Treatment of dyslipidemia is a cornerstone of preventive cardiology, and reduction in low-density lipoprotein (LDL-C) in select populations reduces risk of atherosclerotic cardiovascular disease (ASCVD) events in both primary and secondary prevention.^1,2 The wealth of evidence for LDL-lowering to prevent ASCVD has been synthesized in a variety of dyslipidemia guidelines. Tiberwala et al.³ recently published a comparative analysis of the following five current major lipid treatment guidelines: 2014 American College of Cardiology/American Health Association (ACC/AHA),⁴ 2016 Canadian Cardiovascular Society (CCS),⁵ 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS),⁶ 2016 US Preventive Services Task Force (USPSTF),^7,8 and the 2014 U.S. Veterans Affairs/Department of Defense (VA-DoD).⁹ Examining differences between dyslipidemia guidelines can help identify areas requiring further research and also potential opportunities for harmonization of guidelines.

Estimating Risk

Perhaps one of the most widely reported differences among the above guidelines is their use of different risk estimators (Table 1). ACC/AHA and USPSTF recommend the ACC/AHA Pooled Cohort Risk Equations (PCRE), CCS recommends the Framingham Risk Score (FRS), VA-DoD recommends either PCRE or FRS and ESC/EAS recommends the Systemic Coronary Risk Evaluation (SCORE) estimator. Risk estimators all include age, sex, total cholesterol, HDL cholesterol and systolic blood pressure, but vary on whether they include ethnicity, treatment for hypertension or diabetes. This is a consequence of the choice of target endpoints by expert committees behind the respective guidelines, with some committees including only fatal events in risk estimation (ESC/EAS), while others choosing to include secondary endpoints indirectly linked to atherosclerotic disease (like heart failure) (CCS).

Table 1: Differences Between Risk Estimators

	ACC/AHA Pooled Cohort Equation	Framingham Risk Score	Systemic Coronary Risk Evaluation
Predictors in addition to age, sex, total cholesterol, high density lipoprotein cholesterol and systolic blood pressure	Race, treatment for hypertension, diabetes and smoking status	Treatment for hypertension, diabetes and smoking status	Smoking status
Outcomes: 10-year risk	First hard atherosclerotic cardiovascular disease event (coronary heart disease death, nonfatal myocardial infarction or stroke)	Coronary heart disease, cerebrovascular events, peripheral artery disease and heart failure	First fatal atherosclerotic event (myocardial infarction, stroke, other occlusive arterial disease or sudden cardiac death)

Differences in target outcome selection are offset to a degree by a subsequent variability in the choice of threshold to start therapy by the major guidelines. This suggests an underlying intent among the guideline committees to treat a similar higher risk patient population. Indeed, in a 2016 comparative analysis, ACC/AHA and ESC/EAS guidelines were shown to recommend statin treatment in 44% and 39% of a US population and 50% and 48% in a Polish population of adults age 40 to 65 for primary prevention.¹⁰ However, this high level of agreement does not extend to all populations.^11,12

Furthermore, use of secondary markers in patients with intermediate cardiovascular risk is an area of contention, with notable discordance between established guidelines and global practices. The AHA/ACC and CCS guidelines support coronary artery calcium (CAC) scoring for asymptomatic, intermediate risk middle-aged adults for whom treatment decisions are uncertain. ESC/EAS acknowledges that CAC has the best reclassification ability of currently validated secondary markers of cardiovascular disease; however, it offers no specific practice guidelines. Finally, USPSTF and VA-DoD state there is insufficient evidence to guide its incorporation into routine clinical practice.

Compelling evidence shows that absence of CAC on computerized tomography may reclassify approximately one-half of candidates previously deemed eligible for statin therapy.¹³ Such individuals may choose to focus initially on lifestyle modification and avoid costs and potential adverse effects of pharmacotherapy. Given that incorporating CAC results into shared decision making for intermediate risk patients has the potential to change management, the heterogeneity seen across guidelines may have significant implications for broader practice patterns.

