Introduction:
The 2018 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Management of Blood Cholesterol and the recently published 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease are comprehensive updates to the 2013 lipid and prevention guidelines.^1-4 The new 2018/2019 guidelines build upon the existing risk assessment framework and reintroduce a low-density lipoprotein cholesterol (LDL-C) threshold for consideration of intensified lipid lowering therapy, encourage the addition of proven non-statin therapy, promote further consideration among special populations and those with risk-enhancing factors (REFs) and emphasize shared-decision making and heart-healthy lifestyle decisions.^1,2

The new guidelines continue to recommend statin therapy among four major groups of patients: 1) those with clinical ASCVD; 2) those with LDL-C ≥190mg/dL; 3) those with diabetes mellitus aged 40-75 years old with LDL-C ≥70 mg/dL; and 4) those without diabetes but with LDL-C ≥70 mg/dL and ≥7.5% 10-year ASCVD risk. The 2013 ASCVD Risk Estimator, which incorporates the 10-year pooled cohort equation (PCE), remains the foundational risk calculator, but there is now appropriate recognition that the estimate is really an educated guess and serves as the starting point for the clinician patient risk discussion. The 2018 ASCVD Risk Estimator Plus offers additional advice to the clinician once PCE risk estimates are calculated.1

This review is a follow-up to the Amin et al. 2014 critical appraisal of the 2013 guidelines in the Journal of the American College of Cardiology and highlights the key major updates and provides viewpoints on additional areas of focus for future guidelines.³ The 2014 review highlighted opportunities to improve risk assessment in diverse populations, those with family history of heart disease, special populations at risk for ASCVD due to unique clinical conditions and selective noninvasive assessment of subclinical atherosclerosis. Herein, we review progress beyond the 2013 guidelines, and underscore areas that merit further attention.

Threshold Directed Guidelines and Non-Statin Therapy:
The 2018 guideline re-introduces threshold recommendations for the consideration of additional lipid lowering therapy that were not included in the 2013 version.^4,5 The guideline reiterates that "the more LDL-C is reduced on statin therapy, the greater will be the subsequent risk reduction" echoing prior meta analyses showing that each reduction in LDL-C by 40 mg/dL with a proven lipid lowering agent is associated with roughly a 20-25% relative reduction ASCVD risk.^4-6

Since the release of 2013 guidelines, there have been several randomized controlled trials that evaluated the efficacy of non-statin lipid modifying agents and are now formally included in the new guidelines. The updated guidelines recommend the addition of ezetimibe if LDL-C remains ≥70 mg/DL in those on maximal statin therapy and, if needed, the addition of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for those with very high clinical ASCVD risk. Additionally, ezetimibe initially and then a PCKS9 inhibitor, if needed, should be considered for those with LDL ≥190 mg/dL who do not reach the threshold of 100mg/dL.¹

The first of these trials—IMPROVE-IT (Improved Reduction of outcomes: Vytorin Efficacy International Trial)—examined the use of ezetimibe and simvastatin versus simvastatin alone in patients hospitalized for acute coronary syndrome with baseline LDL-C levels from 50-100 mg/dL. The study showed reduction in primary composite outcome of cardiovascular death, coronary events, or non-fatal stroke by 1.8% over 7 years (HR: 0.9; 95% CI: 0.84-0.96).⁷ Although the net effect of improvement was relatively modest, the secondary and subgroup analyses indicate that those with the greatest absolute risk reduction, and most likely to benefit, are individuals who had a TIMI risk score of ≥3.⁷

Additionally, two major PCSK9 inhibitor studies have shown impressive reductions in LDL-C with improvement in ASCVD outcomes. The FOURIER study (Further Cardiovascular Outcomes Research with PCKS9 inhibition with Elevated Risk) showed a reduction in major cardiovascular events (cardiovascular death, MI, hospitalization for unstable angina, coronary revascularization or stroke) by 1.5% over roughly 2 years (HR: 0.8; 95% CI: 0.73-0.88) with evolocumab in those with chronic ischemic disease. The baseline median LDL-C was reduced by 59% to a median value of 30mg/dL.⁸ Of note, in subgroup analyses, those with peripheral arterial disease, multiple MIs within two years of randomization and multivessel moderate coronary atherosclerosis showed the greater absolute risk reduction in the primary outcome compared those with either myocardial infarction, stroke or polyvascular disease.

