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.


However, the long-term benefits and harms of universal screening have not been tested in RCTs. Observational studies demon- strate that universal screening can identify severe and in scant data universal screening is associated with changes in family lifestyle behaviors. Nonfasting lipid parame- ters are similar to fasting ones, and screening with a nonfasting non HDL-C is a reasonable approach to population screening in childhood. Although research on this topic continues, universal screen- ing may be reasonable given the substantial ben- efits of identifying severe hypercholesterolemia (see Section 4.2., Severe Hypercholesterolemia ), including FH, and possible benefits of lifestyle counseling for multifactorial dyslipidemias.S4.4.4.3-3, 4.5. Other Populations at Risk Recommendation for Other Populations at Risk Referenced studies that support the recommendation are summarized in Online Data Supplements 24 to 30. COR LOE Recommendation IIa B-NR For clinical decision-making in adults of different race/ethnicities, it is reasonable for clinicians to review race/ethnic features that can influence ASCVD risk.S4.5.1-1 so as to adjust choice of statin or intensity of Synopsis Race/ethnicity factors can influence estimations of AS- intensity of treatmentS4.5.1-1 S4.5.1-4 or even lipid drug use.S4.5.1-5,S4.5.1-6 Important examples in- clude the heightened risk of ASCVD in those who iden- tify as South Asians, the increased sensitivity to statins in those who identify as East Asians, and the increased prevalence of hypertension in blacks. An important is- sue in management of ASCVD risk in those who iden- tify as Hispanics/Latinos in the United States is the lack Table 10. Racial/Ethnic Issues in Evaluation, Risk Decisions, and Treatment of ASCVD Risk Racial/Ethnic Groupings Asian * Hispanic/Latino Blacks/African Comments Evaluation ASCVD issues informed by race/ethnicity ASCVD issues informed by race/ ethnicity ASCVD risk in people of South Asian and East Asian origin varies by country of origin; individuals from South Asia (see below) have increased ASCVD risk.


Racial/Ethnic Issues in Evaluation, Risk Decisions, and Treatment of ASCVD Risk Racial/Ethnic Groupings Asian * Hispanic/Latino Blacks/African Comments Evaluation ASCVD issues informed by race/ethnicity ASCVD issues informed by race/ ethnicity ASCVD risk in people of South Asian and East Asian origin varies by country of origin; individuals from South Asia (see below) have increased ASCVD risk. Race/ethnicity and country of origin, together with socioeconomic status and acculturation level, may explain risk factor burden more precisely (eg, ASCVD risk is higher among individuals from Puerto Rico than those from Mexico). ASCVD risk assessment in black women shows increased ASCVD risk compared with their otherwise similar white counterparts There is heterogeneity in risk according to racial/ethnic group and within racial/ethnic groups. Native American/ Alaskan populations have high rates of risk factors for ASCVD compared with non-Hispanic Lipid issues informed by Asian Americans have lower levels of HDL-C than whites. Hispanic/Latino women have higher prevalence of low HDL-C compared to Hispanic/ Latino men. Blacks have higher levels of HDL-C and lower levels of triglycerides than non-Hispanic whites or Mexican Americans. All ethnic groups appear to be at greater risk for dyslipidemia, but important to identify those with more sedentary behavior and less favorable diet. There is higher prevalence of LDL-C among Asian Indians, Filipinos, Japanese, and Vietnamese than among whites. An increased prevalence of high TG was seen in all Asian American subgroups. Metabolic issues informed by race/ Increased MetS is seen with lower waist circumference than in whites. DM is disproportionately present compared with whites and blacks. There is increased prevalence of MetS and DM in Mexican Americans compared with whites and Puerto Ricans. There is increased DM and hypertension. There is increased prevalence of DM. Features of MetS vary by race/ethnicity.


There is increased prevalence of DM. Features of MetS vary by race/ethnicity. Waist circumference, not weight, should be used to determine abdominal adiposity when possible. DM develops at a lower lean body mass and at earlier ages.S4.5.1-19 S4.5.1-21 Majority of risk in South Asians is explained by known risk factors, especially those related to insulin Risk Decisions No separate PCE is available; use PCE for whites. PCE may underestimate ASCVD risk in South Asians. PCE may overestimate risk in No separate PCE is available; use PCE for non-Hispanic whites. If African-American ancestry is also present, then use PCE for blacks. Use PCE for Country-specific race/ ethnicity, along with socioeconomic status, may affect estimation of risk by PCE. (Continued) CLINICAL STATEMENTS AND GUIDELINES of specificity of the term Hispanic/Latino. Race/ethnic- ity and country of origin, together with socioeconomic status and acculturation level, should be discussed and may explain ASCVD risk factor burden more precisely than the generic term Hispanic/Latino.S4.5.1-6 S4.5.1-11 In addition, those who identify as Native American/Alas- kan natives have high rates of risk factors for ASCVD compared to non-Hispanic whites. In many ways, the increase in metabolic risk factors and propensity for dia- betes mellitus resembles the risk profiles of those who identify as Mexican-Americans.S4.5.1-12 Table 10 reviews these and other racial/ethnic issues that may be useful in clinical management. Recommendations for Hypertriglyceridemia Referenced studies that support recommendations are summarized in Online Data Supplements 31 and 32.


Recommendations for Hypertriglyceridemia Referenced studies that support recommendations are summarized in Online Data Supplements 31 and 32. COR LOE Recommendations I B-NR In adults 20 years of age or older with moderate hypertriglyceridemia (fasting or to 5.6 mmol/L]), clinicians should address and treat lifestyle factors (obesity and metabolic syndrome), secondary factors (diabetes mellitus, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that increase triglycerides.S4.5.2-1 In terms of CAC burden, South Asian men were similar to non- Hispanic white men, but higher CAC when than blacks, Latinos, and Chinese Americans. South Asian women had similar CAC scores to whites and other racial/ethnic women, although CAC burden higher in older age.S4.5.1-31 CAC predicts similarly in whites and in those who identify as Hispanic/Latino. In MESA, CAC score was highest in white and Hispanic men, with blacks having significantly lower prevalence and severity of CAC. Risk factor differences in MESA between ethnicities did not fully explain variability in CAC. However, CAC predicted ASCVD events over and above traditional risk factors in all ethnicities.S4.5.1-32 Treatment Lifestyle counseling (use principles of Mediterranean and DASH diets) Use lifestyle counseling to recommend a hearthealthy diet consistent with racial/ethnic preferences to avoid weight gain and address BP and lipids. Use lifestyle counseling to recommend a hearthealthy diet consistent with racial/ ethnic preferences to avoid weight gain and address BP and lipids. Use lifestyle counseling to recommend a hearthealthy diet consistent with racial/ ethnic preferences to avoid weight gain and address BP and lipids. Asian and Hispanic/ Latino groups need to be disaggregated because of regional differences in lifestyle preferences. Challenge is to avoid increased sodium, sugar, and calories as groups acculturate. Intensity of statin therapy and response to LDL- Clowering Japanese patients may be sensitive to statin dosing.


Intensity of statin therapy and response to LDL- Clowering Japanese patients may be sensitive to statin dosing. In an open-label, randomized primaryprevention trial, Japanese participants had a reduction in CVD events with low- intensity doses of pravastatin as compared with placebo.S4.5.1-33 In a secondary-prevention trial, Japanese participants with CAD benefitted from a moderate-intensity dose of No sensitivity to statin dosage is seen, as compared with non-Hispanic white or black individuals. No sensitivity to statin dosage is seen, as compared with non-Hispanic white individuals. Using a lower statin intensity in Japanese patients may give results similar to those seen with higher intensities in non-Japanese patients. Safety Higher rosuvastatin plasma levels are seen in Japanese, Chinese, Malay, and Asian Indians as compared FDA recommends a lower starting dose (5 mg of rosuvastatin in Asians vs. 10 mg in whites). Caution is urged as dose is uptitrated There are no specific safety issues with statins related to Hispanic/Latino Baseline serum CK values are higher in blacks than in The 95th percentile race/ ethnicity- specific and sexspecific serum CK normal levels are available for assessing changes in serum CK. Clinicians should take Asian race into account when prescribing dose of rosuvastatin (See package insert). In adults of East Asian descent, other statins should be used preferentially over *The term Asian characterizes a diverse portion of the world s population. Individuals from Bangladesh, India, Nepal, Pakistan, and Sri Lanka make up most of the South Asian group.S4.5.1-26 Individuals from Japan, Korea, and China make up most of the East Asian group. The term Hispanics/Latinos in the United States characterizes a diverse population group. This includes white, black, and Native American races. Their ancestry goes from Europe to America, including among these, individuals from the Caribbean, Mexico, Central and South America.


