may overestimate or underestimate risk for individu- als or population subgroups. Consequently, PCE esti- mates must be considered in the context of a particu- lar patient s circumstances when deciding whether to use statin therapy. Using the PCE, the 2013 ACC/AHA identified a 10-year risk of ASCVD 7.5% as an RCT-supported threshold for benefit of statin therapy. In this guideline, 10-year risk for ASCVD is categorized as low-risk (<5%), borderline risk (5% to <7.5%), intermediate risk (7.5% to <20%), and high risk ( 20%). In adults 20 to 39 years of age, assess- ment of 30-year or lifetime risk of a first ASCVD event can be used to inform intensity of primary-prevention PCE estimates can be calculated from 2 online links: ACCS4.4.1.1-1 4.4.1.3. Risk-Enhancing Factors Moderate intensity generic statins allow for efficacious and cost-effective primary prevention in patients with a 10-year risk of ASCVD 7.5%.S4.4.1.3-1 Since 2013 ACC/ provided additional support for this finding.


Risk-Enhancing Factors Moderate intensity generic statins allow for efficacious and cost-effective primary prevention in patients with a 10-year risk of ASCVD 7.5%.S4.4.1.3-1 Since 2013 ACC/ provided additional support for this finding. The pooled cohort equation (PCE) is the single most robust tool for esti- mating 10-year risk in US adults 40 to 75 years of age. Its strength can be explained by inclusion of major, in- dependent risk factors. One limitation on the PCE when applied to individuals is that age counts as a risk factor and dominates risk scoring with advancing age. Age is a powerful population risk factor but does not neces- sarily reflect individual risk. Another factor influencing risk are baseline characteristics of populations (baseline risk). These characteristics include both genetic and ac- quired risk factors other than established major risk fac- tors. Variation in baseline risk accounts for difference in risk in different ethnic groups. Absolute risk predictions depend on the baseline risk of a population (eg, the US population). These considerations in patients at inter- mediate risk leave room in the clinician-patient risk dis- cussion to withhold or delay initiation of statin therapy, depending on age, pattern of risk factors, and patient preferences and values. In sum, the PCE is a powerful tool to predict population risk, but it has limitations when applied to individuals. One purpose of the clinician patient risk discussion is to individualize risk status based on PCE as well as other factors that may inform risk prediction. Among these other factors are the risk- enhancing factors discussed in this guideline. These risk-enhancing factors are listed in Table 6, and evi- dence base and strength of association with ASCVD are shown in Table S6. In the general population, they may or may not predict risk independently of PCE.


In the general population, they may or may not predict risk independently of PCE. But in the clinician patient risk discussion they can be useful for identifying specific factors that in- fluence risk. Their presence helps to confirm a higher risk state and thereby supports a decision to initi- ate or intensify statin therapy. They are useful for clarifying which atherogenic factors are present in a particular patient. And in some patients, certain risk- enhancing factors carry greater lifetime risk than de- noted by 10-year risk prediction in the PCE. Finally, several risk-enhancing factors may be specific targets therapy beyond those of the PCE. A few comments may illustrate the potential use- fulness of risk-enhancing factors in the patient discus- sion. LDL-C 160 mg/dL ( 4.1 mmol/L), apoB 130 Table 6. Risk-Enhancing Factors for Clinician Patient Risk Discussion Risk-Enhancing Factors Family history of premature ASCVD (males, age <55 y; females, age <65 y) Primary hypercholesterolemia (LDL-C, 160 189 mg/dL [4.1 4.8 mmol/L); non HDL-C 190 219 mg/dL [4.9 5.6 mmol/L])* Metabolic syndrome (increased waist circumference, elevated triglycerides [>150 mg/dL], elevated blood pressure, elevated glucose, and low HDL-C [<40 mg/dL in men; <50 in women mg/dL] are factors; tally of 3 makes the diagnosis) with or without albuminuria; not treated with dialysis or kidney transplantation) Chronic inflammatory conditions such as psoriasis, RA, or HIV/AIDS History of premature menopause (before age 40 y) and history of pregnancy-associated conditions that increase later ASCVD risk such as preeclampsia High-risk race/ethnicities (eg, South Asian ancestry) Lipid/biomarkers: Associated with increased ASCVD risk Persistently* elevated, primary hypertriglyceridemia ( 175 mg/dL); If measured: Elevated high-sensitivity C-reactive protein ( 2.0 mg/L) Elevated Lp(a): A relative indication for its measurement is family history of premature ASCVD.


Risk-Enhancing Factors for Clinician Patient Risk Discussion Risk-Enhancing Factors Family history of premature ASCVD (males, age <55 y; females, age <65 y) Primary hypercholesterolemia (LDL-C, 160 189 mg/dL [4.1 4.8 mmol/L); non HDL-C 190 219 mg/dL [4.9 5.6 mmol/L])* Metabolic syndrome (increased waist circumference, elevated triglycerides [>150 mg/dL], elevated blood pressure, elevated glucose, and low HDL-C [<40 mg/dL in men; <50 in women mg/dL] are factors; tally of 3 makes the diagnosis) with or without albuminuria; not treated with dialysis or kidney transplantation) Chronic inflammatory conditions such as psoriasis, RA, or HIV/AIDS History of premature menopause (before age 40 y) and history of pregnancy-associated conditions that increase later ASCVD risk such as preeclampsia High-risk race/ethnicities (eg, South Asian ancestry) Lipid/biomarkers: Associated with increased ASCVD risk Persistently* elevated, primary hypertriglyceridemia ( 175 mg/dL); If measured: Elevated high-sensitivity C-reactive protein ( 2.0 mg/L) Elevated Lp(a): A relative indication for its measurement is family history of premature ASCVD. An Lp(a) 50 mg/dL or 125 nmol/L constitutes a risk-enhancing factor especially at higher levels of Lp(a). Elevated apoB 130 mg/dL: A relative indication for its measurement would be triglyceride 200 mg/dL. A level 130 mg/ dL corresponds to an LDL-C 160 mg/dL and constitutes a risk- enhancing factor. *Optimally, 3 determinations. AIDS indicates acquired immunodeficiency syndrome; ABI, ankle-brachial index; apoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; HIV, human immunodeficiency virus; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); and RA, rheumatoid arthritis. CLINICAL STATEMENTS AND GUIDELINES mg/dL (particularly when accompanied by persistently elevated triglycerides), and elevated Lp(a) denote high lifetime risk for ASCVD and favor initiation of statin therapy.


CLINICAL STATEMENTS AND GUIDELINES mg/dL (particularly when accompanied by persistently elevated triglycerides), and elevated Lp(a) denote high lifetime risk for ASCVD and favor initiation of statin therapy. The presence of family history of ASCVD, pre- mature menopause, and patients of South Asian race appear to convey a higher baseline risk and are stron- ger candidates for statin therapy. Conditions associated with systemic inflammation (chronic inflammatory dis- orders, metabolic syndrome, chronic renal disease, and elevated hsCRP) appear to predispose to atherothrom- botic events, which reasonably justifies statin therapy in intermediate-risk patients. 4.4.1.4. Coronary Artery Calcium Substantial advances in estimation of risk with CAC scoring have been made in the past 5 years. One pur- pose of CAC scoring is to reclassify risk identification of patients who will potentially benefit from statin therapy. This is especially useful when the clinician and patient are uncertain whether to start a statin. Indeed, the most important recent observation has been the finding that a CAC score of zero indicates a low ASCVD risk for the subsequent 10 years.S4.4.1.4-1 S4.4.1.4-8 Thus, measurement of CAC potentially allows a cli- nician to withhold statin therapy in patients show- ing zero CAC. There are exceptions. For example, CAC scores of zero in persistent cigarette smokers, patients with diabetes mellitus, those with a strong family history of ASCVD, and possibly chronic inflam- matory conditions such as HIV, may still be associated Neverthe- less, a sizable portion of middle-aged and older pa- tients have zero CAC, which may allow withholding of statin therapy in those intermediate risk patients who would otherwise have a high enough risk according to the PCE to receive statin therapy (Figure 2).