Similar results were observed in the ODYSSEY OUTCOMES (Evaluation of Cardiovascular outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) trial. In those treated with alirocumab, there was a reduction in primary outcome by 1.6% over 2.8 years in those with recent ACS (HR 0.86; 95% CI 0.70 – 0.93).⁹ There was also a 15% reduction in total mortality of borderline statistical significance.

The addition of therapeutic targets reflects current evidence and facilitates practical application in order to adequately treat those who need the greatest cholesterol reduction. The toolkit to reach those targets has also expanded to reflect the importance of non-statin therapies.

Performance in More Diverse and Modern Populations:
After its introduction, the 10-year pooled cohort equation (PCE) was criticized given concerns that ASCVD risk scores often significantly overestimated risk in some groups (Chinese/East-Asian Americans) and underestimated in other ethnic groups (Native Americans and South Asians).^3,10 The previous guideline had a Class I recommendation for global risk scoring in non-Hispanic blacks and white Americans (level of evidence B), but assigned a class IIB recommendation for other races (level of evidence C).⁴

While the PCE remains the same in the newest guideline, there are now special recommendations about Asian-Americans, Hispanic/Latino and blacks grouped into ASCVD issues, lipid issues, metabolic issues, pooled cohort equations, coronary artery calcium score and lifestyle issues by ethnicity.¹ These recommendations alert clinicians to additional risk beyond those represented in the PCE.

Of note, the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study highlights increased ASCVD risk in adults of South Asian origin and blacks partly related to increased rates of diabetes and possibly lipoprotein(a).¹¹ The MASALA study demonstrated a higher risk for coronary heart disease (CHD), which appears to be related to insulin resistance and premature beta cell failure in South Asian populations.¹²

The updated guideline also comments on the use of CAC score in different ethnic populations. The Multi-Ethnic Study of Atherosclerosis (MESA) showed that after risk adjustment for traditional risk factors, the amount of coronary calcification was highest among whites followed by Chinese (77% compared to whites; 95% CI 0.8 to 0.99), Hispanics (74%; 95% CI 61% to 90%) and blacks (69%; 95% CI 59 to 80%).^13,14 While blacks tend to have lower absolute CAC scores than Caucasians with comparable risk factor levels, their overall cardiovascular risks remain elevated.

The current guideline highlights the limitations of the PCE in certain patient groups and provides a framework to upward or downward reclassify an individual's risk as part of the patient-clinician risk discussion.

Family History:
Currently, only a few risk calculators—Reynolds, JBS3, QRISK2—include family history in quantifying a patient's cardiovascular risk.^15-17 A family history of premature coronary disease remains a well-established risk factor for future ASCVD with some data to suggest that family history of CVD in multiple first degree relatives may have similar relative risk increase comparable to that of smoking.¹⁶ The Cooper Center Longitudinal Study evaluated long term risk of family history of 49,255 men and showed that family history of premature ASCVD was associated with a 50% higher lifetime risk of ASCVD and mortality than those without, but only modestly associated with short-term risk.¹⁷

While the 2013 risk models recommended consideration of family history, they did not explicitly include family history into the risk calculator and limited the use of family history to patients in whom there is uncertainty in the risk based treatment decision.^3,10 The current guidelines do not incorporate family history into a quantifiable risk calculator but doe provide guidance on the increased risk those with family history of premature ASCVD may have.

