Lipid Management Guidelines 

Updated: Dec 30, 2015
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Risk Algorithms

The guidelines that cover the screening of patients for elevated serum lipid levels, and the treatment of patients with lipid abnormalities, rest on calculations of individual patients’ risk for a future cardiovascular event. Broadly, risk factors are arbitrarily divided into three major categories: nonmodifiable, modifiable, and emerging. See Table 1, below.

Table 1. Basic Categories of Risk Factors for Future Cardiovascular Events (Open Table in a new window)

Category Risk Factors
Nonmodifiable risk factors Age, sex, family history, genetic predisposition
Modifiable risk factors Smoking, atherogenic diet, alcohol intake, physical activity, dyslipidemias, hypertension, obesity, diabetes, metabolic syndrome
Emerging risk factors Elevation in C-reactive protein (CRP); fibrinogen; coronary artery calcification (CAC); homocysteine; lipoprotein(a); small, dense LDL

An elevated total cholesterol or low density lipoprotein (LDL) cholesterol level and/or a reduced high density lipoprotein (HDL) cholesterol level are traditional risk factors for cardiovascular disease (CVD); when cholesterol elevations occur in combination with other risk factors, a much higher risk for CVD is predicted. Risk algorithms include lipid levels with some combination of the following other traditional risk factors:

  • Age
  • Gender
  • Family history of premature coronary heart disease (CHD; ie, in a first-degree male relative <55 y or female relative <65 y)
  • Smoking
  • Hypertension
  • Diabetes mellitus
  • Obesity
  • Sedentary lifestyle

The most commonly used risk algorithms developed with United States population cohorts include the following:

arteriosclerotic cardiovascular disease risk estimator (AC/AHA-ASCVD)

Commonly used risk algorithms developed with European population cohorts include the following:

  • Systematic Coronary Risk Evaluation (SCORE)
  • QRisk2

Framingham Risk Score

The Framingham Risk Score (FRS) was developed in 1998 to assess the 10-year risk of coronary heart disease (CHD) for individuals with different combinations of risk factors. The data used was from the Framingham Heart Study, an ongoing study begun in 1948 of healthy adults, in a largely white population in Framingham, MA. [1]

Since 1998, many adaptions and revisions of the score have been published. Notable versions include the following:

  • 2002 adaption of the National Heart, Lung and Blood Institute (NHLBI) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (FRS-ATP-III)
  • 2008 10-year Framingham CVD risk score (FRS-CVD)
  • 2006 Lifetime Framingham CVD Risk Score (Lifetime-FRS)
  • 2009 30-year Framingham HCVD risk score (FRS-HCVD)

The 2002 adaption deleted the variables of diabetes and family history of premature coronary heart disease (CHD), added the impact of treatment for hypertension, and used only hard coronary heart disease endpoints in its calculations. [2]

The 2008 adaption included additional cardiovascular events (ie, stroke, transient ischemic attack) that had not previously been assessed. The 10-year CVD risk score is expected to be higher than the 10-year CHD risk score. [3]

The 2006 Lifetime-FRS estimates risk from age 50 based on four risk factors: total cholesterol, systolic blood pressure, cigarette smoking, and diabetes. [4]  The 2014 International Atherosclerosis Society (IAS) guidelines recommends the 2006 Lifetime-FRS for countries where recalibration values can be applied to risk calculations. [5]

The 2009 30-year FRS-HCVD estimates risk from age 45 based on a larger number of major risk factors and uses only hard disease endpoints. [6]

Reynolds Risk Score

The Reynolds Risk Score (RRS) was developed in 2007 with data from a 10-year study of 24,558 US women without diabetes. In addition to traditional risk factors, the algorithm also includes the emerging risk factor of C-reactive protein (CRP) elevation in its risk calculation. In its initial finding, compared with the FRS-ATP-III, 40-50% of intermediate risk women were reclassified into higher-or-lower risk categories. [7] In 2008, the RRS for men was similarly developed, using data from 10,724 US men. [8]

American College of Cardiology/American Heart Association Arteriosclerotic Cardiovascular Disease Risk Estimator

The American College of Cardiology (ACC)/American Heart Association(AHA) Arteriosclerotic Cardiovascular Disease (ASCVD) Risk Estimator, released in 2013, was designed to assess the risk of an initial cardiovascular event and includes participants from racially and geographically diverse cohorts such as the Framingham Heart Study (FHS), the Atherosclerosis Risk in Communities (ARIC) study, the Coronary Artery Risk Development in Young Adults (CARDIA), and the Cardiovascular Health Study (CHS).