Their ancestry goes from Europe to America, including among these, individuals from the Caribbean, Mexico, Central and South America. ASCVD indicates atherosclerotic cardiovascular disease; BP, blood pressure; CAC, coronary artery calcium; CAD, coronary artery disease; CK, creatine kinase; CVD, cardiovascular disease; DASH, Dietary Approaches to Stop Hypertension; DM, type 2 diabetes mellitus; FDA, US Food and Drug Administration; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MESA, Multi-Ethnic Study of Atherosclerosis; MetS, metabolic syndrome; and PCE, pooled cohort equations. Table 10. Continued Racial/Ethnic Groupings Asian * Hispanic/Latino Blacks/African Comments CLINICAL STATEMENTS AND GUIDELINES IIa B-R In adults 40 to 75 years of age with moderate or severe hypertriglyceridemia and ASCVD risk of 7.5% or higher, it is reasonable to reevaluate ASCVD risk after lifestyle and secondary factors are addressed and to consider a persistently elevated triglyceride level as a factor favoring initiation or intensification of statin therapy (see Section 4.4.2.).S4.5.2-2 S4.5.2-6 IIa B-R In adults 40 to 75 years of age with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL [ 5.6 mmol/L]) and ASCVD risk of 7.5% or higher, it is reasonable to address reversible causes of high triglyceride and to initiate statin therapy.S4.5.2-3 S4.5.2-5,S4.5.2-7,S4.5.2-8 IIa B-NR In adults with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL [ 5.7 mmol/L]), and especially fasting triglycerides 1000 mg/dL (11.3 mmol/L)), it is reasonable to identify and address other causes of hypertriglyceridemia), and if triglycerides are persistently elevated or increasing, to further reduce triglycerides by implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol, consumption of omega-3 fatty acids, and, if necessary to prevent acute pancreatitis, fibrate Synopsis Two categories of hypertriglyceridemia consist of moder- ate hypertriglyceridemia (fasting or nonfasting triglycer- ides 175-499 mg/dL [2.0-5.6 mmol/L]) and severe hyper- triglyceridemia (fasting triglycerides 500 mg/dL [ 5.6 mmol/L]).


2-2 S4.5.2-6 IIa B-R In adults 40 to 75 years of age with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL [ 5.6 mmol/L]) and ASCVD risk of 7.5% or higher, it is reasonable to address reversible causes of high triglyceride and to initiate statin therapy.S4.5.2-3 S4.5.2-5,S4.5.2-7,S4.5.2-8 IIa B-NR In adults with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL [ 5.7 mmol/L]), and especially fasting triglycerides 1000 mg/dL (11.3 mmol/L)), it is reasonable to identify and address other causes of hypertriglyceridemia), and if triglycerides are persistently elevated or increasing, to further reduce triglycerides by implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol, consumption of omega-3 fatty acids, and, if necessary to prevent acute pancreatitis, fibrate Synopsis Two categories of hypertriglyceridemia consist of moder- ate hypertriglyceridemia (fasting or nonfasting triglycer- ides 175-499 mg/dL [2.0-5.6 mmol/L]) and severe hyper- triglyceridemia (fasting triglycerides 500 mg/dL [ 5.6 mmol/L]). In the former, excess triglycerides are carried in VLDL. In the latter, most patients have elevated VLDL plus chylomicrons. VLDL are believed to be atherogenic, similar to LDL. There are many causes of elevated VLDL, and it is reasonable to reduce their levels to reduce risk of ASCVD. With severe hypertriglyceridemia, elevations of VLDL raise risk of ASCVD, but increases in chylomi- crons impart risk of acute pancreatitis. Therapies should address excesses in both lipoproteins. Recommendation-Specific Supportive Text 1. In patients with moderate hypertriglyceride- mia, it is reasonable to reduce both atherogenic VLDL and associated risk factors by nonpharma- cological means where possible.


In patients with moderate hypertriglyceride- mia, it is reasonable to reduce both atherogenic VLDL and associated risk factors by nonpharma- cological means where possible. This can best be achieved by identification and treatment of the multiple underlying causes of elevated triglyc- erides (eg, lifestyle causes, secondary disorders, and triglyceride-raising drugs).S4.5.2-1 Triglyceride- raising drugs include oral estrogens, tamoxifen, raloxifene, retinoids, immunosuppressive drugs (cyclosporine, sirolimus, tacrolimus), beta blockers, interferon, atypical antipsychotic drugs, protease inhibitors, thiazide diuretics, glucocorticoids, rosi- glitazone, bile acid sequestrants, L-asparaginase, and cyclophosphamide. 2. Most patients with severe hypertriglyceride- mia have multiple ASCVD risk factors and are at enhanced risk of developing atherosclerotic This risk is conveyed by atherogenic VLDL plus other factors, such as obesity, metabolic syndrome, and hyperglycemia. Although chylomicronemia per se may not be ath- erogenic, in most patients it associates with other For this reason, initiation of statin therapy is reasonable. We stress that statins alone cannot prevent increasing levels of triglycerides in the face of secondary causes (see Recommendation 1) from triggering acute hypertriglyceridemic pancreatitis. Indeed, in the pregnant woman with severe hypertriglyceride- mia, statins are not part of the treatment regimen because they are not recommended at the pres- ent time in pregnancy. (See Section 5., Statin Safety and Statin-Associated Side Effects. )3. Epidemiological studies show that patients with moderate hypertriglyceridemia generally are at increased risk of ASCVD.S4.5.2-2 S4.5.2-4 Few studies that primarily recruited patients with hypertriglyceri- demia have been carried out with triglyceride-low- ering drugs. Statin therapy reduces VLDL similarly to and statin trials include hypertriglyc- eridemic patients.


Statin therapy reduces VLDL similarly to and statin trials include hypertriglyc- eridemic patients. Indeed, there is evidence to show that VLDL excess increases the patient s ASCVD risk and hence benefit from statin therapy.S4.5.2-6 Therefore, if an adult patient with moderate hyper- triglyceridemia has poorly controlled major risk fac- tors for ASCVD and a 10-year risk of ASCVD 7.5% by the PCE, it is reasonable to either initiate or inten- sify statin therapy. (See Section 4.4.2., Primary Prevention in Adults 40 to 75 Years of Age. )4. Most patients with triglycerides 500 mg/dL ( 5.6 mmol/L) have elevations of both VLDL and chylo- microns. Elevations of chylomicrons typically are present when triglycerides are 500 mg/dL ( 5.6 mmol/L), and chylomicronemia may cause acute pancreatitis. The higher the triglyceride level, the greater is the risk.S4.5.2-7 Patients with triglycerides range are at risk of developing unrecognized marked increases in triglycerides, leading to pan- creatitis. Most cases of severe hypertriglyceridemia have a genetic component, but secondary factors To prevent acute pan- creatitis, it is reasonable to reduce triglycerides whenever levels exceed 500 mg/dL (5.6 mmol/L). This reduction can be achieved by addressing and eliminating the underlying factors as described in Recommendations for Hypertriglyceridemia (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES Recommendation 1, implementing a very low- and adding fibrates or omega-3 fatty acids for patients with persistently elevated These are the most reliable pharmacological therapies to reduce triglycerides to a safer level. If a fibrate is neces- sary in a patient being treated with a statin, it is safer to use fenofibrate than gemfibrozil because of lower risk of severe myopathy.S4.5.2-16 Severe or life-threatening hypertriglyceridemia during preg- nancy is best managed in consultation with a lipid 4.5.3.


