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.


Getchius, Manager, Guideline Operations American Heart Association Ivor Benjamin, MD, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medicine Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Prashant Nedungadi, PhD, Science and Medicine Advi- sor, Office of Science Operations Jody Hundley, Production and Operations Manager, Sci- entific Publications, Office of Science Operations *Former Task Force member; current member during the writing effort. CLINICAL STATEMENTS AND GUIDELINES ARTICLE INFORMATION This document was approved by the American College of Cardiology Clinical Policy Approval Committee, the American Heart Association Science Advisory and Coordinating Committee, American Association of Cardiovascular and Pulmonary Rehabilitation, American Academy of Physician Assistants, Associa- tion of Black Cardiologists, American College of Preventive Medicine, American Diabetes Association, American Geriatrics Society, American Pharmacists Asso- ciation, American Society for Preventive Cardiology, National Lipid Association, and Preventive Cardiovascular Nurses Association in October 2018, and the American Heart Association Executive Committee in October 2018. Supplemental materials are available with this article at https://www. ahajournals.org/doi/suppl/10.1161/CIR.0000000000000625. This article has been copublished in the Journal of the American College of Cardiology. Copies: This document is available on the websites of the American College of Cardiology (www.acc.org) and the American Heart Association (professional.heart.org). A copy of the document is also available at https:// professional.heart.org/statements by selecting the Guidelines & Statements button. To purchase additional reprints, call 843-216-2533 or e-mail kelle. ramsay@wolterskluwer.com. The expert peer review of AHA-commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guide- lines development, visit https://professional.heart.org/statements. Select the Guidelines & Statements drop-down menu near the top of the web page, then click Publication Development.


Select the Guidelines & Statements drop-down menu near the top of the web page, then click Publication Development. Permissions: Multiple copies, modification, alteration, enhancement, and/ or distribution of this document are not permitted without the express permis- sion of the American Heart Association. Instructions for obtaining permission are located at https://www.heart.org/permissions. A link to the Copyright Per- missions Request Form appears in the second paragraph (https://www.heart. org/en/about-us/statements-and-policies/copyright-request-form). REFERENCES 1.1. Methodology and Evidence Review S1.1-1. Wilson PWF, Polonsky TS, Miedema MD, et al. Systematic review for the NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1144 61. DOI: 10.1161/CIR.0000000000000626. 1.4. Scope of the Guideline S1.4-1. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170000 participants in 26 randomised trials. Lancet. 2010;376:1670 81. S1.4-2. Chou R, Dana T, Blazina I, et al. Statin use for the prevention of car- diovascular disease in adults: a systematic review for the US Preventive Services Task Force. 2016. Rockville, MD: US Agency for Healthcare Research and Quality, Report No.: 14-05206-EF-2. S1.4-3. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013:CD004816. S1.4-4. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guide- line on the treatment of blood cholesterol to reduce atheroscle- rotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1 45. 1.5. Class of Recommendation and Level of Evidence S1.5-1. Halperin JL, Levine GN, Al-Khatib SM, et al.


Class of Recommendation and Level of Evidence S1.5-1. Halperin JL, Levine GN, Al-Khatib SM, et al. Further evolution of the ACC/ AHA clinical practice guideline recommendation classification system: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2015;133:1426 8. 2. HIGH BLOOD CHOLESTEROL AND ASCVD 2.1. Serum Cholesterol, Lipoproteins, and ASCVD 2.1.2. Cholesterol, LDL-C, and ASCVD S2.1.2-1. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT) JAMA. 1986;256:2823 8. S2.1.2-2. Kannel WB, Castelli WP, Gordon T, et al. Serum cholesterol, lipopro- teins, and the risk of coronary heart disease. The Framingham study. Ann Intern Med. 1971;74:1 12. S2.1.2 3. Lawes CMMVH, S, Law MR, Rogers A. High Cholesterol. Ezzati M, Lopez AD, Rodgers A, et al Comparative Quantification of Health Risks: Global and Regional Burden of Disease Attributable to Selected Major Risk Factors. 2004. Geneva, Switzerland: World Health Organization, 391 496. Available at: http://apps.who.int/iris/ handle/10665/42770. S2.1.2-4. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of ath- erogenic lipoproteins and the risk for cardiovascular events: a meta- analysis of statin trials. J Am Coll Cardiol. 2014;64:485 94. S2.1.2-5. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387 97. S2.1.2-6. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clini- cal outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713 22. S2.1.2-7. Silverman MG, Ference BA, Im K, et al. Association between lower- ing LDL-C and cardiovascular risk reduction among different thera- peutic interventions: a systematic review and meta-analysis. JAMA. 2016;316:1289 97. 2.1.3.