For example, CAC scores of zero in persistent cigarette smokers, patients with diabetes mellitus, those with a strong family history of ASCVD, and possibly chronic inflam- matory conditions such as HIV, may still be associated Neverthe- less, a sizable portion of middle-aged and older pa- tients have zero CAC, which may allow withholding of statin therapy in those intermediate risk patients who would otherwise have a high enough risk according to the PCE to receive statin therapy (Figure 2). Most patients with CAC scores 100 Agatston units have a 10-year risk of ASCVD 7.5%, a widely accepted threshold for initiation of statin therapy.S4.4.1.4-13 With increasing age, 10-year risk accompanying CAC scores of 1 to 99 rises, usually crossing the 7.5% threshold in later middle age.S4.4.1.4-13 When the CAC score is zero, some investigators favor remeasurement of CAC af- CAC measurement has no utility in patients already treated with statins. Statins are associated with slower progression of over- all coronary atherosclerosis volume and reduction of high-risk plaque features, yet statins increase the CAC A prospective randomized study of CAC scoring showed improved risk factor modification without an increase in downstream medical testing or In MESA (Multi-Ethnic Study of Athero- sclerosis), CAC scanning delivered 0.74 to l.27 mSv of radiation, which is similar to the dose of a clinical CAC scans should be ordered by a clinician who is fully versed in the pros and cons of diagnostic radiology. 4.4.2. Primary Prevention Adults 40 to 75 Years of Age With LDL-C Levels 70 to 189 mg/dL (1.7 to 4.8 mmol/L) Primary Prevention Recommendations for Adults 40 to 75 Years of Age With LDL Levels 70 to 189 mg/dL (1.7 to 4.8 mmol/L) Referenced studies that support recommendations are summarized in Online Data Supplement 16.


Primary Prevention Adults 40 to 75 Years of Age With LDL-C Levels 70 to 189 mg/dL (1.7 to 4.8 mmol/L) Primary Prevention Recommendations for Adults 40 to 75 Years of Age With LDL Levels 70 to 189 mg/dL (1.7 to 4.8 mmol/L) Referenced studies that support recommendations are summarized in Online Data Supplement 16. COR LOE Recommendations I A In adults at intermediate-risk, statin therapy reduces risk of ASCVD, and in the context of a risk discussion, if a decision is made for statin therapy, a moderate-intensity statin should be recommended.S4.4.2-1 S4.4.2-8 I A In intermediate-risk patients, LDL-C levels should be reduced by 30% or more, and for optimal ASCVD risk reduction, especially in high-risk patients, levels should be reduced I B-NR For the primary prevention of clinical ASCVD* in adults 40 to 75 years of age without diabetes mellitus and with an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), the 10-year ASCVD risk of a first hard ASCVD event (fatal and nonfatal MI or stroke) should be estimated by using the race- and sex-specific PCE, and adults should be categorized as being at low risk (<5%), borderline risk (5% to <7.5%), intermediate- risk ( 7.5% to <20%), and high-risk I B-NR Clinicians and patients should engage in a risk discussion that considers risk factors, adherence to healthy lifestyle, the potential for ASCVD risk-reduction benefits, and the potential for adverse effects and drug drug interactions, as well as patient preferences, for an individualized treatment IIa B-R In intermediate-risk adults, risk-enhancing factors favor initiation or intensification of IIa B-NR In intermediate-risk or selected borderline-risk adults, if the decision about statin use remains uncertain, it is reasonable to use a CAC score in the decision to withhold, postpone or initiate statin IIa B-NR In intermediate-risk adults or selected borderline-risk adults in whom a CAC score is measured for the purpose of making a treatment decision, AND If the coronary calcium score is zero, it is reasonable to withhold statin therapy and reassess in 5 to 10 years, as long as higher risk conditions are absent (diabetes mellitus, family history of premature CHD, cigarette smoking); If CAC score is 1 to 99, it is reasonable to initiate statin therapy for patients 55 years of age; If CAC score is 100 or higher or in the 75th percentile or higher, it is reasonable to initiate statin therapy.S4.4.2-17,S4.4.2-23 CLINICAL STATEMENTS AND GUIDELINES IIb B-R In intermediate-risk adults who would benefit from more aggressive LDL-C lowering and in whom high-intensity statins are advisable but not acceptable or tolerated, it may be reasonable to add a nonstatin drug (ezetimibe or bile acid sequestrant) to a moderate-intensity IIb B-R In patients at borderline risk, in risk discussion, the presence of risk-enhancing factors may justify initiation of moderate- intensity statin therapy.S4.4.2-17,S4.4.2-24 *Definition of clinical ASCVD includes acute coronary syndrome (ACS), those with history of myocardial infarction (MI), stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral artery disease (PAD) including aortic aneurysm, all of atherosclerotic origin.


Synopsis Adults 40 to 75 years of age in primary prevention can be classified as borderline risk (10-year risk of ASCVD and high-risk (20%). For intermediate-risk patients, moderate- to high-intensity statin therapy should be considered during risk discussion of treatment options. Additional considerations favoring use of statins in in- termediate-risk patients include other independent risk conditions and, in selected individuals, risk-enhancing factors associated with greater ASCVD risk (Table 6). Although the variability of percent LDL-C lowering with high-intensity statin use is wide, its efficacy is proportional to the magnitude of the LDL-C reduction Systematic reviews indicate that those with higher baseline ASCVD risk derive greater absolute benefit from higher percent LDL-C reduction with evi- Accordingly, if a statin is given, LDL-C levels should be reduced by 30% and optimally by 50%. When there is uncertainty, consid- eration of risk-enhancing factors including family his- tory of premature ASCVD and CAC score, categorical risk factors, and selected biomarkers may inform the decision. CAC scoring is especially useful in older adults to improve specificity.S4.4.2-15 A CAC score of zero revises ASCVD risk downward and selects adults who show reduced benefit from starting a statin.S4.4.2-20 Recommendation-Specific Supportive Text 1. Prior guidelines recommended moderate- or high- intensity statins as first-line LDL-C lowering ther- apy in primary prevention of ASCVD after a risk discussion of treatment options. This was based on 3 large-scale exclusively primary-prevention RCTs that demonstrated that moderate-intensity and high-intensity statin were associated with ASCVD risk reduction that outweighed the observable risks. Since those ACC/AHA 2013 guidelines, a large- scale RCT in a racially/ethnically diverse population confirmed statin benefit from a moderate-inten- sity dose of a statin as compared with placebo in intermediate-risk patients.