Treatment Recommendations for Primary and Secondary Prevention

Another contentious issue among different guideline committees that goes beyond risk estimation is the approach to treatment of moderate- to high-risk patients. Although all guidelines unanimously emphasize lifestyle changes as a first line intervention and agree that statin therapy is a mainstay for patients deemed to require lipid-lowering medications, dosing and titration of statin medications differ significantly (Table 2). CCS and ESC/EAS use treat-to-target goals for LDL-reduction whereas ACC/AHA, USPSTF and VA-DoD focus on statin "intensity" (ACC/AHA) or "dose" (USPSTF, VA-DoD) depending on the patient's characteristics.

Table 2: Guideline Statin Recommendations

	ACC/AHA	CCS	ESC/EAS	USPSTF	VA-DoD
Primary prevention (all low density lipoprotein cholesterol (LDL-C) in mg/dl, with 10-year atherosclerotic cardiovascular disease event risk)
Threshold to recommend treatment	a) Age 40-75: if risk ≥ 7.5% b) Age ≥ 21: if LDL-C ≥ 190	a) Age 40-75: if risk ≥ 20% b) Any age and LDL-C ≥ 193	a) Age 40-65: if risk 5-10% and  LDL-C ≥ 100 b) Risk ≥ 10% and LDL-C ≥ 70	Age 40-75: risk ≥ 10% and one other atherosclerotic cardiovascular disease risk factor	a) Men age > 35 and women age > 45 with risk ≥ 12%  b) LDL-C > 190
Recommended treatment in addition to lifestyle	a) Risk ≥ 7.5%: moderate or high intensity b) Risk > 5% but  < 7.5%: moderate intensity	Target ≥ 50% reduction or LDL-C < 77	Maximally tolerated statin dose to achieve target treatment goal	a) Risk > 10%: low-moderate dose b) Risk 7.5-10%: low-moderate dose for select patients	a) Risk > 12%: moderate-dose statin b) Risk 6-12%: moderate for select patients
Secondary Prevention (Patients with Clinical ASCVD)
Recommended treatment in addition to lifestyle	a) Age ≤ 75: high-intensity statin b) If age > 75, contraindications or safety concerns: moderate-intensity statin	a) Target LDL-C < 77 or ≥ 50% reduction b) If LDL-C ≥ 193, reduce by ≥ 50%	Maximally tolerated statin dose to achieve target treatment goal	Not covered	Generally moderate dose, but high dose if ACS, multiple uncontrolled risk factors or recurrent cardiovascular events

Although ACC/AHA retains the recommendation to further titrate statin dosing to achieve a certain percentage in LDL-C reduction, the other US-based guideline committees do not have a specific recommendation for statin titration. They instead suggest the use of low or at most moderate intensity statin therapy for most individuals at risk. This approach not only creates confusion among clinicians in terms of monitoring patients on treatment,¹⁴ but also inevitably leaves a group of patients with suboptimal LDL-C control despite being at high risk of ASCVD and treated with the recommended statin. In light of multiple new trials showing efficacy of non-statins LDL-lowering therapies (in particular, PCSK9 inhibitors and ezetimibe) in achieving better cardiovascular outcomes in statin-treated patients,^15-17 all the above treatment approaches, and especially those that do not account for the need of medication titration, are now outdated and in urgent need for revision. In the meantime, the more recent ACC non-statin recommendations clarify intensification of therapy according to risk groups and on-treatment LDL-C.¹⁸

Treatment in Special Groups and Safety Profile

Guidelines differ in their recommendations for starting and continuing statin therapy for patients older than age 75 or those with life expectancy less than 5 years. ESC/EAS is most aggressive in these populations, recommending initiation of low dose statin therapy for primary prevention if ASCVD is particularly high, whereas ACC/AHA recommends statin usage in elderly primary prevention patients only if the patient is already tolerating statins and a moderate-intensity statin for secondary prevention. Most guidelines do not comment specifically on ESRD; however, VA-DoD advises clinician-patient risk discussion prior to initiating statin whereas CCS recommends against initiating statin therapy in these patients but to continue statins in those on therapy prior to initiating dialysis.