Association between lower- ing LDL-C and cardiovascular risk reduction among different thera- peutic interventions: a systematic review and meta-analysis. JAMA. 2016;316:1289 97. 2.1.3. LDL-C and Other Risk Factors S2.1.3-1. Wilson PW, D Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97: 1837-47. S2.1.3-2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce ath- erosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1 45. S2.1.3-3. Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease pooled cohort risk equations. JAMA. 2014;311:1406 15. S2.1.3-4. Mora S, Wenger NK, Cook NR, et al. Evaluation of the pooled cohort risk equations for cardiovascular risk prediction in a multi- ethnic cohort from the Women s Health Initiative. JAMA Intern Med. 2018;178:1231 40. 2.2. Measurements of LDL-C and Non-HDL-C S2.2-1. Langsted A, Freiberg JJ, Nordestgaard BG. Fasting and nonfasting lipid levels: influence of normal food intake on lipids, lipoproteins, apolipoproteins, and cardiovascular risk prediction. Circulation. 2008;118:2047 56. S2.2-2. Langsted A, Nordestgaard BG. Nonfasting lipids, lipoproteins, and apolipoproteins in individuals with and without diabetes: 58 434 individuals from the Copenhagen General Population Study. Clin Chem. 2011;57:482 9. S2.2-3. Mora S, Rifai N, Buring JE, et al. Comparison of LDL cholesterol concentrations by Friedewald calculation and direct measurement in relation to cardiovascular events in 27331 women. Clin Chem. 2009;55:888 94. S2.2-4. Sidhu D, Naugler C. Fasting time and lipid levels in a commu- nity-based population: a cross-sectional study. Arch Intern Med. 2012;172:1707 10. CLINICAL STATEMENTS AND GUIDELINES S2.2-5. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipopro- teins, and risk of vascular disease. JAMA. 2009;302:1993 2000. S2.2-6.


Major lipids, apolipopro- teins, and risk of vascular disease. JAMA. 2009;302:1993 2000. S2.2-6. Doran B, Guo Y, Xu J, et al. Prognostic value of fasting versus non- fasting low-density lipoprotein cholesterol levels on long-term mor- tality: insight from the National Health and Nutrition Examination Survey III (NHANES-III). Circulation. 2014;130:546 53. S2.2-7. Martin SS, Blaha MJ, Elshazly MB, et al. Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol. 2013;62:732 9. S2.2-8. Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA. 2013;310:2061 8. S2.2-9. Sathiyakumar V, Park J, Golozar A, et al. Fasting versus nonfast- ing and low-density lipoprotein cholesterol accuracy. Circulation. 2018;137:10 9. S2.2-10. Nordestgaard BG, Langsted A, Mora S, et al. Fasting is not rou- tinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentra- tion cut-points a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J. 2016;37:1944 58. S2.2-11. Mora S, Rifai N, Buring JE, et al. Fasting compared with nonfast- ing lipids and apolipoproteins for predicting incident cardiovascular events. Circulation. 2008;118:993 1001. S2.2-12. Brunzell JD, Albers JJ, Chait A, et al. Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceride- mia. J Lipid Res. 1983;24:147 55. S2.2-13. Sniderman AD, Tremblay A, De Graaf J, et al. Phenotypes of hyper- triglyceridemia caused by excess very-low-density lipoprotein. J Clin Lipidol. 2012;6:427 33. 2.3. Measurements of Apolipoprotein B and Lipoprotein (a) S2.3-1. Sniderman AD, Williams K, Contois JH, et al. A meta-analysis of low- density lipoprotein cholesterol, non-high-density lipoprotein choles- terol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4:337 45. S2.3-2.