Since those ACC/AHA 2013 guidelines, a large- scale RCT in a racially/ethnically diverse population confirmed statin benefit from a moderate-inten- sity dose of a statin as compared with placebo in intermediate-risk patients. That RCT enrolled men 55 years of age and women 65 years of age with at least 1 cardiovascular risk factor. In the placebo group, the 10-year risk of hard ASCVD was 8.7%, and the risk of the expanded ASCVD endpoint that included coronary revascularization After 5.6 years, those assigned to rosuvastatin 10 mg/d demonstrated signifi- cant ARR in both co-primary endpoints with an acceptable safety record. By comparison, after a median follow-up of 1.9 years, those assigned a high-intensity dose of rosuvastatin in the JUPITER RCT achieved greater LDL-C-lowering and greater reductions in ASCVD outcomes. This corroborates meta-analyses demonstrating increased net ben- efit of evidence-based LDL-C lowering therapy in those at risk if greater reductions in LDL-C are 2. If in the context of a risk discussion, maximal ASCVD risk reduction is desired, it is reasonable to use a high-intensity statin to lower LDL-C by 50%. This provides increased benefit, espe- cially when 10-year ASCVD risk is 20%. JUPITER enrolled men 50 years of age and women 60 years of age with high-sensitivity C-reactive protein values 2.0 mg/L. Participants randomly assigned to 20 mg/d of rosuvastatin achieved median reductions in LDL-C of 50% and highly significant ASCVD risk reduction at 1.9 years.S4.4.2-6 The trial was stopped prematurely because of a highly significant reduction in cardiovascular death. However, wide individual variability in per- cent LDL-C reduction was noted.


However, wide individual variability in per- cent LDL-C reduction was noted. Importantly, the magnitude of the percent LDL-C reduction deter- The US Preventive Services Task Force systematic review of statin therapy in primary prevention showed a reduced risk of all-cause and cardiovascular death and ASCVD events and noted greater absolute benefits in those at greater baseline risk,S4.4.2-4 consistent with other high-quality systematic reviews and This underscores the need for aggressive and safe risk reduction in the highest-risk groups and the need for follow- up LDL-C testing to determine adherence and adequacy of effect of the prescribed statin.S4.4.2-26 3. In individuals 40 to 75 years of age, 10-year ASCVD risk assessment begins the clinician patient risk Primary Prevention Recommendations for Adults 40 to 75 Years of Age With LDL Levels 70 to 189 mg/dL (1.7 to 4.8 mmol/L) (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES Required information includes age, sex, and race/ethnicity; presence of diabetes mellitus or cigarette smoking and treated hypertension; and a current blood pressure level and fasting or nonfasting TC and HDL-C levels. The PCE include a stroke endpoint and race- specific coefficients. This identifies, for example, a black woman who with similar risk factors is at much higher risk than her white counterpart. The PCE were externally validated in a high-qual- ity natural history study published shortly after the 2013 ACC/AHA cholesterol guidelines were These equations may underesti- mate risk in individuals of South Asian ancestry and other high-risk groups and may overestimate risk in selected lower-risk groups.S4.4.2-10 Unlike other risk estimators, the PCE use only fatal and nonfatal stroke and CHD as endpoints. Other risk estimators that include revascularization and additional cardiovascular endpoints provide risk estimates that cannot be compared directly with those given by the PCE.


Other risk estimators that include revascularization and additional cardiovascular endpoints provide risk estimates that cannot be compared directly with those given by the PCE. Finally, the potential for errors in estimating ASCVD risk at both ends of the risk curve (low risk and high-risk) as noted for individuals can be reviewed in the clinician patient risk discussion (Table 6). 4. The present guidelines continue to empha- size the importance of a clinician patient risk In those with a 10-year ASCVD risk of 7.5%, it is rec- ommended that the discussion occur before a statin prescription is written.S4.4.2-26 This frank discussion, as recommended in the 2013 ACC/ AHA cholesterol guidelines,S4.4.2-26 should con- sider whether ASCVD risk factors have been addressed, evaluate whether an optimal life- style has been implemented, and review the potential for statin benefit versus the potential for adverse effects and drug-drug interactions. Then, on the basis of individual characteristics and including an informed patient preference in shared decision-making, a risk decision about statin therapy can be made (Table 7). Clinicians should indicate that as ASCVD risk increases, so does benefit of evidence-based LDL-C lower- ing therapy. They may wish to review the drug and safety sections of the present guideline and stay informed on safety information that is essential for a balanced discussion. Importantly, for those at intermediate-risk, especially those >55 years of age, risk-enhancing factors or CAC can be used to clarify risk if the risk decision is Risk-enhancing factors, such as family history of premature ASCVD or an LDL-C of 160 to 189 mg/dL (4.1 4.8 mmol/L), identify Table 7. Checklist for Clinician Patient Shared Decision-Making for Initiating Therapy Checklist Item Recommendation ASCVD risk assessment Assign to statin treatment group; use ASCVD Risk Estimator Plus.


Checklist for Clinician Patient Shared Decision-Making for Initiating Therapy Checklist Item Recommendation ASCVD risk assessment Assign to statin treatment group; use ASCVD Risk Estimator Plus.* In lower-risk primary-prevention adults 40-75 y of age with LDL-C 70 mg/dL ( 1.8 mmol/L). Not needed in secondary prevention, in those with LDL-C 190 mg/dL ( 4.9 mmol/L), or in those 40-75 y of age with diabetes mellitus. Assess other patient characteristics that influence risk. See Risk-Enhancing Factors (Section 4.4.1.3. and Table 6). Assess CAC (Section 4.4.1.4.) if risk decision is uncertain and additional information is needed to clarify ASCVD risk. Use decision tools to explain risk (eg, ASCVD Risk Estimator Plus,* Mayo Clinic Statin Choice Decision Aid ). Lifestyle modifications Review lifestyle habits (eg, diet, physical activity, weight or body mass index, and tobacco use). Endorse a healthy lifestyle and provide relevant advice, materials, or referrals (eg, CardioSmart , AHA Life s Simple 7 , NLA Patient Tear Sheets , PCNA Heart Healthy Toolbox , cardiac rehabilitation, dietitian, smoking cessation program). Potential net clinical benefit of pharmacotherapy Recommend statins as first-line therapy. Consider the combination of statin and nonstatin therapy in selected patients. Discuss potential risk reduction from lipid-lowering therapy. Discuss the potential for adverse effects or drug drug interactions. Cost considerations Discuss potential out-of-pocket cost of therapy to the patient (eg, insurance plan coverage, tier level, copayment). Shared decision- making Encourage the patient to verbalize what was heard (eg, patient s personal ASCVD risk, available options, and risks/benefits). Invite the patient to ask questions, express values and preferences, and state ability to adhere to lifestyle changes and medications. Refer patients to trustworthy materials to aid in their understanding of issues regarding risk decisions. Collaborate with the patient to determine therapy and follow-up plan.