Family history of premature ASCVD (males <55 years and females <65 years) has now been incorporated as a risk-enhancing characteristic of PCE recommendations to highlight a higher risk beyond initial PCE risk estimations. Among those with coronary artery calcium (CAC) score of 0 with family history of premature ASCVD, there is still a slightly higher relative risk of an event, which may influence the need for pharmacotherapy.¹⁸ Additionally, adolescent populations with family history of premature ASCVD may benefit from risk assessment and lipid screening.¹

Special Populations at Risk:
The 2013 guidelines did not include special populations at risk including inflammatory disorders such as lupus erythematous and rheumatoid arthritis, pre-eclampsia and chronic kidney disease.^3,4 While it would be impractical to add each condition into a risk adjusted calculator, the new guidelines make special note of these conditions as risk-enhancing factors. Risk-enhancing factors can be used in intermediate risk patients to upward reclassify estimated risk.

Two excluded populations remain in special consideration. Lipid-lowering therapies have not shown significant reduction in ASCVD with those with Stage 5 CKD, such as in SHARP (Study of Heart and Renal Protection),^19,20 and ischemic cardiomyopathy in CORONA (Crestor Versus Placebo in Subjects With Heart Failure) and GISSI-HF (Effects of n-3 PUFA and Rosuvastatin on Mortality-Morbidity of Patients With Symptomatic CHF) trials, especially with a life expectancy of less than 3 years.^21,22 Further studies are needed to understand the role of lipid lowering agents in these populations given their elevated risk for ASCVD.

The current research suggests that specific risk conditions should be considered in the context of shared-decision making to better individualize risk and guide the decision for pharmacotherapy.

Subclinical Atherosclerosis Assessment:
Coronary artery calcium (CAC) scoring improves risk stratification in coronary events and total ASCVD compared to global risk scoring independent of ethnicity as demonstrated in several population databases, including the Multi-Ethnic Study of Atherosclerosis (MESA). In MESA, individuals with no traditional risk factors and CAC >300 had an event rate 3.5 times higher than individuals with three or more risk factors and CAC of zero.^13,14

The prior guideline recommended upgrade in risk with CAC ≥300 or ≥75th percentile for age, sex and ethnicity as a Class IIb recommendation. This recommendation was criticized noting that a threshold of CAC score >300 was too high since significant event rates were seen in secondary populations in CAC score >100. The new guidelines recommend more firm recommendations with consideration of CAC scoring in intermediate risk individuals or those with "unclear" risk with a 10-year ASCVD risk of 7.5-20% (Class IIa) and now recommends cutoff of ≥100 as reasonable threshold to initiate statins. The updated guidelines also highlight examples of candidates who may benefit from CAC scoring including patients reluctant to take a statin, patients concerned about reinstitution of statin, older patients with low burden of risk factors and middle-aged adults with a borderline 10-year risk between 5-7.5%.¹

Since the prior guideline on risk assessment, CAC scoring has been shown to be a reliable tool for upward and downward reclassification of risk in a variety of populations. Its incorporation allows clinicians and patients to better understand personal risk and can help determine to withhold, initiate, or intensify pharmacotherapy.

The Young and the Very Elderly:
There remain several clinically unclear zones regarding screening and indication for lipid lowering therapy. Such is the case in the young and very elderly.

The previous guideline gave a modest Class IIb indication for screening of 30-year or lifetime ASCVD risk based on traditional factors for those aged 20 to 59 years.⁴ The new 2018 and 2019 guidelines add a recommendation to consider statin if there is a family history of premature ASCVD and persistently high LDL ≥160mg/dL.^1,2 In terms of those patients age <19 years, the guidelines now include acceptable, borderline and abnormal lipid values and make recommendations for early screening in those with family history of familial hypercholesterolemia or significant early family history of CVD.¹

The current guidelines suggest clinical assessment and risk discussion with patients over the age of 75 years for primary prevention. The Framingham Heart study illustrates that the cumulative CHD risk increases after age 60 and does not plateau until age 90.²³ Additionally, there has been emerging data to suggest that medical therapy for primary prevention in the elderly can be quite effective in reducing ASCVD risk.