A meta-analysis of low- density lipoprotein cholesterol, non-high-density lipoprotein choles- terol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4:337 45. S2.3-2. Grundy SM, Vega GL, Tomassini JE, et al. Correlation of non-high- density lipoprotein cholesterol and low-density lipoprotein choles- terol with apolipoprotein B during simvastatin + fenofibrate therapy in patients with combined hyperlipidemia (a subanalysis of the SAFARI trial). Am J Cardiol. 2009;104:548 53. S2.3-3. Sniderman AD, Tremblay A, De Graaf J, et al. Phenotypes of hyper- triglyceridemia caused by excess very-low-density lipoprotein. J Clin Lipidol. 2012;6:427 33. S2.3-4. Grundy SM, Vega GL, Tomassini JE, et al. Comparisons of apoli- poprotein B levels estimated by immunoassay, nuclear magnetic resonance, vertical auto profile, and non-high-density lipoprotein cholesterol in subjects with hypertriglyceridemia (SAFARI Trial). Am J Cardiol. 2011;108:40 6. S2.3-5. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016;68:92 125. S2.3-6. Tsimikas S. A Test in Context: Lipoprotein(a): diagnosis, progno- sis, controversies, and emerging therapies. J Am Coll Cardiol. 2017;69:692 711. S2.3-7. Cook NR, Mora S, Ridker PM. Lipoprotein(a) and cardiovascular risk prediction among women. J Am Coll Cardiol. 2018;72:287 96. 2.4. Monitoring Response of LDL-C to Statin Therapy S2.4-1. Cholesterol Treatment Trialist s (CTT) CollaborationBaigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170000 participants in 26 randomised trials. Lancet. 2010;376:1670 81. S2.4-2. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of ath- erogenic lipoproteins and the risk for cardiovascular events: a meta- analysis of statin trials.


Very low levels of ath- erogenic lipoproteins and the risk for cardiovascular events: a meta- analysis of statin trials. J Am Coll Cardiol. 2014;64:485 94. 3. THERAPEUTIC MODALITIES 3.1. Lifestyle Therapies 3.1.1. Diet Composition, Weight Control, and Physical Activity S3.1.1-1. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S76 99. S3.1.1-2. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129:S102 38. S3.1.1-3. Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279 90. S3.1.1-4. Lichtenstein AH, Appel LJ, Brands M, et al. Summary of American Heart Association diet and lifestyle recommendations revision 2006. Arterioscler Thromb Vasc Biol. 2006;26:2186 91. S3.1.1-5. Warburton DE, Charlesworth S, Ivey A, et al. A systematic review of the evidence for Canada s physical activity guidelines for adults. Int J Behav Nutr Phys Act. 2010;7:39. 3.1.2. Lifestyle Therapies and Metabolic Syndrome S3.1.2-1. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol. 2007;49:403 14. S3.1.2-2. Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36:2996 3003. S3.1.2-3. Alberti KG, Eckel RH, Grundy SM, et al.


2015;36:2996 3003. S3.1.2-3. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640 5. S3.1.2-4. Grundy SM. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab. 2007;92:399 404. S3.1.2-5. Aguilar M, Bhuket T, Torres S, et al. Prevalence of the metabolic syn- drome in the United States, 2003 2012 JAMA. 2015;313:1973 4. 3.2. Lipid-Lowering Drugs S3.2-1. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardio- vascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292 333. 3.2.1. Statin Therapy S3.2.1-1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce ath- erosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1 45. S3.2.1-2. Karlson BW, Wiklund O, Palmer MK, et al. Variability of low-density lipoprotein cholesterol response with different doses of atorvas- tatin, rosuvastatin, and simvastatin: results from VOYAGER. Eur Heart J Cardiovasc Pharmacother. 2016;2:212 7. S3.2.1-3. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorv- astatin vs usual-dose simvastatin for secondary prevention after CLINICAL STATEMENTS AND GUIDELINES myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437 45. S3.2.1-4. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. Available at: https://www.accessdata.fda.gov/scripts/ cder/daf/ Accessed January 8, 2018. S3.2.1-5. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive pro- tein. N Engl J Med. 2008;359:2195 207. S3.2.1-6.


Rosuvastatin to prevent vascular events in men and women with elevated C-reactive pro- tein. N Engl J Med. 2008;359:2195 207. S3.2.1-6. Randomised trial of cholesterol lowering in 4444 patients with coro- nary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383 9. S3.2.1-7. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cho- lesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615 22. S3.2.1-8. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investiga- tors. N Engl J Med. 1996;335:1001 9. S3.2.1-9. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301 7. S3.2.1-10. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349 57. S3.2.1-11. MRC/BHF Heart Protection Study of antioxidant vitamin supple- mentation in 20536 high-risk individuals: a randomised placebo- controlled trial. Lancet. 2002;360:23 33. S3.2.1-12. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549 59. S3.2.1-13. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus mod- erate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495 504. S3.2.1-14. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425 35. S3.2.1-15. Nakamura H, Arakawa K, Itakura H, et al.