The pooled cohort equations predict the future risk of cardiovascular disease and also stroke. The variables used were those used in the 10-year Framingham CVD score, but unlike the Framingham CVD, only hard disease endpoints were used in the calculation. [9]

The accuracy of the 2013 ACC/AHA-ASCVD was called into question very soon after its release when investigators calculated the 10-year risk of cardiovascular events in three large-scale primary prevention cohorts—the Women's Health Study (WHS), the Physicians' Health Study (PHS), and the Women's Health Initiative Observational Study (WHI-OS)—and found that the new algorithm overestimated the risk by 75-150% compared with the actual risk in all three cohorts. [10]

Other studies published in 2014 demonstrated increased risk with the ACC/AHA-ASCVD compared with older risk scores. After analysis of data from National Health and Nutrition Examination Surveys (NHANES) from 2005-2010, investigators predicted that use of the ACC/AHA-ASCVD to calculate risk would result in an increase of 12.8 million individuals eligible for statin therapy largely driven by older patients and treating individuals without cardiovascular disease. Among those aged 60 to 75 years, 87.4% of men and 53.6% of women would now be eligible for lipid-lowering medication, which is up from one-third and 21.2% respectively under the older ATP-III guidelines. [11]

Using the NCDR PINNACLE (National Cardiovascular Data Registry Practice Innovation and Clinical Excellence) data from 2008 to 2012, Maddox and colleagues calculated an increase of 32.4% in patients eligible for statin therapy with use of the ACC/AHA-ASCVD. [12]

QRisk2

The QRISK (2007) and the updated QRISK2 (2008) are algorithms developed for the United Kingdom population to better predict 10-year risk of CVD. [13, 14] In 2009, the UK National Health Service (NHS) began using QRISK2 across its system and since 2010, the UK’s National Institute for Health and Care Excellence (NICE) has recommended QRISK2 as the preferred risk score for assessing cardiovascular risk.

The QRISK2 algorithm includes all the major risk factors of the FRS-ATP-III score, plus the following [14] :

  • Self-reported ethnicity
  • Measures of social deprivation
  • Body mass index (BMI)
  • Chronic kidney disease
  • Atrial fibrillation
  • Rheumatoid arthritis
  • Family history of heart disease

Systematic Coronary Risk Evaluation

The Systematic COronary Risk Evaluation (SCORE) utilized pooled data of over 250,000 individuals from 12 European studies in its development. First published in 2003, the algorithm calculated the 10-year CVD death risk with separate scores for CHD and stroke fatality. [15] In subsequent revisions, the total CVD risk was also calculated.

Calibrations for high- and low-risk regions of Europe have been developed, based on each country’s mortality statistics. In addition, in the 2012 revision, published in the CVD guidelines released by the Fifth Joint Task Force of the European Society of Cardiology, a cardiovascular risk age calculation was added. The calculation is intended to be used as a communication aid, particularly with younger individuals with low risk estimates. [16]

Comparing Risk Scores

Controversy surrounds the use of CVD risk scores as the basis for guidelines for primary prevention interventions, particularly recommendations for the management of lipid disorders and identifying patients who would benefit from pharmaceutical interventions.

Issues of accuracy of risk calculations are not limited to the ACC/AHA-ASCVD risk estimator. All of the above scores have been validated and perform well in discriminating persons who will develop CVD from those who will not. However, the match between the prediction and actual outcome (score calibration) greatly varies when the algorithms are applied to populations with differing demographics than those of the cohort from which it was developed. [17]

Numerous studies reported calibration disparity in risk assessment using the scores above. For example, a 2015 study utilizing data from the Multi-Ethnic Study of Atherosclerosis (MESA), measured calibration for five risk scores and found the following overestimates for the risk of cardiovascular events [18] :

  • FRS-CHD: 53% in men, 48% in women
  • FRS-CVD: 37% in men, 8% in women
  • FRS-ATP-III: 154% in men, 46% in women
  • ACC/AHA-ASCVD: 86% in men, 67% in women

In this study, the RRS was the best calibrated model, with investigators reporting the lowest discordance between actual and predicted events (-3%). [18]

Two separate studies in 2014 compared the ACC/AHA-ASCVD risk estimator and SCORE in European cohorts. In the first study, which used data from a Dutch cohort 55 years of age and older, the percentages of patients would be eligible for statin therapy, according to the various algorithms, were as follows [19] :

  • ACC/AHA-ASCVD:  96.4% of men and 65.8% of women
  • SCORE: 66.1% of men and 39.1% of women
  • FRS-ATP-III 52.0% of men and 35.5% of women

Similarly, in a separate study of a Swiss cohort 50 years and older, the investigators reported that 30 times the number of men were eligible for statin therapy using the ACC/AHA-ASCVD risk estimation as compared with SCORE. In the 60-70 year old age group, twice as many men and six times as many women were considered at high risk. [20]