In elderly patients, most recently the EWTOPIA 75 (Ezetimibe in Prevention of Cerebro- and Cardiovascular Events in Middle- to High-Risk, Elderly (75 Years Old or Over) Patients with Elevated LDL-Cholesterol) trial announced at AHA in 2018 suggested that the use of ezetimibe for primary prevention may reduce ASCVD events. The trial was conducted in Japan examining participants older than 75 years (mean age of 81 years) with LDL ≥140 mg/dL not already on statin therapy. Patients were randomized to dietary counseling or dietary counseling with ezetimibe. Five-year follow up showed a reduction in primary ASCVD events (HR = 0.659; 0.504-0.862).²⁴

Additional Areas of Focus in Future Lipid Guidelines:
There are several areas that deserve additional consideration: the role of metabolic syndrome, clarification of lifestyle modifiers and potential triglyceride threshold goals.

While the 2018 and 2019 guidelines make note of metabolic syndrome as a risk modifier, there needs to be special attention to adequately screen risk in younger patients in the setting of the rising obesity epidemic. In the United States, the prevalence of obesity has tripled in the last 50 years from 13% in 1960-1962 to 36.5% from 2011-2014.²⁵ Obese patients generally have LDL- cholesterol in the normal range but tend to have a more atherogenic profile with more elevated triglycerides and small dense LDL particles. Non-HDL-C or the Martin/Hopkins derived LDL-C is better associated with ASCVD risk in these individuals.²⁶

Additionally, specific target goals for lifestyle changes including diet and exercise need to be further explored going forward. While it is generally accepted that DASH and Mediterranean diets and regular exercise remain important for primary and secondary prevention, specific guidelines for these goals remain vague. For instance, the National Lipid Association guidelines and American College of Sports Medicine recommend more specific goals for physical activities such as 200-300 minutes/week of moderate intensity physical activity or >2000 kcal/week. Most studies seem to indicate that at least 1500-2000 kcal/week of physical activity is needed to modestly reduced LDL-C. Exercise has been shown to reduce inflammation markers including TNF-alpha, IL-1, IL-6, LDL susceptibility to oxidation, and endothelial dysfunction.^27-29

Finally, the role of triglycerides and their impact on cardiovascular disease will likely be an emerging area of interest. While the new guidelines are not specific about triglyceride target thresholds, they include nonfasting triglycerides ≥175 mg/dL as a risk-enhancing factor. The recently published REDUCE-IT trial (Reduction of Cardiovascular Events With EPA - Intervention Trial) demonstrated a 25% reduction in cardiovascular events in those receiving high dose icosapent ethyl compared to placebo group. This study included middle aged subjects with known cardiovascular disease and higher risk diabetes patients with elevated triglycerides.³⁰ The prior JELIS (Japan eicosapentaenoic acid [EPA] Lipid Intervention Study) study showed that a combination of statin and pure EPA reduced risk of ischemic events in a Japanese population.³¹

Targeted treatment of triglycerides in certain high-risk patients may be beneficial to reduce ASCVD risk, but further studies remain necessary. We await the FDA to decide if this proprietary type of pure EPA should get a broader indication for use based on this impressive trial.

Conclusion:
The updated guidelines build on the 10-year pooled ASCVD risk score introduced in the 2013 recommendations with further consideration of ethnically diverse populations, special populations at risk, more specific guidelines for subclinical atherosclerosis treatment and re-introduction of threshold goals especially for secondary prevention. Much of the concern voiced in response to the 2013 guidelines has been addressed, but new areas needed to explored including selective screening of young in the setting of rising obesity epidemic, primary prevention in the elderly, the role of triglyceride thresholds for pharmacologic therapy and more accurate risk estimators taking into account family history, special populations and ethnic differences. Ideally, the PCE-Plus might include a direct, clickable adjustment factors to enhance the risk prediction tool.

Most importantly, the new guidelines continue to emphasize shared-decision making between physicians and patients and emphasize that guidelines and risk estimation are meant to serve as a starting point for clinical decision making. As mentioned in our 2014 discussion, we continue to move in the right direction with the new guidelines, and it will be important to see how these guidelines are implemented in busy clinical practice.