If a fibrate is neces- sary in a patient being treated with a statin, it is safer to use fenofibrate than gemfibrozil because of lower risk of severe myopathy.S4.5.2-16 Severe or life-threatening hypertriglyceridemia during preg- nancy is best managed in consultation with a lipid 4.5.3. Issues Specific to Women Recommendations for Issues Specific to Women Referenced studies that support recommendations are summarized in Online Data Supplements 33 to 35. COR LOE Recommendations I B-NR Clinicians should consider conditions specific to women, such as premature menopause (age <40 years) and history of pregnancy- associated disorders (hypertension, preeclampsia, gestational diabetes mellitus, small-for-gestational-age infants, preterm deliveries), when discussing lifestyle intervention and the potential for benefit of I C-LD Women of childbearing age who are treated with statin therapy and are sexually active should be counseled to use a reliable form of I C-LD Women of childbearing age with hypercholesterolemia who plan to become pregnant should stop the statin 1 to 2 months before pregnancy is attempted, or if they become pregnant while on a statin, should have the statin stopped as soon as the pregnancy is discovered.S4.5.3-7 S4.5.3-12 Synopsis Although atherosclerosis typically occurs later in wom- en than in men, CVD remains the leading cause of death in women. Statins clearly reduce ASCVD events in women as well as in men with ASCVD. The 2015 meta-analysis by the CTT Collaboration showed no heterogeneity by gender for the risk of major vascular events with statin therapy in participants with a history of vascular disease.S4.5.3-13 A history of certain pregnan- cy-related conditions and premature menopause (age <40 years) have been associated with increased ASCVD risk. However, current best practice emphasizes that statins should not be taken during pregnancy.


However, current best practice emphasizes that statins should not be taken during pregnancy. Thus, women of childbearing age who are on statin therapy and are sexually active should use a reliable form of contraception to avoid pregnancy. When pregnancy is planned, stopping statin therapy 1 to 2 months be- fore pregnancy is attempted is suggested as reason- able guidance. When an unplanned pregnancy occurs, statins should be stopped immediately when the preg- nancy is discovered. Both cholesterol and triglycerides rise with pregnancy, and those with genetic lipid dis- orders should consider consulting a clinician with lipid expertise before starting the pregnancy. Recommendation-Specific Supportive Text 1. Several conditions specific to women (eg, hyper- tensive disorders during pregnancy, preeclampsia, gestational diabetes mellitus, delivering a preterm or low-birth-weight infant,S4.5.3-2 S4.5.3-4 and prema- ture menopause [age <40 years]S4.5.3-5,S4.5.3-6,S4.5.3-14 ) have been shown to increase ASCVD risk. The present guideline includes preeclampsia and premature menopause (age <40 years) as risk- enhancing factors for statin therapy because they appear to increase ASCVD risk in the same range as other risk-enhancing factors. On the other hand, the mechanism or cause of preterm birth is often unknown; therefore, it is difficult to rou- tinely include this condition as a risk-enhancing factor for statin therapy. Furthermore, if gesta- tional diabetes mellitus predisposes a woman to metabolic syndrome or diabetes mellitus, these are already identified as risk-enhancing or major ASCVD risk factors. After pregnancy and through- out the life course of every woman, a thorough pregnancy history should be obtained, and risk factors and risk-enhancing factors should be identified. Interventions should include aggres- sive lifestyle counseling to reduce ASCVD risk and when appropriate, statin therapy, if ASCVD risk estimation indicates that the potential for benefit from statin therapy outweighs the potential for adverse effects.


Interventions should include aggres- sive lifestyle counseling to reduce ASCVD risk and when appropriate, statin therapy, if ASCVD risk estimation indicates that the potential for benefit from statin therapy outweighs the potential for adverse effects. Decisions should be made in the context of a risk discussion and should take into consideration an informed patient preference. 2. All statins are currently contraindicated in pregnant women, primarily as a result of a 2004 series of cases of first-trimester statin exposure reported to the FDA, which showed 20 cases of malformation, including 5 severe defects of the central nervous system and 5 unilateral limb deficiencies.S4.5.3-7 In all cases of adverse birth outcomes, the statin used was lipophilic. No malformation was identified in the 14 infants exposed to pravastatin (hydrophilic). Since this case series, cohort studies of statin expo- sure in pregnancy did not show an increase in and in fact, the safety of pravastatin is under study for the prevention of preeclampsia in high-risk pregnant women.S4.5.3-15 In a meta-analysis of 6 studies of pregnant women exposed to statins, no increased risk of birth defects was observed compared with control subjects. However, there was an increased risk of CLINICAL STATEMENTS AND GUIDELINES miscarriage in the statin-exposed women versus Furthermore, in a recent retrospec- tive cohort study that used time-to-event analysis as a covariate, the adjusted hazard ratio of sponta- neous pregnancy loss in the statin-exposed group The increase in miscarriages may be related to confounders, such as older age, CVD risk factors, and other medications. 3. A reasonable approach is to stop statins 1 to 2 months before pregnancy is attempted. When pregnancy is unplanned, statin therapy should be stopped promptly and not restarted until after pregnancy and breastfeeding are completed.


When pregnancy is unplanned, statin therapy should be stopped promptly and not restarted until after pregnancy and breastfeeding are completed. Cholesterol levels rise in pregnancy, with a similar percentage rise in normal women and those with heterozygous FH. Women with FH do not appear to have a higher risk of preterm delivery or of having infants with low birth weight or congenital malfor- mations than unaffected women, but undetected bias cannot be ruled out.S4.5.3-16 An experienced lipid specialist should be consulted for women with homozygous FH whose care is beyond the scope of the present guideline. Also, triglyceride levels rise progressively with each trimester, and women with triglyceride levels 500 mg/dL (5.6 mmol/L) at the onset of pregnancy may develop severe hypertriglyceridemia during the third trimester of pregnancy, which can lead to pancreatitis.S4.5.3-17 Advising patients on lifestyle (including both diet and physical activity), optimally managing diseases like diabetes mellitus and hypothyroidism, and choosing medications that are less likely to raise tri- glycerides can reduce levels of triglycerides before pregnancy begins. Treatment of severe hypertri- glyceridemic pregnancy is also beyond the scope of the present guideline and requires consultation with an experienced lipid specialist. 4.5.4. Adults With CKD Recommendations for Adults With CKD Referenced studies that support recommendations are summarized in Online Data Supplements 36 to 38.


Adults With CKD Recommendations for Adults With CKD Referenced studies that support recommendations are summarized in Online Data Supplements 36 to 38. COR LOE Recommendations IIa B-R In adults 40 to 75 years of age with LDL-C are at 10-year ASCVD risk of 7.5% or higher, CKD not treated with dialysis or kidney transplantation is a risk-enhancing factor and initiation of a moderate-intensity statin or moderate-intensity statins combined with ezetimibe can be useful.S4.5.4-1,S4.5.4-2 IIb C-LD In adults with advanced kidney disease that requires dialysis treatment who are currently on LDL-lowering therapy with a statin, it may be reasonable to continue the statin.S4.5.4-2 III: No Benefit B-R In adults with advanced kidney disease who require dialysis treatment, initiation of a statin is not recommended.S4.5.4-3,S4.5.4-4 Synopsis CKD is a risk-enhancing factor for ASCVD. In risk dis- cussion with intermediate-risk patients, the presence of CKD favors initiation of statin therapy. In adults with advanced kidney disease requiring dialysis treatment who are currently on pharmacological LDL-lowering therapy with a statin, it may be reasonable to continue In adults with CKD that requires dialysis treatment, initiation of a statin is not recommended on the basis of 2 large-scale RCTs.S4.5.4-3,S4.5.4-4 Recommendation-Specific Supportive Text not on dialy- sis) and presence of albuminuria (albumin-to- creatinine ratio 30 mcg/mg) are independently associated with elevated risk of ASCVD. Hence, in intermediate-risk patients, CKD counts as a risk- enhancing factor. According to some studies,S4.5.4-5 the cardiovascular risk for persons with reduced eGFR may be as high as that observed among patients with diabetes mellitus and no CKD. Presence of albuminuria with reduced eGFR multiplies this CVD risk.