A 2012 study of men (aged 50-79) and women (aged 47-79) nm ). In general, the RSS predicted increased risk in women and decreased risk in men. The authors concluded that adopting the RRS for the screening of US adults would result in increased clinical management in 1.6 million women and decreased management in 2.10 million men. [21]

A 2014 study comparing the validity of three CVD risk algorithms in a middle-income Asian population in Malaysia found agreement in risk assessment between the US-developed FRS and the European-developed Systematic Coronary Risk Evaluation (SCORE), but the SCORE model was more accurate for predicting risk in men while the FRS was better at predicting risk in women. A third algorithm (World Health Organization/International Society of Hypertension score) performed poorly with both men and women. [22]

Next:

Screening

Screening guidelines for lipid disorders have been issued by the following organizations:

  • U.S Preventive Services Task Force (USPSTF)
  • American College of Cardiology (ACC)/American Heart Association(AHA)
  • National Heart, Lung and Blood Institute (NHLBI)
  • American Association of Clinical Endocrinologists (AACE)
  • National Lipid Association (NLA)
  • Department of Veterans Affairs (VA)/Department of Defense (DOD)
  • European Society of Cardiology(ESC)/European Atherosclerosis Society (EAS)

The majority of screening guidelines recommend a full fasting lipid profile including total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides, although some guidelines allow for a non-fasting lipid panel. The age at which to begin screening varies among the guidelines and may differ for men and women. A comparison of the recommendations can be found in Tables 2 and 3, below.

Table 2. Guidelines for Lipid Screening in Adults. (Open Table in a new window)

Issuing Organization Year Populations to be Screened Screening Measurement Screening Interval
USPSTF [23] 2008 (update in progress) Men ≥35 years: Universal screening



Men 20-34 years: if at increased risk for coronary heart disease (CHD)



Women ≥20 years: if at increased risk for CHD



Fasting or non-fasting lipid panel Uncertain; every 5 years, with shorter intervals for individuals with elevated lipid levels and longer intervals for those not at increased risk with normal lipid levels
ACC/AHA [24] 2013 Adults 20-78 years None given Every 4-6 years if free of ASCVD
NHLBI (ATP-III) [2] 2002 Adults ≥20 years: Universal Screening Fasting lipid panel; Calculation of non-HDL-C when TG>200mg/dL Every 5 years
AACE [25] 2012 Men 20-44 years and Women 20-54 years: Universal screening as part of global risk assessment for CHD Fasting lipid panel;



Calculation of non-HDL-C more accurate if TG >200 and <500 mg/dL, diabetes, insulin resistance, or established CAD



Every 5 years; more frequent assessment for patients with family history of CHD before age 55 for father or first-degree male relatives or age 65 for mother or first-degree female relatives



Annually for adults with diabetes



NLA [26] 2014 Adults ≥20 years: Universal Screening Fasting or non-fasting lipid panel Every 5 years
VA/DOD [27] 2014 Men >35 years and women >45 years: Universal Screening Fasting or non-fasting Non-fasting lipid panel Every 5 years for low CVD risk



Every 2 years for intermediate risk or the appearance of a new CVD risk factor



ESC/EAS [28] 2011 Adults with any of the following risk factors:



  • Type 2 diabetes
  • Obesity
  • Hypertension
  • Smoker
  • Chronic inflammatory disease
  • Chronic kidney disease
  • Family history of premature cardiovascular disease (CVD) or familial dyslipidemia
Men ≥40 years and Women ≥50 years or post-menopausal: Consider screening



Fasting lipid panel with calculation of non-HDL-C  and TC/HDL-C ratio;



apoB or apoB/apoA1 ratio considered alternate risk factors



None given

CAD = Coronary artery disease; CHD = Coronary heart disease; CVD = Cardiovascular disease; HDL-C = High-density lipoprotein cholesterol; TC = Total cholesterol; TG = Triglycerides

Table 3. Guidelines for Lipid Screening in Children and Adolescents (Open Table in a new window)

Issuing Organization Year Populations to be Screened Screening Measurement Screening Interval
USPSTF [29] 2007 (update in progress) Insufficient evidence for or against screening for ages <20 years N/A N/A
NHLBI (endorsed by American Academy of Pediatrics) [30] 2011 <1 year: No screening



 



 



1-8 years: if family history of heart disease or high cholesterol or child has other risk factor or high-risk medical condition



 



9-11 years: Universal screening



 



 



 



12-16 years: if family history of heart disease or high cholesterol or child has other risk factor or high-risk medical condition



 



≥17 to <20 years: Universal screening



 



≥20 to <21 years: Universal screening



N/A



 



 



 



Fasting lipid panel



 



 



Nonfasting non-HDL-C; abnormal results followed up with fasting lipid panel



 