2005;352:1425 35. S3.2.1-15. Nakamura H, Arakawa K, Itakura H, et al. Primary prevention of car- diovascular disease with pravastatin in Japan (MEGA Study): a pro- spective randomised controlled trial. Lancet. 2006;368:1155 63. S3.2.1-16. Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in inter- mediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374:2021 31. S3.2.1-17. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170000 participants in 26 randomised trials. Lancet. 2010;376:1670 81. S3.2.1-18. Naito R, Miyauchi K, Daida H. Racial differences in the cholesterol- lowering effect of statin. J Atheroscler Thromb. 2017;24:19 25. S3.2.1-19. Collins R, Reith C, Emberson J, et al. Interpretation of the evi- dence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532 61. S3.2.1-20. American College of Cardiology. American College of Cardiology LDL-C Manager. Available at: http://tools.acc.org/ldl. Accessed January 8, 2018. 3.2.2. Nonstatin Therapies S3.2.2-1. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387 97. S3.2.2-2. Kashani A, Sallam T, Bheemreddy S, et al. Review of side-effect profile of combination ezetimibe and statin therapy in randomized clinical trials. Am J Cardiol. 2008;101:1606 13. S3.2.2-3. Khan AR, Bavishi C, Riaz H, et al. Increased risk of adverse neu- rocognitive outcomes with proprotein convertase subtilisin-kexin type 9 inhibitors. Circ Cardiovasc Qual Outcomes. 2017;10: e003153. S3.2.2-4. Robinson JG, Rosenson RS, Farnier M, et al. Safety of very low low- density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials. J Am Coll Cardiol. 2017;69:471 82. S3.2.2-5. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clini- cal outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713 22. S3.2.2-6.


Evolocumab and clini- cal outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713 22. S3.2.2-6. Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a ran- domized trial of evolocumab. N Engl J Med. 2017;377:633 43. 3.2.3. Nonstatin Add-on Drugs to Statin Therapy S3.2.3-1. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372:2387 97. S3.2.3-2. Jacobson TA, Ito MK, Maki KC, et al. National lipid association rec- ommendations for patient-centered management of dyslipidemia: part 1 full report. J Clin Lipidol. 2015;9:129 69. S3.2.3-3. Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of ali- rocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36:1186 94. S3.2.3-4. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500 9. 4. PATIENT MANAGEMENT GROUPS 4.1. Secondary ASCVD Prevention S4.1-1. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549 59. S4.1-2. Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus usual care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;18:220 8. S4.1-3. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170000 participants in 26 randomised trials. Lancet. 2010;376:1670 81. S4.1-4. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532 61. S4.1-5.


Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532 61. S4.1-5. Group HPSC. Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular out- comes in 20536 people with peripheral arterial disease and other high-risk conditions. J Vasc Surg. 2007;45:645 54.; discussion 53 4. S4.1-6. Randomised trial of cholesterol lowering in 4444 patients with coro- nary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383 9. S4.1-7. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investiga- tors. N Engl J Med. 1996;335:1001 9. S4.1-8. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349 57. S4.1-9. Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med. 1997;336:153 62. S4.1-10. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:23 33. S4.1-11. Knopp RH, d Emden M, Smilde JG, et al. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in sub- jects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabe- tes mellitus (ASPEN). Diabetes Care. 2006;29:1478 85. S4.1-12. Koren MJ, Hunninghake DB. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid- lowering disease management clinics: the alliance study. J Am Coll Cardiol. 2004;44:1772 9. S4.1-13. Serruys PW, de Feyter P, Macaya C, et al.


S4.1-13. Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for pre- vention of cardiac events following successful first percutane- ous coronary intervention: a randomized controlled trial. Jama. 2002;287:3215 22. CLINICAL STATEMENTS AND GUIDELINES S4.1-14. Bohula EA, Morrow DA, Giugliano RP, et al. Atherothrombotic risk stratification and ezetimibe for secondary prevention. J Am Coll Cardiol. 2017;69:911 21. S4.1-15. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387 97. S4.1-16. Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a ran- domized trial of evolocumab. N Engl J Med. 2017;377:633 43. S4.1-17. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clini- cal outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713 22. S4.1-18. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovas- cular outcomes after acute coronary syndrome. N Engl J Med. 2018. In press. S4.1-19. Wilson PWF, Polonsky TS, Miedema MD, et al. Systematic review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/ NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1144 61. DOI: 10.1161/CIR.0000000000000626. S4.1-20. Hlatky MA, Kazi DS. PCSK9 inhibitors: economics and policy. J Am Coll Cardiol. 2017;70:2677 87. S4.1-21. Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhi bitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA. 2016;316:743 53. S4.1-22. Gandra SR, Villa G, Fonarow GC, et al. Cost-effectiveness of LDL-C lowering with evolocumab in patients with high cardiovascular risk in the United States. Clin Cardiol. 2016;39:313 20. S4.1-23. Bellosta S, Corsini A. Statin drug interactions and related adverse reactions. Expert Opin Drug Saf. 2012;11:933 46. S4.1-24.