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Appraisal of the National Lipid Association recommendations on cholesterol management
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In the past year, we have observed a major shift in thinking about the management of dyslipidemia, which was exemplified by the release of the 2013 American College of Cardiology/American Heart Association cholesterol treatment guideline.
The guideline defines four “statin-benefit groups” and focuses on statin doses rather than cholesterol level targets. Its implementation has the potential to make many more patients eligible for statin use for primary prevention after a detailed clinician-patient discussion.
Critiques have focused on the use of only randomized clinical trial evidence in guideline development; shortcomings in the Pooled Cohort Risk Equations; a focus on statins as the only proven pharmacotherapy; and the elimination of target LDL and non-HDL levels.
Subsequently, the National Lipid Association convened an expert panel to review all of the available evidence and provide an alternative set of recommendations for the management of dyslipidemia, with the notable consideration of both randomized clinical trials and observational data. The National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia (hereinafter referred to as “the NLA recommendations”) are the subject of this editorial.
Risk assessment, classification
The NLA recommends that all patients with atherosclerotic CVD (ASCVD) have a lipoprotein profile at or shortly after diagnosis and, like the 2013 ACC/AHA guideline, all adults aged 20 years and older in the primary prevention setting have a lipoprotein profile at least every 5 years.
Matthew J. Czarny
The risk-assessment algorithm then begins with identification of those at “very high risk,” including patients with clinical ASCVD (defined as a history of ACS, arterial revascularization, transient ischemic attack or stroke, atherosclerotic peripheral artery disease) and those with diabetes plus two or more ASCVD risk factors or end-organ complications of diabetes (urine albumin/creatinine ratio ≥30 mg/g, chronic kidney disease or retinopathy).
“High-risk” patients are defined as those with three or more major ASCVD risk factors, diabetes plus one major ASCVD risk factor and no end-organ damage, stage 3B or 4 CKD or LDL ≥190 mg/dL.
Seth S. Martin
“Moderate-risk” patients are defined as those with two major ASCVD risk factors (approximate 10-year ASCVD risk 5% to <15%).
“Low-risk” patients are defined as those with one or no major ASCVD risk factors.
However, the risk of all patients in the moderate-risk category can be further refined through the use of quantitative risk scoring or other “risk indicators,” which will allow some patients to be reclassified to high risk. In addition, low-risk patients should be assessed for any risk indicators that may elevate their risk to moderate or high. Of note, there is no mention of use of quantitative risk scoring or risk indicators to lower an individual’s risk estimate.
Roger S. Blumenthal
The NLA guidelines do not recommend any one particular quantitative risk-scoring system, but suggest that a high-risk classification should be given to those with a 2001 Adult Treatment Panel III Framingham risk score of at least 10%, a 2013 Pooled Cohort Equation 10-year risk of at least 15% (unlike the >7.5% threshold for the 2013 ACC/AHA guidelines) or a Framingham long-term CVD risk of at least 45%. Other risk indicators that may be considered to further refine the risk classification of patients at low or moderate risk by risk factor counting may include a major ASCVD risk factor present to a severe degree (eg, a strong family history), coronary artery calcium (CAC) score of at least 300 Agatston units, LDL ≥160 mg/dL or non-HDL ≥190 mg/dL or high-sensitivity C-reactive protein ≥2 mg/dL. Patients at moderate risk by the major risk factors who have one or more of these indicators could be classified as high risk.
Targets of therapy
The NLA recommends that patients in the very–high-risk group have the most aggressive treatment goals, which are non-HDL <100 mg/dL and LDL <70 mg/dL, with an optional goal of apolipoprotein B <80 mg/dL. The treatment goals for low-, moderate-, and high-risk patients are non-HDL <130 mg/dL and LDL <100 mg/dL, with an optional goal of ApoB <90 mg/dL.
The NLA panel concluded that non-HDL is a better primary goal than LDL because it represents all atherogenic particles and more strongly predicts adverse outcomes. Therefore, they recommend using non-HDL as the primary target; if this target has been reached and LDL is above goal, further therapy should aim to get LDL to the target. ApoB can be considered a secondary goal once the non-HDL target has been reached because it generally is a marker of residual on-treatment risk.
Lipid-lowering therapies
The NLA recommends lifestyle interventions without pharmacotherapy as the initial treatment for low-to-moderate ASCVD risk patients with a lipid profile not at goal. These include a diet low in saturated fat, at least moderate physical activity, weight loss for those with BMI ≥25 kg/m2 and smoking cessation if needed. Referral to nutrition and exercise specialists also is encouraged to increase the likelihood of achieving meaningful change. Patients should be re-evaluated with a clinic visit and a lipid profile at least 3 months after the initiation of lifestyle interventions to determine progress toward goals. Patients who have not reached goals should be considered for “dietary adjuncts,” including plant sterols and fiber supplementation, and the lifestyle interventions should be reinforced.