Collaborate with the patient to determine therapy and follow-up plan. *ASCVD Risk Predictor Plus is available at: http://tools.acc.org/ASCVD-Risk- Estimator-Plus/#!/calculate/estimate/ and http://static.heart.org/riskcalc/app/ index.html#!/baseline-risk. Accessed September 1, 2018. Mayo Clinic Statin Decision Aid information is available at: https:// statindecisionaid.mayoclinic.org. CardioSmart health information is available at: https://www.cardiosmart. org/About. AHA Life's Simple 7 information is available at: https://www.heart.org/en/ healthy-living/healthy-lifestyle/my-life-check lifes-simple-7. NLA Patient Tear Sheets information is available at: https://www.lipid.org/ practicetools/tools/tearsheets. PCNA Heart Healthy Toolbox information is available at: http://pcna.net/ clinical-tools/tools-for-healthcare-providers/heart-healthy-toolbox. AHA indicates American Heart Association; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CKD, chronic kidney disease; HIV, human immunodeficiency virus; LDL-C, low-density lipoprotein cholesterol; PCNA, Preventive Cardiology Nurses Association and NLA, National Lipid Association. CLINICAL STATEMENTS AND GUIDELINES individuals whose ASCVD risk may indicate risk of genetic hypercholesterolemia and hence who may benefit from a moderate- to high-intensity (Table 6). 5. In those with intermediate ASCVD risk, defined as an ASCVD risk of 7.5% to 20%, knowledge of risk-enhancing factors is useful in understand- ing patient characteristics that increase ASCVD risk both short and long-term (Table 6). As in the 2013 ACC/AHA guideline, an ASCVD score does not assign a statin; it begins the decision process, which includes consideration of risk-enhancing factors. For example, in an RCT,S4.4.2-9 a family history of premature ASCVD identified women 60 years of age with elevated high-sensitivity C-reactive protein but without ASCVD who ben- efitted from high-intensity statin therapy. Those with primary elevations of LDL-C 160 mg/dL (4.1 mmol/L) have elevated lifetime ASCVD risk and benefit from statin therapy.S4.4.2-21,S4.4.2-22,S4.4.2-25, Increased ASCVD riskS4.4.2-2 is seen with metabolic syndrome;S4.4.2-20 inflammatory diseases, including psoriasisS4.4.2-31 and RA; and HIV when treated with protease inhibitors.S4.4.2-32 In women, a history of pregnancy complicated by preeclampsia or premature menopause (age <40 years) also enhances ASCVD risk (see Section 4.4.5.3.).


Those with primary elevations of LDL-C 160 mg/dL (4.1 mmol/L) have elevated lifetime ASCVD risk and benefit from statin therapy.S4.4.2-21,S4.4.2-22,S4.4.2-25, Increased ASCVD riskS4.4.2-2 is seen with metabolic syndrome;S4.4.2-20 inflammatory diseases, including psoriasisS4.4.2-31 and RA; and HIV when treated with protease inhibitors.S4.4.2-32 In women, a history of pregnancy complicated by preeclampsia or premature menopause (age <40 years) also enhances ASCVD risk (see Section 4.4.5.3.). If measured, ABI <0.9 has been shown to reclassify risk by the 2013 Risk Assessment The presence of risk-enhancing factors may affect the threshold for statin initia- tion or intensification (see Sections 4.4.2, 4.4.4, and 4.5). Finally, in selected individuals, biomark- ers, if measured, may identify individuals with increased risk of ASCVD events. Lp(a) levels, especially in those with a family history of prema- ture ASCVD, can increase risk.S4.4.2-16 However, no available RCT evidence supports Lp(a) levels as a target of therapy. Moderate primary elevations of triglycerides, non HDL-C (TC minus HDL-C), and, if measured, apolipoprotein B (apoB) can improve selection of those at increased ASCVD risk.S4.4.2-22 6. Evidence shows that a CAC score of zero can down-risk individuals who otherwise would qualify for a statin on the basis of their ASCVD 10-year risk. The ability to select those who would benefit greatly from statin therapy, as shown by RCTs in primary-prevention populationsS4.4.2-6,S4.4.2-8 and yet to withhold statin therapy in those least likely to benefit would improve specificity.S4.4.2-34 For example, a CAC score of zero in an analysis of pooled US population-based studies accurately discriminated between lower and higher CHD risk in older adults.S4.4.2-19,S4.4.2-27 The BioImage Study in older adultsS4.4.2-15 showed improved detection of individuals not likely to benefit from statins when the CAC score was zero.


The ability to select those who would benefit greatly from statin therapy, as shown by RCTs in primary-prevention populationsS4.4.2-6,S4.4.2-8 and yet to withhold statin therapy in those least likely to benefit would improve specificity.S4.4.2-34 For example, a CAC score of zero in an analysis of pooled US population-based studies accurately discriminated between lower and higher CHD risk in older adults.S4.4.2-19,S4.4.2-27 The BioImage Study in older adultsS4.4.2-15 showed improved detection of individuals not likely to benefit from statins when the CAC score was zero. Selected examples of candidates for CAC scoring who might benefit from knowing their CAC score is zero are listed in Table 8. Clinicians should not down-risk patients who are persistent cigarette smokers, have diabetes mellitus, or have a strong family history of ASCVD, as well as pos- sibly those with chronic inflammatory conditions whose CAC of zero does not rule out risk from 7. In adults at intermediate-risk (predicted 10-year risk of 7.5% to <20%), substantial data indicate how CAC measurement can be effective in mean- ingfully reclassifying risk in a large proportion of In such inter- mediate-risk adults, those with a CAC score 100 Agatston units or CAC 75th percentile appear to have ASCVD event rates suggesting that statin therapy would be beneficial.S4.4.2-17,S4.4.2-23 Those with a CAC of zero appear to have 10-year event rates in a lower range that suggests statin therapy may be of limited value for these patients, with few exceptions including patients with diabetes mellitus, persistent smoking, and family history or premature ASCVD.


In adults at intermediate-risk (predicted 10-year risk of 7.5% to <20%), substantial data indicate how CAC measurement can be effective in mean- ingfully reclassifying risk in a large proportion of In such inter- mediate-risk adults, those with a CAC score 100 Agatston units or CAC 75th percentile appear to have ASCVD event rates suggesting that statin therapy would be beneficial.S4.4.2-17,S4.4.2-23 Those with a CAC of zero appear to have 10-year event rates in a lower range that suggests statin therapy may be of limited value for these patients, with few exceptions including patients with diabetes mellitus, persistent smoking, and family history or premature ASCVD. Cigarette smoking remains a strong risk factor even in the presence of CAC score of zero.S4.4.2-50,S4.4.2-51 In asymptomatic dia- betes mellitus, a CAC score of zero is associated with a favorable 5-year prognosis; but after 5 years, the risk of mortality increases significantly for diabetic individuals even in the presence of a baseline CAC score of zero.S4.4.2-52 In patients with a family history of ASCVD, CAC score of zero may impart less short-term benefit from statin therapy, but considering a high lifetime risk, long-term Table 8.