ACC/AHA and ESC/EAS note in patients with solid organ transplant, HIV, rheumatologic and inflammatory diseases to use clinical judgment as they likely have actual cardiovascular risk greater than predicted by risk estimators and to take into account drug-drug interactions. Major society guidelines seem especially inconsistent in these populations, as there exist less data from which to guide safety and treatment decisions. Given that these patients make up a considerable population of patients globally, this is an issue of investigative importance and the need for concordance among societies becomes increasingly relevant.

Towards Unified Guidelines for Atherosclerosis

Overall, the presence of multiple guidelines for the prevention of atherosclerotic disease underscores the importance of the subject from a clinical and public health perspective and also highlights the rapidly changing landscape of the evidence behind lipid management. It is clear that the various lipid prevention guidelines share more similarities than differences but differ in certain details that are vital for selection of treatment strategies. Perhaps genomic and lifestyle variation among populations from different continents, and differences in resources, may provide justification for differential preventive care. However, recent multicenter trials that did not show a significant interaction between different geographic populations and the benefit of cholesterol treatment.^15-17 Furthermore, there is little justification for the presence of three different conflicting guidelines in the United States. Since the preponderance of evidence from new large randomized trials in ASCVD clearly supports the paradigm "lower is better with proven therapies" for cholesterol management and begs for revision of all major guidelines, this should be seen as an excellent opportunity for harmonization between guideline recommendations from different societies to eliminate confusion among clinicians and allow for more efficacious patient-centered treatment.¹⁹

References

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 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986;256:2823-8.
2. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
3. Tibrewala A, Jivan A, Oetgen WJ, Stone NJ. A comparative analysis of current lipid treatment guidelines: nothing stands still. J Am Coll Cardiol 2018;71:794-9.
4. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
5. Anderson TJ, Gregoire J, Pearson GJ, et al. 2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2016;32:1263-82.
6. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2016;37:2999-3058.
7. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, et al. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force recommendation statement. JAMA 2016;316:1997-2007.
8. Chou R, Dana T, Blazina I, Daeges M, Jeanne TL. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA 2016;316:2008-24.
9. Downs JR, O'Malley PG. Management of dyslipidemia for cardiovascular disease risk reduction: synopsis of the 2014 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guideline. Ann Intern Med 2015;163:291-7.
10. Lee JC, Zdrojewski T, Pencina MJ, et al. Population effect of differences in cholesterol guidelines in Eastern Europe and the United States. JAMA Cardiol 2016;1:700-7.
11. Mortensen MB, Nordestgaard BG. Comparison of five major guidelines for statin use in primary prevention in a contemporary general population. Ann Intern Med 2018;168:85-92.
12. Mortensen MB, Nordestgaard BG, Afzal S, Falk E. ACC/AHA guidelines superior to ESC/EAS guidelines for primary prevention with statins in non-diabetic Europeans: the Copenhagen General Population Study. Eur Heart J 2017;38:586-94.
13. Nasir K, Bittencourt MS, Blaha MJ, et al. Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2015;66:1657-68.
14. Virani SS, Pokharel Y, Steinberg L, et al. Provider understanding of the 2013 ACC/AHA cholesterol guideline. J Clin Lipidol 2016;10:497-504.
15. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
16. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014;168:682-9.
17. 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.
18. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 focused update of the 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 expert consensus decision pathways. J Am Coll Cardiol 2017;70:1785-1822.
19. Bennet CS, Dahagam CR, Virani SS, et al. Lipid management guidelines from the Departments of Veteran Affairs and Defense: a critique. Am J Med 2016;129:906-12.

Keywords: Dyslipidemias, Aged, Arthritis, Rheumatoid, Atherosclerosis, Blood Pressure, Cardiovascular Diseases, Cholesterol, Cholesterol, HDL, Cohort Studies, Coronary Vessels, Diabetes Mellitus, Drug Interactions, Genomics, Heart Failure, HIV Infections, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Kidney Failure, Chronic, Life Expectancy, Life Style, Lipoproteins, LDL, Primary Prevention, Renal Dialysis, Risk Factors, Secondary Prevention, Tomography, Veterans

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