Presence of albuminuria with reduced eGFR multiplies this CVD risk. The risk is graded and increases with severity of eGFR impairment, with observed threshold of risk beginning around 75 , whereas the risk associated with albuminuria is linear.S4.5.4-6 Trials show abso- lute benefit from statin use, and this benefit is consistent across eGFR stages. However, the RRR per LDL-C lowering may be lower with more advanced CKD. Albuminuria is independently associated with CVD risk. However, the one trial done for primary prevention in persons with albu- minuria and preserved eGFR had too few events to be conclusive.S4.5.4-7 2. According to this recommendation, in patients with CKD who are currently taking a statin, it may be reasonable to continue the statin. In sup- port of this, in the SHARP trial (Study of Heart and Renal Protection) (simvastatin plus ezetimibe versus placebo), >30% of persons transitioned to After weighting for subgroup-spe- cific reductions in LDL-C was performed, the pro- portional effects on major atherosclerotic events were similar in patients on dialysis and those who were not on dialysis. 3. Although persons on dialysis have the high- est absolute risk of events (and thus poten- tial for higher ARR), the proportion of deaths thought to be due to atherosclerotic events is The lack of benefit in RCTs with statin initiation among persons on dialysis raises the question of competing risks. Unfortunately, there CLINICAL STATEMENTS AND GUIDELINES are not enough data to distinguish the potential for benefit from statin therapy between those on peritoneal dialysis and those on hemodialysis. 4.5.5. Adults With Chronic Inflammatory Disorders and HIV Recommendations for Adults With Chronic Inflammatory Disorders and HIV Referenced studies that support recommendations are summarized in Online Data Supplement 39.


Adults With Chronic Inflammatory Disorders and HIV Recommendations for Adults With Chronic Inflammatory Disorders and HIV Referenced studies that support recommendations are summarized in Online Data Supplement 39. COR LOE Recommendations IIa B-NR In adults 40 to 75 years of age with LDL-C have a 10-year ASCVD risk of 7.5% or higher, chronic inflammatory disorders and HIV are risk-enhancing factors and in risk discussion favor moderate-intensity statin therapy or high-intensity statin IIa B-NR In patients with chronic inflammatory disorders or HIV, a fasting lipid profile and assessment of ASCVD risk factors can be useful as a) a guide to benefit of statin therapy and b) for monitoring or adjusting lipid-lowering drug therapy before and 4 to 12 weeks after starting inflammatory disease modifying therapy or antiretroviral IIa B-NR In adults with RA who undergo ASCVD risk assessment with measurement of a lipid profile, it can be useful to recheck lipid values and other major ASCVD risk factors 2 to 4 months after the patient s inflammatory disease has been Synopsis Chronic inflammatory disorders and HIV infection are conditions that often enhance risk. Clinicians should first focus on helping patients with these diagnoses to optimize their lifestyle habits. After a 3- to 6-month trial of lifestyle improvements, including cessation of cigarette smoking, the patient s 10-year ASCVD risk estimate should be reassessed. If the patient s ASCVD risk estimate is 5% over 10 years, it is reasonable to begin moderate-intensity statin therapy. If the pa- tient or clinician remains uncertain about the need for statin therapy or if the patient has had side effects with a statin in the past, a CAC scan can be used to improve risk assessment.


If the pa- tient or clinician remains uncertain about the need for statin therapy or if the patient has had side effects with a statin in the past, a CAC scan can be used to improve risk assessment. The absence of CAC in a nonsmoking man 40 years of age or a nonsmoking woman 45 years of age would indicate that the pa- tient is likely at very low risk of an ASCVD event over the subsequent decade. Such patients can then focus on lifestyle habits and delay the decision about statin therapy for about 5 years. Similarly, a CAC score 75th percentile for a patient s age and sex or an ab- solute score 100 Agatston units would support the decision to use statin therapy and intensify lifestyle modifications. Recommendation-Specific Supportive Text 1.


Similarly, a CAC score 75th percentile for a patient s age and sex or an ab- solute score 100 Agatston units would support the decision to use statin therapy and intensify lifestyle modifications. Recommendation-Specific Supportive Text 1. Inflammation promotes atherosclerosis and is a key feature of many chronic rheumatologic inflam- matory joint disorders, such systemic lupus ery- thematosus, RA, and psoriasis.S4.5.5-1 Inflammation mediates the progression of atherosclerosis, as well as instability, erosion, and rupture of vulnera- ble atherosclerotic plaques.S4.5.5-2 Among individu- als with RA, the risk of an MI has been estimated to be similar to that of an adult with diabetes mel- litus or one who is about 10 years older without A large meta-analysis found that persons with RA had an approximately 50% increased risk of CVD death.S4.5.5-4 Individuals with systemic lupus erythematosus and advanced psoriasis have a similarly increased risk of CVD.S4.5.5-5 S4.5.5-7 HIV infection is associated with an increased risk of an ASCVD event even if viremia has been con- trolled by antiretroviral therapy.S4.5.5-8 There is an increased risk of MI in association with long-term use of antiretroviral therapy, and MI rates are increased in individuals with HIV.S4.5.5-9 Traditional ASCVD risk factors, long-term use of antiret- roviral therapy, prolonged immune activation, and inflammation are mediators of atheroscle- rosis progression and development.S4.5.5-9,S4.5.5-10 Coinfection with hepatitis C virus is frequently present in HIV-infected individuals and further increases ASCVD risk.S4.5.5-11,S4.5.5-12 2. The accuracy of the ASCVD risk estimator has not been well validated for adults with chronic inflam- matory disorders or HIV infection. Assessment of traditionalriskfactorsoftenhasresultedinunderesti- mationofactualriskandthepotentialforundertreat- ment with pharmacological therapy.S4.5.5-13,S4.5.5-14 Traditional risk factors should be assessed early in the disease process and then modified.


Assessment of traditionalriskfactorsoftenhasresultedinunderesti- mationofactualriskandthepotentialforundertreat- ment with pharmacological therapy.S4.5.5-13,S4.5.5-14 Traditional risk factors should be assessed early in the disease process and then modified. Rates of smok- ing in HIV-infected adults have generally been 2 to 3 times that of the general population.S4.5.5-15,S4.5.5-16 Multiple studies have demonstrated underestima- tion of ASCVD risk in patients with chronic inflam- matory conditions or HIV.S4.5.5-15,S4.5.5-16 Antiretroviral therapy may adversely affect lipid levels, glycemic control, and endothelial functionS4.5.5-17 S4.5.5-19 and has been associated with adverse changes in body composition (lipodystrophy). However, use of newer agents may lessen the metabolic derange- ments of antiretroviral therapy. Similarly, the use of prednisone in chronic inflammatory diseases may worsen glycemic control and dyslipidemia.S4.5.5-20 The most common lipid abnormality phenotype in persons with HIV infection is an elevated triglycer- ide level with a low HDL-C. In HIV-infected adults, CLINICAL STATEMENTS AND GUIDELINES triglycerides should preferentially be measured in the fasting state. 3. Patients with RA who are untreated or who have high disease activity generally have decreased levels of TC, triglycerides, HDL-C, and LDL-C.S4.5.5-21 These lower lipid levels are likely attributable in part to increased inflammation and may lead to functional proatherogenic changes, such as decreased cho- lesterol efflux capacity of HDL-C.S4.5.5-22 Treatment with anti-inflammatory medications, such as tumor necrosis factor alpha inhibitors or methotrexate, is associated with an increase in and normalization of lipid levels and a reduction in the ratio of TC Thus, to produce a more accurate risk estimate, ASCVD risk estimation should be repeated when the patient has a stable and low disease activity with normalization of their lipid lev- els; lower lipid levels measured during high disease activity may lead to a significant underestimation of ASCVD risk for patients with RA. 5.


Patients with RA who are untreated or who have high disease activity generally have decreased levels of TC, triglycerides, HDL-C, and LDL-C.S4.5.5-21 These lower lipid levels are likely attributable in part to increased inflammation and may lead to functional proatherogenic changes, such as decreased cho- lesterol efflux capacity of HDL-C.S4.5.5-22 Treatment with anti-inflammatory medications, such as tumor necrosis factor alpha inhibitors or methotrexate, is associated with an increase in and normalization of lipid levels and a reduction in the ratio of TC Thus, to produce a more accurate risk estimate, ASCVD risk estimation should be repeated when the patient has a stable and low disease activity with normalization of their lipid lev- els; lower lipid levels measured during high disease activity may lead to a significant underestimation of ASCVD risk for patients with RA. 5. STATIN SAFETY AND STATIN- ASSOCIATED SIDE EFFECTS Recommendations for Statin Safety and Statin-Associated Side Effects Referenced studies that support recommendations are summarized in Online Data Supplements 40 and 41.