Cigarette smoking remains a strong risk factor even in the presence of CAC score of zero.S4.4.2-50,S4.4.2-51 In asymptomatic dia- betes mellitus, a CAC score of zero is associated with a favorable 5-year prognosis; but after 5 years, the risk of mortality increases significantly for diabetic individuals even in the presence of a baseline CAC score of zero.S4.4.2-52 In patients with a family history of ASCVD, CAC score of zero may impart less short-term benefit from statin therapy, but considering a high lifetime risk, long-term Table 8. Selected Examples of Candidates for CAC Measurement Who Might Benefit From Knowing Their CAC Score Is Zero CAC Measurement Candidates Who Might Benefit From Knowing Their CAC Score Is Zero Patients reluctant to initiate statin therapy who wish to understand their risk and potential for benefit more precisely Patients concerned about need to reinstitute statin therapy after discontinuation for statin-associated symptoms Older patients (men, 55-80 y of age; women, 60-80 y of age) with low burden of risk factorsS4.4.2-25 who question whether they would benefit from statin therapy Middle-aged adults (40-55 y of age) with PCE-calculated 10-year risk of ASCVD 5% to <7.5% with factors that increase their ASCVD risk, although they are in a borderline risk group Caveats: If patient is intermediate risk and if a risk decision is uncertain and a CAC score is performed, it is reasonable to withhold statin therapy unless higher risk conditions such as cigarette smoking, family history of premature ASCVD, or diabetes mellitus are present, and to reassess CAC score in 5-10 years. Moreover, if CAC is recommended, it should be performed in facilities that have current technology that delivers the lowest radiation possible. ASCVD indicates atherosclerotic cardiovascular disease; CAC, coronary artery calcium; LDL-C, low-density lipoprotein cholesterol; and PCE, pooled cohort equations.


ASCVD indicates atherosclerotic cardiovascular disease; CAC, coronary artery calcium; LDL-C, low-density lipoprotein cholesterol; and PCE, pooled cohort equations. CLINICAL STATEMENTS AND GUIDELINES benefit cannot be discounted.S4.4.2-53 The same holds for CAC score of zero and a high 10 year risk (eg, 20%).S4.4.2-34 For those with CAC scores of 1 to 99 Agatston units, 10-year ASCVD event rates are 3.8%, 6.5%, and 8.3% for age groups sug- gesting that CAC scores in this range favor statin initiation only in adults >55 years of age and indi- cating that risk reclassification is modest for indi- viduals with CAC scores of 1 to 99. Therefore, for patients with CAC scores of 1 to 99, it is reasonable to repeat the risk discussion. If these patients remain untreated, repeat CAC measure- ment in 5 to 10 years may have some value in reassessing for CAC progression, but data are A systematic review and meta-analysis suggests that knowledge that a patient s CAC score is greater than zero is Selected examples of candidates for CAC scoring who might benefit from know- ing that their CAC score is zero are listed in Table 8. There is an increased likelihood that lifestyle therapies and drug therapy will be started or con- tinued with significant, albeit modest, changes in risk factor levels and predicted risk levels. 8. Clinicians may need to address reducing ASCVD risk in higher-risk primary-prevention patients who either do not wish to take a statin or can- not tolerate the recommended intensity of statin therapy. In such patients, it may be reasonable to use LDL-C lowering drugs that have been proven safe and effective in RCTs, either as monotherapy or combined with a statin.S4.4.2-9 One alternative is a cholesterol absorption inhibitor.


In such patients, it may be reasonable to use LDL-C lowering drugs that have been proven safe and effective in RCTs, either as monotherapy or combined with a statin.S4.4.2-9 One alternative is a cholesterol absorption inhibitor. An RCT in adults 40 years of age with advanced CKD and without known CHD at baseline found that the addition of ezetimibe to a moderate-intensity statin lowered LDL-C 43 mg/dL (1.1 mmol/L) After a median 4.9 years, ezeti- mibe and simvastatin 40 mg per day resulted in a 17% proportional reduction in major athero- sclerotic events compared with placebo.S4.4.2-2 Another alternative is a nonsystemic bile acid sequestrant. Bile acid sequestrants used as mono- therapy reduced CHD endpoints in a large pri- Bile acid sequestrants can bind other drugs, so other medications must be avoided for 1 hour before and at least 3 to 4 hours after administration. Adding psyllium can minimize constipation and can reduce the bile acid sequestrant dose.S4.4.2-56 These therapies should be considered in the context of a risk dis- cussion that reviews potential for benefit along with tolerability and safety issues. 9. Benefit from statin therapy is seen in lower-risk Consideration of enhancing factors in selected younger individuals in this lower risk range, will improve the ability to detect younger patients who develop MI before age 50 Nonetheless, the challenge among those in a lower ASCVD risk category is to include those who would benefit yet avoid cast- ing too wide a net, to minimize treating those who would derive little benefit from statin assign- ment. This risk group benefits greatly from a clini- cian patient risk discussion.


This risk group benefits greatly from a clini- cian patient risk discussion. To arrive at a shared risk decision, clinicians should assess the patient s priorities for health care, perceived ASCVD risk, and prior risk-reduction experiences and should use best practices to communicate numerical The presence of risk-enhancing fac- tors provides useful information about short term ASCVD risk favoring initiation of statin therapy Although a CAC score can be use- ful in selected individuals, it will be positive less often in this lower-risk group than in those with higher levels of ASCVD risk and is not recom- 4.4.3. Monitoring in Response to LDL-C Lowering Therapy Recommendation for Monitoring Referenced studies that support the recommendation are summarized in Online Data Supplement 17. COR LOE Recommendation I A Adherence to changes in lifestyle and effects of LDL-C lowering medication should be assessed by measurement of fasting lipids and appropriate safety indicators 4 to 12 weeks after statin initiation or dose adjustment and every 3 to 12 months thereafter based on need to assess adherence or safety.S4.4.3-1 S4.4.3-3 Recommendation-Specific Supportive Text 1. Goals for LDL-C lowering in response to life- style therapies or a prescribed intensity of statin therapy are defined by percentage responses. Clinical efficacy is monitored by measurement of percentage reductions in LDL-C relative to base- line levels. Baseline LDL-C can be estimated by pretreatment measurements, chart reviews, or measurement after a short interruption of drug therapy. Some clinicians are reluctant to interrupt therapy, although risk is low. Unless a baseline level is established, it will be difficult to evaluate response to therapy. Good adherence to various LDL-lowering diets will reduce LDL-C levels by Moderate-intensity statins can be expected to reduce LDL-C levels by another 30% to 49%, and high-intensity statins by 50% CLINICAL STATEMENTS AND GUIDELINES (Table 3, Section 3.2.).


Good adherence to various LDL-lowering diets will reduce LDL-C levels by Moderate-intensity statins can be expected to reduce LDL-C levels by another 30% to 49%, and high-intensity statins by 50% CLINICAL STATEMENTS AND GUIDELINES (Table 3, Section 3.2.). The addition of ezetimibe or bile acid sequestrants to statin therapy typically provides an additional 15% to 25% reduction in LDL-C. Much greater additive reductions occur by adding a PCSK9 inhibitor to statin plus ezetimibe. In clinical practice, lifestyle and statin therapy are commonly introduced together. The maximum percentage change will occur by 4 to 12 weeks after starting a statin or combined therapy. At this time, drug efficacy or initial adherence to therapy can be evaluated. Periodic remeasurements will make it possible to confirm adherence to therapy. Because recommended intensities of drug thera- pies will vary in adolescents, young adults, adults 40 to 75 years of age, those with severe hyper- cholesterolemia, and those receiving therapy for secondary prevention, the recommended LDL-C levels to achieve will also vary. 4.4.4. Primary Prevention in Other Age Groups 4.4.4.1. Older Adults Additional recommendations for adults >75 years of age are included in Section 4.1. (Secondary ASCVD Pre- vention) and Section 4.3. (Diabetes Mellitus in Adults). Recommendations for Older Adults Referenced studies that support recommendations are summarized in Online Data Supplements 18 and 19.