Patients who have reached their lipid profile goals by the third office visit should be followed at 6- to 12-month intervals. For those who have not reached their goals, drug therapy should be considered. Furthermore, patients at high to very high risk for ASCVD could initiate drug therapy at even the first visit, simultaneous with the initiation of lifestyle interventions. The NLA recommends that initiation of any drug therapy should be a decision that is highly individualized to each particular patient.
Statins are the recommended primary pharmacotherapy, and it is left to the patient and physician to determine whether to start with a high dose and maintain it, or down-titrate to the desired effect or start with a moderate dose and up-titrate. The exception to this “statin-first” rule is patients with triglycerides ≥500 mg/dL, for whom the primary goal is triglyceride lowering to prevent pancreatitis (consistent with the 2013 ACC/AHA guideline). For these patients, initial therapy should include a triglyceride-lowering drug such as a fibrate, long-chain omega-3 fatty acids or nicotinic acid. After initiation of pharmacotherapy, the lipid profile should be periodically monitored (every 4 to 12 months), and the statin regimen adjusted to reach the desired goal.
Several strategies can be considered for patients with intolerance to a statin, including a change to another statin, daily dose reduction or once- to three-times weekly dosing. Patients intolerant of statins despite these strategies, as well as patients not meeting lipid profile goals despite maximal statin therapy, should be considered for non-statin drug therapy. Although not specifically mentioned in the NLA guidelines, this would appear to be a reasonable place to include ezetimibe (Zetia, Merck) preferentially, based on the long-awaited positive results of the IMPROVE-IT trial.
Comparison to 2013 ACC/AHA guidelines
A cursory look at the 2013 ACC/AHA guidelines and the NLA recommendations reveals differences in their approaches to ASCVD risk stratification and risk management.
First, the NLA approach to risk stratification is based in classical risk-factor counting. Patients are assigned to risk groups ranging from low to very high, based on the presence of known ASCVD or the accumulation of risk factors for ASCVD. Quantitative risk estimations and newer risk indicators, including the CAC score, are used to refine risk classifications, particularly in the moderate-risk group.
The NLA guideline states that quantitative risk estimators tend to underestimate risk in the high- and very high-risk groups, and therefore have limited utility in those settings. Conversely, quantitative risk estimates and other risk indicators, including the CAC score, can be very helpful when trying to determine whether a moderate-risk patient has a 10-year ASCVD risk closer to 5% or to 15%. Such a differentiation can have a big impact on the patient–clinician discussion about risks and benefits of statin therapy.
In contrast, the ACC/AHA guideline focuses on the four statin-benefit groups, which are patients with clinical ASCVD, LDL ≥190 mg/dL, and an LDL of 70 mg/dL to 189 mg/dL with either diabetes or a 10-year ASCVD risk ≥7.5% by the 2013 Pooled Cohort Equations. These statin-benefit groups are those at high enough risk for ASCVD that pharmacological therapy with a moderate- or high-intensity statin should be considered. Although those with clinical ASCVD, LDL ≥190 mg/dL and diabetes would be classified into the high- or very high-risk groups by the NLA recommendations and thus be eligible for immediate statin therapy depending on their lipid profile in relation to their goals, the major difference between the two is in the management of the primary prevention cohort at moderate risk for ASCVD.
The ACC/AHA guideline includes significantly more patients in the moderate-risk group than the NLA recommendations, with a threshold of a 10-year ASCVD risk of at least 7.5% by the Pooled Cohort Equations. This is arguably the most controversial part of the guideline, excluding the focus on statin dose rather than lipid goals. There have been concerns that the Pooled Cohort Equations overestimate ASCVD risk by as much as double in certain groups, and that age dominates the risk in older populations, with most men older than 60 years and women older than 70 years having a 10-year risk of at least 7.5%. However, a recent analysis of the REGARDS study showed that the Pooled Cohort Equations were accurate in prediction of ASCVD risk in a community population eligible for, but not already on, statin therapy.
In contrast, the NLA recommends a more traditional risk-factor counting approach, and in those at moderate risk by this measure, they suggest a Pooled Cohort Equations 10-year ASCVD risk threshold of at least 15% for classification as high risk. Patients at high risk are eligible to start statin therapy at the first clinical visit, whereas those at low and moderate risk should have a minimum of 6 months of lifestyle interventions before statin initiation. Therefore, the NLA recommendations result in a longer time to statin therapy as well as a lower likelihood of statin initiation as compared with the ACC/AHA guideline.
Reconciling differences
How can these seemingly large discrepancies be reconciled? An attractive solution is the Agatston CAC score. Patients at 7.5% to 15% 10-year risk for ASCVD are in a relatively heterogeneous group, and some separation of patients at lower risk and higher risk can be done with assessment of the risk indicators suggested by the NLA, such as a very strong family history of ASCVD or extraordinarily heavy smoking. However, in patients without such clear indicators, the CAC score can be exceedingly helpful. The absence of CAC defines a low-risk population, whereas a high CAC burden (CAC score >300) is associated with significant ASCVD event rate.