STATIN SAFETY AND STATIN- ASSOCIATED SIDE EFFECTS Recommendations for Statin Safety and Statin-Associated Side Effects Referenced studies that support recommendations are summarized in Online Data Supplements 40 and 41. COR LOE Recommendations I A A clinician patient risk discussion is recommended before initiation of statin therapy to review net clinical benefit, weighing the potential for ASCVD risk reduction against the potential for statin-associated side effects, statin drug interactions, and safety, while emphasizing that side effects can be addressed I A In patients with statin-associated muscle symptoms (SAMS), a thorough assessment of symptoms is recommended, in addition to an evaluation for nonstatin causes and I B-R In patients with indication for statin therapy, identification of potential predisposing factors for statin-associated side effects, including new-onset diabetes mellitus and SAMS, is recommended before initiation of I B-R In patients with statin-associated side effects that are not severe, it is recommended to reassess and to rechallenge to achieve a maximal LDL-C lowering by modified dosing regimen, an alternate statin or in combination with nonstatin therapy.S5-3 S5-8 I B-R In patients with increased diabetes mellitus risk or new-onset diabetes mellitus, it is recommended to continue statin therapy, with added emphasis on adherence, net clinical benefit, and the core principles of regular moderate-intensity physical activity, maintaining a healthy dietary pattern, and sustaining modest weight loss.S5-8 S5-12 I C-LD In patients treated with statins, it is recommended to measure creatine kinase levels in individuals with severe statin- associated muscle symptoms, objective muscle weakness, and to measure liver transaminases (aspartate aminotransferase, alanine aminotransferase) as well as total bilirubin and alkaline phosphatase (hepatic panel) if there are symptoms suggesting I B-R In patients at increased ASCVD risk with chronic, stable liver disease (including non-alcoholic fatty liver disease) when appropriately indicated, it is reasonable to use statins after obtaining baseline measurements and determining a schedule of monitoring and safety checks.S5-16 S5-18 IIa B-R In patients at increased ASCVD risk with severe statin-associated muscle symptoms or recurrent statin-associated muscle symptoms despite appropriate statin rechallenge, it is reasonable to use RCT proven nonstatin therapy that is likely to provide net clinical III: No Benefit B-R Coenzyme Q10 is not recommended for routine use in patients treated with statins or for the treatment of SAMS.S5-20,S5-21 III: No Benefit C-LD In patients treated with statins, routine measurements of creatine kinase and transaminase levels are not useful.S5-13 S5-15 Synopsis Statin therapy is usually well tolerated and safe.S5-1,S5-14, As with other classes of medications, associ- ated side effects are seen.


Instead of the label statin intolerance, the present guideline prefers statin-associ- ated side effects because the large majority of patients are able to tolerate statin rechallenge with an alterna- tive statin or alternative regimen, such as reduced dose or in combination with nonstatins. Although infrequent or rare in clinical trials, statin-associated side effects can be challenging to assess and manage.S5-25,S5-26 The most frequent are SAMS. SAMS usually are subjective myalgia, reported observationally in 5% to 20% of SAMS often result in nonadherence and can adversely impact ASCVD outcomes.S5-27 S5-29 Statins modestly increase risk of incident diabetes mel- litus in susceptible individuals,S5-8 S5-11 but this should not be cause for discontinuation (Table 11). The present guideline recommends a comprehensive approach to statin-associated symptoms. The clinician should reas- sess, rediscuss, and encourage rechallenge as the ini- tial approach unless side effects are severe. Ongoing communication is integral to patient care, as is regular monitoring to check for adherence, adequacy of re- sponse, new associated symptoms, and reaffirmation Recommendations for Statin Safety and Statin-Associated Side Effects (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES Recommendation-Specific Supportive Text 1. A clinician patient risk discussion focused on indi- cations, benefits, risks of statin-associated side effects, and patient concerns and preferences should precede initiation of statin treatment.S5-2 This dialogue is the foundation of a longitudinal care partnership that is based on informed deci- sion-making. Future encounters should address statin response, emphasize adherence, and reaf- firm benefit. Statin-associated symptoms should be comprehensively assessed, and because most can be well managed,S5-3 S5-7 the goal should be to optimize patient-centered strategies for ASCVD prevention. 2.


Statin-associated symptoms should be comprehensively assessed, and because most can be well managed,S5-3 S5-7 the goal should be to optimize patient-centered strategies for ASCVD prevention. 2. The majority of SAMS are subjective myalgia (pain, aches) in the absence of other findings.S5-13,S5-25,S5-30 Myalgia is more likely to be statin associated if it is bilateral, involves proximal muscles, has its onset within weeks to months after initiation of statins, and resolves after discontinuation of statins.S5-13,S5-14 A thorough assessment of symptoms is recom- mended, in addition to evaluation for nonstatin etiologies, assessment of predisposing factors, and a physical exam. Objective muscle weakness Table 11. Statin-Associated Side Effects (SASE) Statin-Associated Side Effects Frequency Predisposing Factors Quality of Evidence Statin-associated muscle symptoms (SAMS) Myalgias (CK normal) Infrequent (1% to 5%) in RCTs; frequent (5% to 10%) in observational studies and clinical setting Age, female sex, low body mass index, high-risk medications (CYP3A4 inhibitors, OATP1B1 inhibitors), comorbidities (HIV, renal, liver, thyroid, preexisting myopathy), Asian ancestry, excess alcohol, high levels of physical activity, and trauma RCTs cohorts/ observational Myositis/myopathy (CK > ULN) with concerning symptoms or objective weakness Rare RCTs cohorts/ observational Rhabdomyolysis (CK >10 ULN + renal injury) Rare RCTs cohorts/ observational Statin-associated autoimmune myopathy (HMGCR antibodies, incomplete resolution) Rare Case reports New-onset diabetes mellitus Depends on population; more frequent if diabetes mellitus risk factors are present, such as body mass index 30, fasting blood glucose 100 mg/dL; metabolic syndrome, or A1c 6%.


Statin-Associated Side Effects (SASE) Statin-Associated Side Effects Frequency Predisposing Factors Quality of Evidence Statin-associated muscle symptoms (SAMS) Myalgias (CK normal) Infrequent (1% to 5%) in RCTs; frequent (5% to 10%) in observational studies and clinical setting Age, female sex, low body mass index, high-risk medications (CYP3A4 inhibitors, OATP1B1 inhibitors), comorbidities (HIV, renal, liver, thyroid, preexisting myopathy), Asian ancestry, excess alcohol, high levels of physical activity, and trauma RCTs cohorts/ observational Myositis/myopathy (CK > ULN) with concerning symptoms or objective weakness Rare RCTs cohorts/ observational Rhabdomyolysis (CK >10 ULN + renal injury) Rare RCTs cohorts/ observational Statin-associated autoimmune myopathy (HMGCR antibodies, incomplete resolution) Rare Case reports New-onset diabetes mellitus Depends on population; more frequent if diabetes mellitus risk factors are present, such as body mass index 30, fasting blood glucose 100 mg/dL; metabolic syndrome, or A1c 6%. Diabetes mellitus risk factors/metabolic syndrome RCTs/meta-analyses High-intensity statin therapy Liver Transaminase elevation 3 ULN Infrequent RCTs/cohorts/ observational Case reports Hepatic failure Rare Central nervous system Memory/cognition Rare Case reports; no increase in memory/ cognition problems in 3 large-scale RCTs Cancer No definite association RCTs/meta-analyses Other Renal function Unfounded Cataracts Unfounded Tendon rupture Unfounded Hemorrhagic stroke Unfounded Interstitial lung disease Unfounded Low testosterone Unfounded CK indicates creatine kinase; HIV, human immunodeficiency virus; HMGCR, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; SAMS, statin-associated muscle symptoms; SAAM, statin-associated autoimmune myopathy; SASE, statin associated side effects; and ULN, upper limit of normal. CLINICAL STATEMENTS AND GUIDELINES (myopathy) and associated significant increase in CK (myositis) are rareS5-1,S5-22,S5-30 but require prompt statin cessation and evaluation for reversible causes. Rhabdomyolysis (CK >10 times upper limit of normal, with evidence of renal injury) is exceed- ingly rare and usually encountered in the setting of a patient with several predisposing comorbidities and concomitant high-risk medications.S5-1,S5-22,S5-30 It requires immediate medical attention. 3.