Recommendations for Older Adults Referenced studies that support recommendations are summarized in Online Data Supplements 18 and 19. COR LOE Recommendations IIb B-R In adults 75 years of age or older with an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), initiating a moderate-intensity statin may be reasonableS4.4.4.1-1 S4.4.4.1-8 IIb B-R In adults 75 years of age or older, it may be reasonable to stop statin therapy when functional decline (physical or cognitive), multimorbidity, frailty, or reduced life- expectancy limits the potential benefits of IIb B-R In adults 76 to 80 years of age with an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), it may be reasonable to measure CAC to reclassify those with a CAC score of zero to avoid statin therapy.S4.4.4.1-10,S4.4.4.1-11 Synopsis Mounting risk factors and subclinical disease are en- demic in the rapidly growing population of older adults. Data from RCTS4.4.4.1-1 S4.4.4.1-4 and a related meta-analy- support primary prevention with statin thera- py in older adults up to age 79 years, but some studies Nonetheless, data in older subsets ( 80 years of age) remain sparse.S4.4.4.1-6 S4.4.4.1-8 Furthermore, as adults grow older they are more susceptible to statin- including those that arise from altered pharmacokinetics and pharmacodynam- ics, as well as the impact of side effects on health is- sues such as multimorbidity, polypharmacy, frailty, and cognitive decline. In some patients, the aggregate risks associated with statins may exceed their likely benefits.


In some patients, the aggregate risks associated with statins may exceed their likely benefits. Limited life spans may also undercut the minimum time for likely statin benefits, especially the 4 to 5 years as- sociated with statins stroke-reducing benefits.S4.4.4.1-15 Decisions to not initiate statins, or even to depre- scribe them, are reasonable in older adults when aggregate risks outweigh potential for meaningful A shared decision-making process between clinicians and patients that targets individualized decisions is warranted, with regular reas- sessments over time. CAC determinationS4.4.4.1-10,S4.4.4.1-11 focuses statin therapy on those who benefit most. For older adults with CAC scores of zero, the likelihood of benefits from statin therapy does not outweigh the risks. Recommendation-Specific Supportive Text 1. An RCT enrolling 5084 men and women 70 to 82 years of age showed no benefit from pravas- tatin 40 mg/d versus placebo in the primary- Another RCT using pravastatin 40 mg per day versus usual care in older adults showed no statin benefitS4.4.4.1-19 but there were important concerns about both adherence in those assigned to pravastatin and drop-in statin therapy in those assigned to A recent meta- combining data from JUPITER and HOPE-3 in those 70 years of age showed a statistically significant 26% RRR for nonfa- tal MI, nonfatal stroke, or cardiovascular death. A prospective cohort studyS4.4.4.1-5 comparing healthy older patients (age 70 years) who used statins with those who did not showed signifi- cantly lower risk of death but nonsignificant car- diovascular event reduction in the statin group. Other recent meta-analysesS4.4.4.1-6 S4.4.4.1-8 support primary prevention for adults in their 70s. Thus, clinician patient discussion of risk versus benefit remains particularly important with inconsistent support and few data for adults >80 years of age.


Thus, clinician patient discussion of risk versus benefit remains particularly important with inconsistent support and few data for adults >80 years of age. Even a small increase in geriatric-specific adverse effects with statins could offset any car- Statins may be indi- cated if, after a clinician patient discussion, the potential for benefit is thought to outweigh the risks of adverse effects, drug drug interactions, and cost. 2. A counterpoint to the rationale for statin therapy in primary prevention for adults of older ages is the compelling rationale to discontinue therapy in older adults with severe age-related man- agement complexities. Customary risks associ- ated with statins may be intensified by age (eg, CLINICAL STATEMENTS AND GUIDELINES and distinctive risks may also develop because of the broader age context (eg, multimorbidity, polypharmacy, sarcopenia, falls, frailty, and cognitive decline),S4.4.4.1-15 potentially confounding effective statin therapy. Aggregate risks increase with age and may become dis- proportionate to the extent that risks outweigh potential for meaningful benefit. Deprescribing statins becomes an important option to be Related studies are evolv- ing, particularly in the palliative care domain. One randomized trialS4.4.4.1-9 and several nonran- domized studies (albeit of relatively lower qual- ity) show feasibility and utility of deprescribing in older adults with significant management Nonetheless, these studies also show that decisions about statins are not intui- tive because many frailer or more complex patients may prefer to stay on statins precisely because they are at greatest cardiovascular risk.S4.4.4.1-16 Therefore, it is warranted that decisions about statin therapy be individualized and derived from clinician patient discussions. Moreover, given the predictable fluc- tuations of health dynamics, such shared decisions should be reconsidered regularly. 3.


Moreover, given the predictable fluc- tuations of health dynamics, such shared decisions should be reconsidered regularly. 3. Multiple studies indicate the utility of CAC mea- surement in identifying the absence of atheroscle- rotic pathophysiology in older adultsS4.4.4.1-10,S4.4.4.1-11 Moreover, with reduced costs, the long-term con- sequences of using low-dose computed tomogra- phy for CAC screening are much less concerning for older patients. If CAC score is zero, the patient may be reclassified to a lower-risk status to avoid The BioImage study also indicated that scanning for carotid plaque did not down-classify as many individuals as did a CAC score of zero but still improved specificity of Limiting statin therapy to those with CAC scores greater than zero, com- bined with clinical judgment and patient prefer- ence, could provide a valuable awareness with which to inform shared decision-making. 4.4.4.2. Young Adults (20 to 39 Years of Age) Much of atherosclerosis begins in young adulthood.S4.4.4.2-1 Progression of atherosclerosis thereafter becomes clini- cally manifest as ASCVD in middle age or later years. Thus, prevention of clinical ASCVD optimally begins early in life. In children or adolescents, atherosclerosis may begin to appear in those with hypercholesterol- emia; in this age range, more aggressive cholesterol- lowering may be indicated. Development of atheroscle- rosis in young adults most commonly is multifactorial and occurs most rapidly in individuals with multiple risk factors (eg, hypercholesterolemia, hypertension, ciga- rette smoking, diabetes mellitus, and obesity).S4.4.4.2-2 As discussed in these guidelines (Section 4.2.) FH of- ten goes undiagnosed. Young adults with primary el- evations of LDL-C 190 mg/dl have a long-term ASCVD and statin therapy is recommended. In adults with hypercholesterolemia, cascade screening often identifies other family members with elevated LDL-C (Section 4.2.).