A recent study showed that a CAC score of at least 100 was associated with elevated ASCVD event rates regardless of the number of lipid abnormalities (22.7 to 29.5 per 1,000 person-years), whereas a CAC score of 0 was associated with low ASCVD event rates regardless of the burden of dyslipidemia (2.7 to 2.9 per 1,000 person-years). Of note, the NLA recommendations do not mention the use of the CAC score or any other risk indicators to reclassify patients to a lower-risk category, but rather only to a higher-risk category. Therefore, perhaps the use of a CAC score (costing about $75 to $100 out of pocket) could bring the two risk-assessment strategies into agreement for patients at moderate risk for ASCVD.
What is done with these risk assessments also differs markedly between the NLA recommendations and the ACC/AHA guideline. First, a notable similarity is that both recommend lifestyle interventions as first-line therapy, including aerobic exercise, a healthy diet, and weight loss and smoking cessation when applicable, although the ACC/AHA guideline does not recommend a specified time interval for these interventions before reassessment. The similarities end there, however.
The NLA recommendations focus on non-HDL and LDL goals, and the determination of the possible benefit of statin therapy relies on the patient’s non-HDL and LDL measurements in comparison to the goals. Patients at very high risk for ASCVD have a non-HDL goal <100 mg/dL and an LDL goal <70 mg/dL, whereas those in all other risk groups have goals of <130 mg/dL and <100 mg/dL, respectively, and medical therapy is titrated to achieve the goal. This strategy is based in the theory that ASCVD risk reduction is directly related to reduction in non-HDL levels, which is derived from both clinical trial and observational data.
The ACC/AHA guideline focus on statin intensity; all patients in one of the statin-benefit groups should be on a moderate- to high-intensity statin. In contrast to the NLA, this is rooted in the observation that all randomized controlled trials of statin therapy focused on comparison of a fixed-statin regimen with placebo or comparison of a higher- vs. lower-intensity statin regimen, rather than non-HDL goals. The ACC/AHA guideline emphasizes the proven benefits of statins; the NLA acknowledges the superiority of statin efficacy, but does not treat the statin as the therapeutic goal.
Finally, there is concern that the loss of non-HDL and LDL targets can lead to a loss of motivation for progress. Simply targeting a statin dose may lead some patients to feel that they have reached the goal by simply taking the statin, despite the encouragement and admonitions of their cardiologist to aggressively pursue the lifestyle modifications that are needed. The ACC/AHA guideline does recommend lipid profiles be followed to assess statin response and adherence, but does not set cholesterol goals.
In contrast, the NLA-recommended cholesterol goals allow patients to set a goal to be achieved by the combination of lifestyle interventions and pharmacologic therapy. There is something about knowing one’s numbers and the mere setting of goals that makes people want to achieve them, so removing cholesterol goals in favor of target statin doses may remove some of the impetus for lifestyle change. Both guidelines support the concept that lower is better with proven therapies and now ezetimibe seems to be a proven second-line agent on the basis of the results of IMPROVE-IT.
Conclusion
The NLA recommendations for ASCVD risk assessment and management offer a perspective that is much more reminiscent of the Adult Treatment Panel III than the 2013 ACC/AHA guideline. Major areas of departure from the ACC/AHA guideline include the integration of clinical trial and observational data; the focus on risk-factor counting in risk assessment; the 6-month trial of lifestyle interventions for those at low and moderate risk; and the emphasis on non-HDL and LDL goals rather than statin doses. The lack of a strong recommendation for statin use in moderate-risk patients with a 10-year ASCVD risk of 7.5% to 15% sheds light on this controversial target for drug therapy that may be clarified by the appropriate use of a CAC score to further refine risk.
In the end, both the NLA and ACC/AHA recommendations focus on patient-centered discussions by which an individualized plan of care can be formulated. We hope to see the expert writers of both guidelines come together in the future to produce a more unified approach that other countries will also follow.
References:
Goff DC Jr., et al. Circulation. 2014;129(25 Suppl 2):S49-73.
Jacobson TA, et al. J Clin Lipidol. 2014;8:473-488.
Martin SS, et al. Circulation. 2014;129:77-86.
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Pencina MJ, et al. N Engl J Med. 2014;370:1422-1431.
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Stone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-45.
Wenger NK, et al. J Am Coll Cardiol. 2014;64:2193-2195.
For more information:
Matthew J. Czarny, MD, and Seth S. Martin, MD, are clinical fellows at The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease. Martin also is a member of the Cardiology Today Fellows Advisory Board. Roger S. Blumenthal, MD, is director of the Ciccarone Center for the Prevention of Heart Disease and is the CHD and Prevention Section Editor of Cardiology Today.
Disclosures: The authors report no relevant financial disclosures.