Rhabdomyolysis (CK >10 times upper limit of normal, with evidence of renal injury) is exceed- ingly rare and usually encountered in the setting of a patient with several predisposing comorbidities and concomitant high-risk medications.S5-1,S5-22,S5-30 It requires immediate medical attention. 3. Before lipid-lowering therapy with a statin is initiated, a comprehensive evaluation of mus- culoskeletalsymptoms(withdocumentation)isrec- ommended because such symptoms are common at baseline in the general adult population.S5-3 S5-6 Beforetherapy,itisalsoimportanttoidentifypredis- posing factors for SAMS, including demographics, comorbid conditions, and use of medications that can adversely affect statin metabolismS5-3,S5-13,S5-14 (Table 11). Proactive and preemptive identification of patients at potential increased risk of statin- associated side effects should help guide informed clinical decision-making and is supportive of the goals of safe and effective therapy. 4. Several creatively designed randomized crossover trials in patients with SAMSS5-3 S5-7 support a man- agement strategy of statin discontinuation until symptoms improve, followed by rechallenge with a reduced dose, alternative agent, or alternative dosing regimen while monitoring for recurrent symptoms. If the approach of reassess, rediscuss (net clinical benefit), and rechallenge is used, a majority of patients will be able to be successfully treated with at least one or several statins.S5-29,S5-31 In patients at increased ASCVD risk, the goal should be to treat with the guideline-recommended max- imally tolerated statin dose. Patients who experi- ence rhabdomyolysis with statin therapy may need to discontinue statin use indefinitely, although reversible causes should be sought.S5-32 Clinicians should be aware of a rare disorder, statin-associ- ated autoimmune myopathy (muscle weakness, marked and persistent CK elevation, presence of HMG CoA reductase [HMGCR] antibodies, necrotizing myopathy, and lack of or incomplete resolution on statin discontinuation), that requires statin cessation and additional therapy directed at the autoimmune process.S5-32 Patients with statin- associated autoimmune myopathy may benefit from seeing a neurologist specializing in neuro- muscular disorders.


Patients who experi- ence rhabdomyolysis with statin therapy may need to discontinue statin use indefinitely, although reversible causes should be sought.S5-32 Clinicians should be aware of a rare disorder, statin-associ- ated autoimmune myopathy (muscle weakness, marked and persistent CK elevation, presence of HMG CoA reductase [HMGCR] antibodies, necrotizing myopathy, and lack of or incomplete resolution on statin discontinuation), that requires statin cessation and additional therapy directed at the autoimmune process.S5-32 Patients with statin- associated autoimmune myopathy may benefit from seeing a neurologist specializing in neuro- muscular disorders. 5. Evidence indicates that statins modestly increase the risk of incident or statin-associated new-onset diabetes mellitus in individuals with predisposing risk factors for diabetes mellitus, components of the metabolic syndrome, and higher-intensity statin The specific mechanisms leading to statin-associated diabetes mellitus remain unclear, although it is unlikely that statins directly cause diabetes mellitus. Rather, it appears that a small number of individuals with diabetic susceptibility cross the threshold to incident diabetes mellitus after statin therapy. is initiated It is important that patients are informed of the potential risk of new- onset diabetes mellitus before initiation of statin therapy. Because the benefits of statin therapy are shown to outweigh the risks of new-onset diabetes mellitus, the possibility of incident diabetes mellitus should not be a contraindication to statin therapy or indication for statin discontinuation.S5-8,S5-14,S5-33 In individuals at increased risk of both ASCVD and incident diabetes mellitus, it is recommended that counseling based on the ADA prevention approach be provided. This approach encourages regular moderate physical activity, maintaining a healthy dietary pattern, and sustaining modest weight loss (according to the core principles of the Diabetes 6. In patients with statin-associated side effects, it is recommended that CK be measured in the case of severe SAMS and in the presence of objective mus- cle weakness.


In patients with statin-associated side effects, it is recommended that CK be measured in the case of severe SAMS and in the presence of objective mus- cle weakness. After baseline liver transaminases, the FDA recommends measuring transaminases (aspar- tate aminotransferase [serum glutamic-oxaloacetic transaminase] and alanine aminotransferase [serum glutamic-pyruvic transaminase]) if there are signs or symptoms suggesting hepatotoxicity.S5-13 S5-15 upper limit of normal) is an infrequent statin-associ- ated side effect that often resolves with dose reduc- tion or rechallenge with alternative statins.S5-1,S5-22 Severe statin-associated hepatotoxicity is rare, and the incidence is not impacted by routine monitor- ing of transaminases.S5-34 A thorough evaluation for nonstatin etiologies is warranted when signifi- cant transaminase elevation persists. Importantly, statins are not contraindicated in patients with increased ASCVD risk with chronic, stable liver dis- ease (eg, nonalcoholic fatty liver), and limited data suggest potential benefit.S5-16 S5-18 8. Severe statin-associated side effects are rare, and recurrent SAMS are infrequent when a thorough reassessment and management strategy of reas- sess, rediscuss, and rechallenge is used. In patients at increased ASCVD risk with severe statin-asso- ciated side effects or recurrent SAMS, nonstatin therapy should be considered when there is net 9. The clinical diagnosis of SAMS remains chal- lenging, given that the majority of symptoms are subjective and definitive diagnostic criteria do not exist.S5-13 Multiple potential mechanisms have been suggested to contribute to SAMS, CLINICAL STATEMENTS AND GUIDELINES including depletion of ubiquinone or coenzyme Q10. Available evidence, however, does not sup- port the use of coenzyme Q10 supplementation for routine use in patients treated with statins or for the treatment of SAMS.S5-20,S5-21 10.


Available evidence, however, does not sup- port the use of coenzyme Q10 supplementation for routine use in patients treated with statins or for the treatment of SAMS.S5-20,S5-21 10. The majority of SAMS are subjective myalgia in the absence of other findings,S5-3,S5-13,S5-14,S5-23,S5-30 and an asymptomatic increase in transaminases (>3 times upper limit of normal) is an infrequent statin-associated side effect.S5-1,S5-22,S5-24 Therefore, CK and transaminase levels should not be rou- tinely measured given the unlikely impact on clinical outcomes, and the lack of established cost Recommendations for Implementation Referenced studies that support recommendations are summarized in Online Data Supplements 42 to 46. COR LOE Recommendations I A Interventions focused on improving adherence to prescribed therapy are recommended for management of adults with elevated cholesterol levels, including telephone reminders, calendar reminders, integrated multidisciplinary educational activities, and pharmacist-led interventions, such as simplification of the drug regimen to I B-NR Clinicians, health systems, and health plans should identify patients who are not receiving guideline-directed medical therapy and should facilitate the initiation of appropriate guideline-directed medical therapy, using multifaceted strategies to improve guideline implementation.S6-5,S6-6 I B-NR Before therapy is prescribed, a patient- clinician discussion should take place to promote shared decision-making and should include the potential for ASCVD risk- reduction benefit, adverse effects, drug-drug interactions, and patient preferences.S6-7,S6-8 Synopsis Guideline publication does not guarantee guideline implementation. Healthcare delivery is complex, and barriers to guideline implementation can occur at the patient, clinician, health system, and health plan levels, leading to gaps in care. A more concerted effort, with multifaceted strategies aimed at the patient, clinician, health system, and health plan, is needed to overcome the barriers and achieve wider guideline implementa- tion (Table S7).


A more concerted effort, with multifaceted strategies aimed at the patient, clinician, health system, and health plan, is needed to overcome the barriers and achieve wider guideline implementa- tion (Table S7). The patient is a key player in success- ful guideline implementation, and the clinician patient discussion is crucial to the successful initiation and con- tinuation of guideline-directed management and thera- py (Table 7). As part of the clinician patient discussion, the patient should be encouraged to state what was heard, ask questions, express values and preferences, and state ability and willingness to adhere to lifestyle changes and medications. This is where a discussion of out-of-pocket costs can occur. Clinicians should use multiple interventions to promote adherence, including asking more specific questions about adherence, aim- ing for once-daily dosing, using automated reminders, participating in multidisciplinary educational activities, and using pharmacist-led interventions. Recommendation-Specific Supportive Text 1. Interventions focused on improving adherence to prescribed therapy are recommended for man- agement of adults with elevated cholesterol lev- els. A Cochrane systematic review demonstrated that intensification of patient care interventions improves both short- and long-term adherence to medication, as well as meaningful reduction in LDL-C levels. Interventions include telephone reminders, calendar reminders, integrated mul- tidisciplinary educational activities, simplification of the drug regimen to once-daily dosing, and Clinicians may wish to review Table S7 in the Web Supplement, Strategies to Improve Guideline Implementation by Setting and Target Audience Measures to Improve Lipid Medication Adherence. 2. Clinicians do not follow guidelines for many and cholesterol guideline implementation has not been optimal.S6-10 S6-13 Interventions aimed at the clinician may improve guideline implemen- tation.