In adults with hypercholesterolemia, cascade screening often identifies other family members with elevated LDL-C (Section 4.2.). However even moderate hypercholesterolemia can accelerate development of atherosclerosis.S4.4.4.2-4 Sec- ondary causes of elevated cholesterol hypothyroidism (TSH), obstructive liver disease (liver panel), renal disease and nephrosis (creatinine and urine analysis) as well as dietary and medication history should be addressed Elevations of LDL-C persisting af- ter excluding secondary causes suggests genetic forms of hypercholesterolemia. Young adults who experience prolonged exposure to hyperlipidemia prior to age 55 are shown to have significantly increased risk of coro- nary heart disease.S4.4.4.2-6 Intensive lifestyle change has the potential to reduce the hyperlipidemia and associ- ated ASCVD risk factor burden. A smaller group, but even at higher risk, are young adults with persistent, moderate hypercholesterolemia (LDL-C 160-189 mg/dL), especially when risk-enhanc- ing factors, such as a family history of premature AS- CVD, are present. Since there is increased probability of genetic FH in this LDL-C range, clinical judgment would suggest that these high risk young adults will benefit from long-term statin therapyS4.4.4.2-7 (Section 4.2.). In- deed, it has been shown that those with higher LDL-C can gain as much or more benefit from cholesterol re- duction as do those with lower pretreatment LDL-C but at higher risk.S4.4.4.2-8,S4.4.4.2-9 In young adults without phenotypically severe hy- percholesterolemia, risk assessment should begin by estimation of lifetime risk.S4.4.4.2-10 The pooled cohort equations (PCE) can be used to estimate lifetime risk starting at age 21 years (see Section 4.4.2.). This information can inform a focused risk discussion designed to improve high-risk lifestyle behaviors in- cluding tobacco use, sedentary lifestyle and/or poor When young adults with hyper- cholesterolemia or multiple risk factors are identified, lifestyle intervention is indicated.


This information can inform a focused risk discussion designed to improve high-risk lifestyle behaviors in- cluding tobacco use, sedentary lifestyle and/or poor When young adults with hyper- cholesterolemia or multiple risk factors are identified, lifestyle intervention is indicated. To date, no long- term RCTs with cholesterol-lowering drugs have been carried out in those 20 to 39 years age. However, a primary prevention RCT in those younger individuals at low to moderate short-term risk, but at high lifetime risk has been proposed.S4.4.4.2-13 One approach to identifying young adults who could benefit from statins or drug combination would be to detect significant coronary atherosclerosis with coronary artery calcium (CAC) scores. Its use for this purpose has been suggested.S4.4.4.2-14 But again, ab- sence of RCT data precludes guideline recommenda- tions at this time. CLINICAL STATEMENTS AND GUIDELINES 4.4.4.3. Children and Adolescents Recommendations for Children and Adolescents Referenced studies that support recommendations are summarized in Online Data Supplements 18 to 21. COR LOE Recommendations I A In children and adolescents with lipid disorders related to obesity, it is recommended to intensify lifestyle therapy, including moderate caloric restriction and regular aerobic physical activity.S4.4.4.3-1 S4.4.4.3-4 I B-NR In children and adolescents with lipid abnormalities, lifestyle counseling is beneficial for lowering IIa B-R In children and adolescents 10 years of age or older with an LDL-C level persistently 190 mg/dL or higher ( 4.9 mmol/L) or 160 mg/dL or higher (4.1 mmol/L) with a clinical presentation consistent with FH (see Section 4.2.)


COR LOE Recommendations I A In children and adolescents with lipid disorders related to obesity, it is recommended to intensify lifestyle therapy, including moderate caloric restriction and regular aerobic physical activity.S4.4.4.3-1 S4.4.4.3-4 I B-NR In children and adolescents with lipid abnormalities, lifestyle counseling is beneficial for lowering IIa B-R In children and adolescents 10 years of age or older with an LDL-C level persistently 190 mg/dL or higher ( 4.9 mmol/L) or 160 mg/dL or higher (4.1 mmol/L) with a clinical presentation consistent with FH (see Section 4.2.) and who do not respond adequately with 3 to 6 months of lifestyle therapy, it is reasonable to initiate statin IIa B-NR In children and adolescents with a family history of either early CVD* or significant hypercholesterolemia, it is reasonable to measure a fasting or nonfasting lipoprotein profile as early as age 2 years to detect FH or rare forms of IIa B-NR In children and adolescents found to have moderate or severe hypercholesterolemia, it is reasonable to carry out reverse-cascade screening of family members, which includes cholesterol testing for first-, second-, and when possible, third-degree biological relatives, for detection of familial forms of hy IIa C-LD In children and adolescents with obesity or other metabolic risk factors, it is reasonable to measure a fasting lipid profile to detect lipid disorders as components of the IIb B-NR In children and adolescents without cardiovascular risk factors or family history of early CVD, it may be reasonable to measure a fasting lipid profile or nonfasting non HDL-C once between the ages of 9 and 11 years, and again between the ages of 17 and 21 years, to detect moderate to severe lipid *Family history of early CVD is defined here as MI, documented angina, or atherosclerosis by angiography in parents, siblings, grandparents, aunts, or uncles (<55 years of age for men, <65 years of age for women).


and who do not respond adequately with 3 to 6 months of lifestyle therapy, it is reasonable to initiate statin IIa B-NR In children and adolescents with a family history of either early CVD* or significant hypercholesterolemia, it is reasonable to measure a fasting or nonfasting lipoprotein profile as early as age 2 years to detect FH or rare forms of IIa B-NR In children and adolescents found to have moderate or severe hypercholesterolemia, it is reasonable to carry out reverse-cascade screening of family members, which includes cholesterol testing for first-, second-, and when possible, third-degree biological relatives, for detection of familial forms of hy IIa C-LD In children and adolescents with obesity or other metabolic risk factors, it is reasonable to measure a fasting lipid profile to detect lipid disorders as components of the IIb B-NR In children and adolescents without cardiovascular risk factors or family history of early CVD, it may be reasonable to measure a fasting lipid profile or nonfasting non HDL-C once between the ages of 9 and 11 years, and again between the ages of 17 and 21 years, to detect moderate to severe lipid *Family history of early CVD is defined here as MI, documented angina, or atherosclerosis by angiography in parents, siblings, grandparents, aunts, or uncles (<55 years of age for men, <65 years of age for women). mmol/L), non HDL-C 220 mg/dL ( 5.7 mmol/L), or known primary hypercholesterolemia. Synopsis Abnormal lipid levels are relatively common in chil- dren and adolescents, affecting approximately 1 in 5 Confirmed lipid disorders are less common but occur frequently in the presence of obe- sity, often accompanied by cardiovascular risk factors, and contribute to increased rates of cardiovascular and metabolic morbidity and mortality.


Synopsis Abnormal lipid levels are relatively common in chil- dren and adolescents, affecting approximately 1 in 5 Confirmed lipid disorders are less common but occur frequently in the presence of obe- sity, often accompanied by cardiovascular risk factors, and contribute to increased rates of cardiovascular and metabolic morbidity and mortality. Severe hypercholes- terolemia (LDL 190 mg/dL ( 4.9 mmol/L)) affects ~1 in 250 children and adolescents. Testing for lipid disorders can identify both severe hypercholesterolemia and mul- tifactorial lifestyle-related dyslipidemia. Nonfasting lipid testing is effective for initial screening purposes, and non HDL-C is a reasonable screening test. No available evidence evaluates benefits of childhood lipid screen- ing for modifying CVD events or associated long-term harm. However, significantly abnormal lipid levels track from childhood to adulthood. Furthermore, subclinical atherosclerosis, as measured by carotid intima-media thickness, is abnormal in children with FH. Strong evi- dence shows that lifestyle modification improves lipid levels in childhood without adverse effects on growth and maturation; however, effect sizes are small, and adherence may wane over time. Statins and nonstatins lower TC and LDL-C with minimal adverse effects in children and adolescents with severe hypercholesterol- emia. There are scant data on pharmacological treat- ment of multifactorial lifestyle-related dyslipidemia. Recommendation-Specific Supportive Text 1. In children and adolescents with lipid abnor- malities and obesity, lifestyle-modification ther- apy should be intensified over and above usual therapy for childhood obesity and should include moderate caloric restriction and sufficient physi- cal activity (eg, 30-60 minutes of moderate to vigorous activity on most days). Utilization of resources for nutritional education and counsel- ing is encouraged. 2.


