Review of the Guidelines for the Management of LDL-Related ASCVD Risk

Low-density lipoprotein (LDL) plays an important etiologic role in the initiation and progression of atherosclerotic cardiovascular disease (ASCVD). Lowering LDL by medications, diet, or partial ileal bypass surgery have been shown to improve ASCVD risk factors and may reduce the risk of myocardial infarction, stroke, and coronary heart disease (CHD) death. However, despite clear evidence of benefit, there are still inadequate numbers of patients on appropriate lipid-lowering therapy resulting in significant gaps in care for management of LDL-related ASCVD risk. Though there may be multiple factors contributing to suboptimal lipid management, the authors of this article propose that confusion regarding implementation of the numerous and sometimes discordant clinical practice guidelines may contribute to gaps in care.1 There are important differences among the guidelines in the process and methodology for formulation of recommendations, inclusion or exclusion of expert opinion and evidence from large randomized clinical trials and meta-analyses, methodology for grading the strength and level of evidence, recommended risk assessment tools, specific lipoprotein targets of therapy, and consideration of special patient populations.

The International Atherosclerosis Society (IAS), European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS), Canadian Cardiovascular Society (CCS), the American Association of Clinical Endocrinologists (AACE), and the American College of Cardiology (ACC)/American Heart Association (AHA) have all published recommendations for lipid therapy with broad applicability in large populations worldwide.2-6 All share a common emphasis on ASCVD risk assessment to target therapy to those patients at greatest risk. However, the recommended algorithms and the priority of prediction of 10-year versus lifetime risk of ASCVD events differ significantly among these guidelines. The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults introduced a new risk assessment tool, the CV Risk Calculator, based on equations derived from large, diverse, community-based cohorts of non-Hispanic whites and non-Hispanic blacks in the United States.  This algorithm predicts the 10-year risk of first hard ASCVD event (nonfatal myocardial infarction, coronary heart disease death, fatal, or nonfatal stroke). Similarly, the CCS guidelines recommend calculation of 10-year risk of total ASCVD events, but the suggested risk assessment tool is the Framingham risk calculator or the modified Framingham risk score.  The ESC/EAS guidelines also focus on 10-year risk, but the estimation by the SCORE system predicts only fatal ASCVD events (first fatal heart attack, stroke, fatal occlusive arterial disease, or sudden cardiac death). The AACE recommends either the original Framingham risk score for the prediction of 10-year risk of CHD event (myocardial infarction or coronary heart disease death) or the Reynolds Risk Score which predicts 10-year risk of MI, ischemic stroke, coronary revascularization, and cardiovascular death. The IAS guidelines assign priority to lifetime risk of total ASCVD morbidity and mortality assessed by one of four tools, rather than 10-year risk, as experts consider this to be the purpose of primary prevention.  The new ACC/AHA CV Risk Calculator also provides an estimation of lifetime or 30-year risk of first hard ASCVD event, but this algorithm has been validated only for individuals ages 20-59.

Probably the most substantive differences among published guidelines are recommendations regarding the specific lipoprotein target of interest and lipoprotein goals of therapy. The IAS favors non-high-density lipoprotein cholesterol (HDL-C) as the target of lipid-lowering therapy and considers it to be more reflective of atherogenicity in the presence of hypertriglyceridemia. Optimal levels of atherogenic lipoproteins are defined, but the potency of therapy is based on the provider’s clinical judgment. The ESC/EAS guidelines recommend LDL-C as the primary target of therapy and LDL-C goals are similar to those of the NCEP ATP III guidelines. LDL-C is also the primary treatment target in the CCS guidelines, but non-HDL-C and apolipoprotein B (apoB) are considered to have strong evidence as alternative treatment targets for optimal risk reduction. Treatment goals are identified for all three measures. Like the IAS, the AACE experts favor non-HDL-C as the treatment target, particularly in the presence of elevated triglycerides and specify goals of therapy. ApoB is recommended to assess the success of lowering the number of LDL particles. The 2013 ACC/AHA guidelines recommend a novel strategy for the management of LDL-related ASCVD risk. The panel identifies four groups of patients with strong evidence of benefit of statin therapy for prevention of ASCVD and then recommends a specific intensity of statin therapy for each group. No recommendations for or against specific targets or treatment goals (LDL-C or non-HDL-C) are proposed due to what the experts consider to be insufficient evidence.

Adding to the confusion for management of LDL-related risk is the multitude of published guidelines for special populations such as children, older adults >75 years, women, and patients with cardiometabolic risk, diabetes, chronic kidney disease, and familial hypercholesterolemia, among others.7-13 Clearly the number of guidelines and the substantive differences in recommendations may contribute to confusion among providers and lead to non-optimal management of at-risk patients. Effective strategies are needed to assist clinicians in the selection and implementation of evidence-based guidelines and for patients to improve compliance with proven preventive lipid-lowering therapy. We recommend that professional societies work more closely together in the future to develop guidelines that are based on unified principles of treatment for reduction of ASCVD risk, utilizing evidence from large randomized clinical trials as well as other types of research that inform health care professionals regarding mechanisms of atherogenesis.


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  7. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: summary report. Pediatrics 2011;128 Suppl 5:S213-56.
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  9. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. Circulation 2011;123:1243-62.
  10. Brunzell JD, DavidsonM, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement fromthe American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care 2008;31:811-22.
  11. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care 2014;37 Suppl 1:S14-80.
  12. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011;5 Suppl 3:S1-8.
  13. Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Int Suppl 2013;3:259-305.

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