Table 1: Concerns Raised in 2013 ACC/AHA Risk Assessment Guidelines Compared with Updated 2018 and 2019 Guidelines

	2013 Guidelines	2018 & 2019 Guidelines
Performance in More Diverse and Modern Populations	Pooled cohort equations limited to white or black populations.	The new guidelines group ethnic/racial risk factors by ASCVD, lipid, coronary artery calcium score and metabolic issues. They highlight potential for underestimation of risk in South Asians and overestimation in East Asians.
Exclusion of Family History in the Model	Family history was excluded in the 2013 risk models.	While family history is not part of the pooled cohort equation calculator, the new guidelines emphasize premature family history of ASCVD as an additional risk factor. The guidelines also recommend pediatric lipid screening in those with family history of early ASCVD.
Special Populations at Risk	There was limited mention of special populations at risk.	The new guidelines highlight multiple additional risk enhancers especially for those in borderline or intermediate risk category including metabolic syndrome, chronic kidney disease, chronic inflammatory conditions, history of premature menopause, pre-eclampsia and primary hypertriglyceridemia.
Inclusion of Stroke in Risk Score Outcome	The risk assessment guideline highlighted stroke among its important ASCVD outcomes but cautioned careful extrapolation of statin eligibility in this population given diverse etiology of stroke.	Unchanged in new guidelines.
High-Risk Threshold	The risk assessment utilized an intermediate risk category of 5-7.5% and high risk category of ≥7.5% for 10-year ASCVD risk factors. These thresholds were criticized because most patients will across the 7.5% threshold on the basis of age alone.	The new guidelines modify risk categories as low risk (<5%), borderline risk (5-7.5%), intermediate risk (7.5-20%) and high risk (≥ 20%) for further risk stratification.
Subclinical Atherosclerosis Assessment	The threshold of >300 CAC score was criticized as too high since this score is more consistent with advanced plaque.	The new guidelines recommend considering CAC ≥100 or ≥ 5th percentile as a threshold to consider statin therapy. Also, the guidelines state that in individuals with a CAC = 0, statin therapy could potentially be held.
10-years Versus Lifetime Risk	The guideline gives a modest recommendation for assessing lifetime ASCVD risk for younger adults not at increased 10-year risk, but it remained unclear if traditional risk factors will fully capture long term risk.	The new guidelines recognize changing dietary habits, higher rates of obesity/metabolic syndrome, potential importance of elevated triglycerides and residual inflammation as additional risk factors in younger populations. Further studies are needed to understand how to capture life time risk in these younger populations.

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Keywords: Dyslipidemias, Acute Coronary Syndrome, American Heart Association, Angina, Unstable, Antibodies, Monoclonal, Arthritis, Rheumatoid, Asian Americans, Atherosclerosis, Cardiomyopathies, Cardiovascular Diseases, Calcium, Cholesterol, LDL, Cohort Studies, Counseling, Coronary Artery Disease, Decision Making, Diet, Mediterranean, Diabetes Mellitus, Eicosapentaenoic Acid, Exercise, Fatty Acids, Omega-3, Goals, Follow-Up Studies, Heart Failure, Hispanic Americans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Hospitalization, Indians, North American, Hypertriglyceridemia, Inflammation, Insulin Resistance, Interleukin-6, Interleukin-1, Life Style, Lipoprotein(a), Longitudinal Studies, Metabolic Syndrome, Myocardial Infarction, Numbers Needed To Treat, Obesity, Outcome Assessment, Health Care, Peripheral Arterial Disease, Primary Prevention, Pre-Eclampsia, Random Allocation, Reference Values, Renal Insufficiency, Chronic, Risk Adjustment, Risk Assessment, Risk Factors, Risk Reduction Behavior, Secondary Prevention, Simvastatin, Smoking, Stroke, Subtilisins, Triglycerides, Tumor Necrosis Factors

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