Utilization of resources for nutritional education and counsel- ing is encouraged. 2. Lifestyle-modification interventions in childhood and adolescence show short- and long-term benefits to lipid levels and subclinical atheroscle- rosis measures in RCTsS4.4.4.3-5 S4.4.4.3-8 and obser- vational studies of children and adolescents with lipid disorders.S4.4.4.3-3,S4.4.4.3-9 No adverse effects on growth or maturation have been The impact of these inter- ventions on lipid levels and subclinical atheroscle- rosis is small; no studies report CVD event rates. There are likely other unmeasured health benefits of lifestyle-modification interventions for chronic disease outcomes (eg, obesity, diabetes mellitus, and cancer). These benefits support the recom- mendation to treat children and adolescents with lipid disorders with lifestyle-modification interven- tions, generally by using a family-based approach and promoting a heart-healthy diet, plenty of physical activity, avoidance of cigarette smoking, maintenance of a healthy weight, maintenance of normal blood pressure, and maintenance of nor- mal glycemia. CLINICAL STATEMENTS AND GUIDELINES 3. Statins and nonstatins lower TC and LDL-C in chil- dren and adolescents with FH,S4.4.4.3-30 and other health conditions that put them at increased risk of CVD.S4.4.4.3-31,S4.4.4.3-32 Evidence from these RCTs demonstrates low short- and medium-term adverse event rates (abnormalities in liver func- tion test, creatine kinase [CK] levels, and reported myopathy) with statin use in children and ado- lescents with FH.S4.4.4.3-30 Limited data show ben- efit from statins to subclinical atherosclerosis in FH. These data, coupled with the increased risk of CVD in untreated severe hypercholester- olemia, support the use of statins in children and adolescents at ages 10 years who have and have not responded to 3 to 6 months of lifestyle therapy.


These data, coupled with the increased risk of CVD in untreated severe hypercholester- olemia, support the use of statins in children and adolescents at ages 10 years who have and have not responded to 3 to 6 months of lifestyle therapy. Statins may be considered at age 8 years in the presence of con- cerning family history, extremely elevated LDL-C level, or elevated Lp(a), in the context of informed shared decision-making and counseling with the patient and family. The intensity of treatment should be based on the severity of the hyper- cholesterolemia and should incorporate patient/ family preference. Scant data on the use of ezeti- mibe in children with severe hypercholesterolemia show reasonable LDL-C lowering with no signifi- cant adverse effects.S4.4.4.3-13 Nonsystemic bile acid sequestrants can be useful for LDL-C lowering, but tolerability is an issue.S4.4.4.3-13 S4.4.4.3-16 4. Lipid testing during childhood can identify the severe hypercholesterolemia phenotype.S4.4.4.3-35 Severe hypercholesterolemia, which includes FH, can be identified in children and adolescents with an LDL-C level 190 mg/dL ( 4.9 mmol/L). Moreover, children and adolescents with LDL-C 160 mg/dL ( 4.1 mmol/L) and a family history of early atherosclerosis or similarly elevated cho- lesterol in 1 parent likely are those with FH and related genetic disorders associated with accel- Subclinical ath- erosclerosis data suggest divergence between affected and unaffected children and adolescents beginning at age 10 years,S4.4.4.3-28 which sup- ports screening by this age, although this topic is still considered controversial.S4.4.4.3-36 Screening is advised beginning at age 2 years if a family his- tory is suggestive of either early CVD or significant primary hypercholesterolemia.


Moreover, children and adolescents with LDL-C 160 mg/dL ( 4.1 mmol/L) and a family history of early atherosclerosis or similarly elevated cho- lesterol in 1 parent likely are those with FH and related genetic disorders associated with accel- Subclinical ath- erosclerosis data suggest divergence between affected and unaffected children and adolescents beginning at age 10 years,S4.4.4.3-28 which sup- ports screening by this age, although this topic is still considered controversial.S4.4.4.3-36 Screening is advised beginning at age 2 years if a family his- tory is suggestive of either early CVD or significant primary hypercholesterolemia. Identification of a child with severe hypercholesterolemia should prompt screening of extended family members (eg, reverse-cascade screening), according to studies outside the United States demonstrating efficacy of this approach.S4.4.4.3-37 Screening for severe hypercholesterolemia on the basis of fam- ily history includes an expanded group of family members (eg, grandparents, aunts, and uncles) in addition to parents and siblings because siblings of children are unlikely to have had cardiovascular events or been identified with significant choles- 5. One advantage of measuring lipids in children and adolescents is to identify genetic abnormali- ties in lipid metabolism that may be present in other family members. Regardless of the age at which abnormalities are detected, reverse-cas- cade screening in families is highly effective for the identification of family members at risk of 6. Observational studies of children and adolescents show that obesity and other lifestyle-related behaviors and metabolic syndrome risk fac- tors including lipid abnormalities,S4.4.4.3-25,S4.4.4.3-26 and with subclinical atherosclerosis into young occur at higher rates than in lean and otherwise healthy children and adolescents. Longitudinal cohort data show mod- erate tracking of cardiovascular risk factors from childhood to adulthood in the general pediatric suggesting some persistence of the underlying pathophysiology and potential benefit of identifying lipid disorders in childhood. 7.


Longitudinal cohort data show mod- erate tracking of cardiovascular risk factors from childhood to adulthood in the general pediatric suggesting some persistence of the underlying pathophysiology and potential benefit of identifying lipid disorders in childhood. 7. Selective screening for lipid disorders on the basis of family history (Recommendation 1) or lifestyle- related factors (Recommendation 2) identifies only a portion of childhood lipid abnormalitiesS4.4.4.3-19, (Table 9). Therefore, concordant with the 2011 National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines Table 9. Normal and Abnormal Lipid Values in Childhood* Acceptable, mg/dL Borderline, mg/dL Abnormal, mg/dL Triglycerides Triglycerides Values given are in mg/dL. To convert to SI units, divide the results for TC, LDL-C, HDL-C, and non HDL-C by 38.6; for triglycerides, divide by 88.6. *Values for plasma lipid and lipoprotein levels are from the NCEP Expert Panel on Cholesterol Levels in Children. Non HDL-C values from the Bogalusa Heart Study are equivalent to the NCEP Pediatric Panel cutpoints for LDL-C. The cutpoints for high and borderline high represent approximately the 95th and 75th percentiles, respectively. Low cutpoints for HDL-C represent approximately the 10th percentile. HDL-C indicates high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NCEP, National Cholesterol Education Program; SI, Syst me international d unit s (International System of Units); and TC, total cholesterol. CLINICAL STATEMENTS AND GUIDELINES for Cardiovascular Health and Risk Reduction in Children and Adolescents,S4.4.4.3-41 universal pedi- atric lipid screening has been advised in recent specifically focusing on ages 9 to 11 years and then ages 17 to 21 years because TC and LDL-C levels decrease 10% to 20% during puberty. However, the long-term benefits and harms of universal screening have not been tested in RCTs.