Clinicians do not follow guidelines for many and cholesterol guideline implementation has not been optimal.S6-10 S6-13 Interventions aimed at the clinician may improve guideline implemen- tation. Educational outreach or academic detailing visits are generally effective for improving process- of-care, clinical, cost-reduction, and cost-effec- Audits of individual clinical performance and feedback are generally effective in improving process-of-care and clinical outcomes.S6-5 Reminders and individual pay-for-performance are generally effective for cost reduction.S6-5 Even if guideline-directed management and therapy are prescribed, patients may be nonadher- ent or not get the prescribed medication for a vari- ety of reasons.S6-14 Patients who are initially adherent to statin therapy may not demonstrate long-term Adherent patients, with and without clinical ASCVD, have improved outcomes and reduced costs.S6-15,S6-17 S6-20 Formulary restrictions and prior authorization requirements have been associated with care delays and nonadherence.S6-21 Interventions aimed at the patient may improve adherence and clinical outcomes. Guideline implementation strategies that are aimed at the patient, clinician, health system, and health plan are needed. Barriers to guideline CLINICAL STATEMENTS AND GUIDELINES implementation should be analyzed in advance, and implementation strategies should be tailored to the setting and target audience. Multiple strat- egies may be needed to effectively implement (Table S7 in the Web Supplement). 3. Patients who participate in shared decision-making may have better health outcomes, better health- care experiences, and lower costs.S6-7,S6-8 During the clinician patient risk discussion with shared decision-making, the patient participates with the clinician in deciding lifestyle modifications, medica- tion treatment, and goals of therapy. The clinician should explain the patient s risk of clinical ASCVD and how the treatment recommendations reduce ASCVD risk.


The clinician should explain the patient s risk of clinical ASCVD and how the treatment recommendations reduce ASCVD risk. The patient should verbalize values, attitudes, abilities, concerns, and personal goals for making lifestyle changes and taking medications, including concerns about cost.S6-22 The clinician may use a checklist to facilitate shared decision-making with the patient (Table S8 in the Web Supplement). The clinician should use tools and techniques to support shared decision-making.S6-7,S6-22 S6-26 Decision aids may allow the patient to be more knowledgeable, have better risk perception, and have a clearer understanding of their values.S6-8,S6-27 Question prompt lists may increase knowledge by including questions about the purpose or goal of treatment, the risk with and without treatment, how the medication should be taken, potential side effects and how to manage them, when to notify the office, and monitoring and follow-up. Motivational and decision coaching may also promote patient knowledge and satisfaction. 7. COST AND VALUE CONSIDERATIONS 7.1. Economic Value Considerations: ACC/AHA clinical guidelines now recognize the im- portance of considering economic value in making recommendations, in accordance with the principles established by an expert group.S7.1-1 tors further reduce LDL-C when combined with other LDL-lowering drugs, and they reduced composite car- diovascular events in 2 RCTs of high-risk, secondary- prevention patients with clinical ASCVD.S7.1-2 The cost- effectiveness and economic value of PCSK9 inhibitors have been assessed by using simulation models (Online Data Supplements 47 and 48); the published models are based on different sets of assumptions. Compared with statin therapy for secondary prevention, PCSK9 inhibitors have incremental cost-effectiveness ratiosS7.1-3 from $141700 to $450000 per quality-adjusted life- year (QALY) added, at mid-2018 list prices. None of the published models report good value (<$50000 per QALY added; Table 12), and virtually all indicate low value ( $150000 per QALY added).


None of the published models report good value (<$50000 per QALY added; Table 12), and virtually all indicate low value ( $150000 per QALY added). All models pro- jected mortality benefit by assuming that mortality rate reductions either parallel LDL-C loweringS7.1-4 or parallel RRRs for nonfatal ASCVD events. All models project higher lifetime cost from use of PCSK9 inhibitors because the cost will exceed any sav- ings from prevention of cardiovascular events. To be cost-effective by conventional standards, the cost of PCSK9 inhibitors will have to be reduced on the order of 70% to 85% in the United States.S7.1-3 At any given price, the economic value of PCSK9 inhibitors will be improved by restricting their use to patients at very high-risk of ASCVD events, as recommended in the present guidelines. The inverse relationship between improved survival and the incremental cost-effective- ness ratio (Figure 3) indicates that the economic val- ue of PCSK9 inhibitors will be improved by selecting higher-risk patients. One simulation model suggested that restricting the use of PCSK9 inhibitor therapy to patients with baseline LDL-C levels 119 mg/dL ( 3 mmol/L), instead of 70 mg/dL ( 1.8 mmol/L), would improve their cost-effectiveness to $150000 per QALY added, instead of $268000.S7.1-5 Another study pro- jected a similar improvement in economic value.S7.1-6 Thus, raising the threshold for LDL-C on maximal statin therapy to initiate a PCSK9 inhibitor should im- prove its cost-effectiveness (Figure 3). Only 2 economic models have specifically examined the value provided by PCSK9 inhibitors for primary pre- vention in patients with heterozygous FH (Online Data found low value when PCSK9 inhibitors were used for FH ($503000 per QALY added), whereas the second modelS7.1-8 reported inter- mediate value (incremental cost-effectiveness ratio of $75900 per QALY added). Consequently, the value of PCSK9 inhibitor therapy in FH is uncertain.


Consequently, the value of PCSK9 inhibitor therapy in FH is uncertain. Table 12. Proposed Integration of Level of Value Into Clinical Guideline Recommendations* Level of Value High value: Better outcomes at lower cost or ICER <$50000 per QALY gained Intermediate value: $50000 to <$150000 per QALY gained Low value: $150000 per QALY gained Uncertain value: Value examined, but data are insufficient to draw a conclusion because of absence of studies, low-quality studies, conflicting studies, or prior studies that are no longer relevant Not assessed: Value not assessed by the writing committee Proposed abbreviations for each value recommendation:Level of value: H to indicate high value; I, intermediate value; L, low value; U, uncertain value; and NA, value not assessed. *Dollar amounts used in this table are based on US GDP data from 2012 and were obtained from WHO-CHOICE Cost-Effectiveness Thresholds.S7.1-9 Reproduced from Anderson et al.S7.1-1 GDP indicates gross domestic product; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-years; and WHO-CHOICE, World Health Organization Choosing Interventions that are Cost-Effective. CLINICAL STATEMENTS AND GUIDELINES 8. LIMITATIONS AND KNOWLEDGE GAPS 8.1. Randomized Controlled Trials ACC/AHA guidelines are based largely on the outcomes of RCTs. Cholesterol guidelines have fortunately benefited from a large number of RCTs of cholesterol-lowering thera- pies. They have established that greater reductions of LDL- C are accompanied by greater reductions in risk of ASCVD. Robust RCTs exist for both primary and secondary preven- tion. Most of the data from RCTs have been obtained with statin therapy. Important limited data have also been ob- tained with nonstatins as add-on drugs to statin therapy. Nevertheless, more data are needed to determine the full scope of the benefit of nonstatin drugs. Several important questions need to be addressed by additional RCTs. 1.


Several important questions need to be addressed by additional RCTs. 1. In secondary prevention, does a lower limit for LDL-C attainment exist, beyond which the incre- mental benefit attained is worth neither the risks nor the cost of additional therapy? 2. In secondary prevention, what are the indications for adding PCSK9 inhibitors to maximal statin therapy? 3. In patients with ASCVD who have statin-associ- ated side effects, are PCSK9 inhibitors an effective and safe substitute for high-intensity statins? 4. In primary prevention for adults 45 to 75 years of age (LDL-C <90 mg/dL [<2.3 mmol/L]) with or without diabetes mellitus, what is the incremental risk reduction imparted by high-intensity statins as compared with moderate-intensity statins? 5. In primary prevention for adults 45 to 75 years of age (LDL-C <190 mg/dL [<4.9 mmol/L]) with or without diabetes mellitus, what is the incremen- tal risk reduction imparted by moderate-intensity statins plus ezetimibe as compared with moder- ate-intensity statins alone? 6. Is statin therapy efficacious and safe in older patients (>75 years of age)? If so, what is a net benefit of statin therapy in this age group? 7. In patients with severe hypercholesterolemia, what are the efficacy and net benefit of PCSK9 inhibitors as add-on treatment to maximal statin therapy? 8. What is the efficacy of moderate-intensity and high-intensity statin therapy in patients with risk- enhancing factors (eg, chronic inflammatory dis- ease, CKD, metabolic syndrome)? 8.2. Risk Assessment In primary prevention, the appropriate selection of pa- tients for cholesterol-lowering drug therapy is highly de- pendent on risk assessment. Previous guidelines made Figure 3. Cost-effectiveness analysis for PCSK9 inhibitors.


Previous guidelines made Figure 3. Cost-effectiveness analysis for PCSK9 inhibitors. Conceptual relationship between the clinical effectiveness of PCSK9 inhibitor therapy, measured in QALYs added compared with statin therapy, on the horizontal axis, and their clinical value, measured in dollars per QALY added, on the vertical axis. The top curve indicates the relationship at full U.S list price of PCSK9 inhibi- tor therapy ($14000/y), the middle curve indicates the relationship if the price were reduced by 50% (ie, to $7000/y), and the bottom curve indicates the relation- ship if the price were reduced by 75% (ie, to $3500/y). Reproduced from Hlatky et al.S7.1-3 CV indicates cardiovascular; and QALY, quality-adjusted life-years. CLINICAL STATEMENTS AND GUIDELINES use of risk-assessment algorithms (eg, Framingham risk scoring or PCE) to estimate risk. Although these equa- tions are useful, they may overestimate or underesti- mate risk for individual patients. For this reason, the introduced the clinician patient risk discussion to facilitate clinical decisions about appropriate therapy. In the present guidelines, the clinician patient risk discussion has been amplified and made an integral part of the clinical decision. In addition, in cases in which uncertainty exists, the mea- surement of CAC has been proposed as a third step in making a treatment decision. Each of these steps could be improved for future guidelines. 8.2.1. Continuing Refinement of PCE Because the population baseline risk may be continually declining in the US population, ongoing epidemiological study is needed to assess and update population risk. An example is the development of QRISK in the U.K. popula- tion, which is continually expanding its scope. 8.2.2. Improvement in Lifetime Risk Estimate The present guidelines include a lifetime ASCVD risk al- gorithm for those 20 to 59 years of age, but it is based on an insufficient database.


Improvement in Lifetime Risk Estimate The present guidelines include a lifetime ASCVD risk al- gorithm for those 20 to 59 years of age, but it is based on an insufficient database. Along with a risk algorithm for short-term risk of ASCVD (eg, 10 years), a more robust lifetime risk algorithm would facilitate the clini- cian patient risk discussion for treatment decisions. 8.2.3. Refinement of Clinician Patient Risk Discussion An ongoing study of how a clinician can best interact with a patient to arrive at an informed decision must be done, taking multiple factors into consideration. This is particularly important because cholesterol-lowering therapy is meant to be a lifetime therapy. 8.2.4. Monitoring and Adjustment of Treatment The clinician patient risk discussion will likely prove in- adequate unless an ongoing interaction between the patient and clinician occurs. This involves monitoring the effectiveness of therapy and adherence to therapy. Thus, the clinician patient risk discussion should in- clude more than the initial treatment decision. Ongoing research on how to improve the entire process of initial decision-making and long-term follow-up is necessary. 8.2.5. Prognostic Significance of CAC The present guideline makes use of the available data to predict the risk associated with CAC. These data need to be amplified by new and ongoing studies to guide treatment decisions. Particular uncertainty exists about the predictive value of intermediate CAC scores. In addition, the predictive significance of a CAC score of zero must be further verified in follow-up studies. For patients with a CAC score of zero, it is currently uncer- tain when and if follow-up CAC measurements should be done to reassess risk status.


For patients with a CAC score of zero, it is currently uncer- tain when and if follow-up CAC measurements should be done to reassess risk status. ACC/AHA TASK FORCE MEMBERS Glenn N. Levine, MD, FACC, FAHA, Chair; Patrick T. O Gara, MD, MACC, FAHA, Chair-Elect; Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair*; Sana M. Al-Khatib, MD, MHS, FACC, FAHA; Joshua A. Beckman, MD, MS, FAHA; Kim K. Birtcher, PharmD, MS, AACC; Biykem Bozkurt, MD, PhD, FACC, FAHA*; Ralph G. Brindis, MD, MPH, MACC*; Joaquin E. Cigarroa, MD, FACC; Lesley H. Curtis, PhD, FAHA*; Anita Deswal, MD, MPH, FACC, FAHA; Lee A. Fleisher, MD, FACC, FAHA; Federico Gentile, MD, FACC; Samuel Gidding, MD, FAHA*; Zachary D. Goldberger, MD, MSc, FACC, FAHA; Mark A. Hlatky, MD, FACC, FAHA; John Ikonomidis, MD, PhD, FAHA*; Jos A. Joglar, MD, FACC, FAHA; Laura Mauri, MD, MSc, FAHA*; Mariann R. Piano, RN, PhD, FAHA; Susan J. Pressler, PhD, RN, FAHA*; Barbara Riegel, PhD, RN, FAHA*; Duminda N. Wijeysundera, MD, PhD PRESIDENTS AND STAFF American College of Cardiology C. Michael Valentine, MD, FACC, President Timothy W. Attebery, MBA, FACHE, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice Presi- dent, Science, Education, Quality, and Publishing MaryAnne Elma, MPH, Senior Director, Science, Educa- tion, Quality, and Publishing Amelia Scholtz, PhD, Publications Manager, Science, Education, Quality, and Publishing American College of Cardiology/ American Heart Association Katherine A. Sheehan, PhD, Director, Guideline Strat- egy and Operations Abdul R. Abdullah, MD, Senior Manager, Guideline Science Thomas S.D.


ACC/AHA TASK FORCE MEMBERS Glenn N. Levine, MD, FACC, FAHA, Chair; Patrick T. O Gara, MD, MACC, FAHA, Chair-Elect; Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair*; Sana M. Al-Khatib, MD, MHS, FACC, FAHA; Joshua A. Beckman, MD, MS, FAHA; Kim K. Birtcher, PharmD, MS, AACC; Biykem Bozkurt, MD, PhD, FACC, FAHA*; Ralph G. Brindis, MD, MPH, MACC*; Joaquin E. Cigarroa, MD, FACC; Lesley H. Curtis, PhD, FAHA*; Anita Deswal, MD, MPH, FACC, FAHA; Lee A. Fleisher, MD, FACC, FAHA; Federico Gentile, MD, FACC; Samuel Gidding, MD, FAHA*; Zachary D. Goldberger, MD, MSc, FACC, FAHA; Mark A. Hlatky, MD, FACC, FAHA; John Ikonomidis, MD, PhD, FAHA*; Jos A. Joglar, MD, FACC, FAHA; Laura Mauri, MD, MSc, FAHA*; Mariann R. Piano, RN, PhD, FAHA; Susan J. Pressler, PhD, RN, FAHA*; Barbara Riegel, PhD, RN, FAHA*; Duminda N. Wijeysundera, MD, PhD PRESIDENTS AND STAFF American College of Cardiology C. Michael Valentine, MD, FACC, President Timothy W. Attebery, MBA, FACHE, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice Presi- dent, Science, Education, Quality, and Publishing MaryAnne Elma, MPH, Senior Director, Science, Educa- tion, Quality, and Publishing Amelia Scholtz, PhD, Publications Manager, Science, Education, Quality, and Publishing American College of Cardiology/ American Heart Association Katherine A. Sheehan, PhD, Director, Guideline Strat- egy and Operations Abdul R. Abdullah, MD, Senior Manager, Guideline Science Thomas S.D. Getchius, Manager, Guideline Operations American Heart Association Ivor Benjamin, MD, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medicine Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Prashant Nedungadi, PhD, Science and Medicine Advi- sor, Office of Science Operations Jody Hundley, Production and Operations Manager, Sci- entific Publications, Office of Science Operations *Former Task Force member; current member during the writing effort.