 



 



Fasting lipid panel



 



 



Nonfasting non-HDL-C or fasting lipid panel



 



Nonfasting non-HDL-C or fasting lipid panel



N/A



 



 



As indicated



 



 



 



Once



 



 



 



 



As indicated



 



 



 



Once 



 



 



Once



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Next:

Management

Guidelines for the management of lipid disorders have been issued by the following organizations:

  • American College of Cardiology (ACC)/American Heart Association(AHA)
  • American Association of Clinical Endocrinologists (AACE)
  • National Lipid Association (NLA)
  • Department of Veteran’s Affairs (VA)/Department of Defense (DOD)
  • International Atherosclerosis Society (IAS)
  • European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS)

Like the ACC/AHA-ASCVD risk calculator, the 2013 joint ACC/AHA guidelines have been mired in controversy. The new guidelines departed significantly from previous iterations by abandoning the traditional LDL and non-HDL cholesterol targets. Physicians are no longer asked to treat patients who have cardiovascular disease to an LDL of less than 100 mg/dL or the optional goal of less than 70 mg/dL.

Instead, the new guidelines identify four groups of primary- and secondary-prevention patients in whom physicians should focus their efforts to reduce cardiovascular-disease events. Depending on the type of patient, physicians should choose the appropriate "intensity" of statin therapy to achieve relative reductions in LDL cholesterol.

The clinical guidelines currently state that for patients with atherosclerotic cardiovascular disease, high-intensive statin therapy should be used to achieve at least a 50% reduction in LDL cholesterol unless otherwise contraindicated or when the patient experiences statin-associated adverse events. In that case, doctors should use a moderate-intensity statin.

Similarly, for those with LDL-cholesterol levels ≥190 mg/dL, a high-intensity statin should be used with the goal of achieving at least a 50% reduction in LDL cholesterol levels. However, for patients >75 years of age and those with safety concerns and CAD, a moderate-intensity statin can be used.

For those with diabetes aged 40 to 75 years of age, a moderate-intensity statin, defined as a drug that lowers LDL cholesterol 30-49%, should be used, whereas a high-intensity statin is a reasonable choice if the patient also has a 10-year risk of atherosclerotic cardiovascular disease exceeding 7.5%.

For the individual aged 40 to 75 years without cardiovascular disease or diabetes but who has a 10-year risk of clinical events >7.5% and an LDL cholesterol level of 70 to 189 mg/dL, the panel recommends treatment with a moderate- or high-intensity statin. Also, in a significant departure from previous guidelines, the 2013 ACC/AHA guidelines recommend measurement of LDL-C during therapy only as an assessment of adherence and response to therapy. [24]

The AACE and NLA have declined to endorse the guidelines. In particular, the AACE disagrees with removal of the LDL targets and the idea that statin therapy alone is sufficient for all at-risk patients, noting that many who have multiple risk factors, including diabetes and established heart disease, will need additional therapies. [25]

A summary of the recommendations for intervention are detailed in Table 4, below.

Table 4. Guidelines for Intervention (Open Table in a new window)

Adult Guidelines Year Risk Algorithm Intervention Population Treatment Goal Intervention
American College of Cardiology/American Heart Association (ACC/AHA) [24] 2013 ACC/AHA-ASCVD Adults ≥21 years old in any of the following risk groups:
  1. Known ASCVD
  2. LDL-C >190 mg/dL
  3. 40-75 years old, with diabetes and LDL-C levels 70-189 mg/dL and no ASCVD
  4. ≥7.5% 10 year ASCVD risk with LDL-C levels 70-189 mg/dL
By Risk Group:
  1. ≥50% reduction in LDL-C
  2. ≥50% reduction in LDL-C
  3. 30-50% reduction in LDL-C
  4. 30-50% reduction in LDL-C
High-intensity statin therapy for most patients in groups 1 and 2, and for group 3 patients if ≥7.5% 10- year ASCVD risk; consider for group 4



 



 



Moderate-intensity statins for group 1-2 patients >75 years or with statin-associated adverse events, and for most group 3-4 patients



American Association of Clinical Endocrinologists(AACE) [25] 2012 Men: FRS



Women: RRS



All adults: LDL-C level >100 mg/dL



Very High Risk: LDL-C level >70 mg/dL



Primary:



All adults: LDL-C <100 mg/dL



Very High Risk: LDL-C <70 mg/dL



Secondary:



HDL-C >40 mg/dL



Non-HDL-C  30 mg/dL above LDL-C goal



TG <150 mg/dL



apoB <90 mg/dL; <80 for those with CVD or diabetes and additional risk factor(s)



Lifestyle changes (First- Line):



Physical activity, nutrition counseling, smoking cessation and weight loss.



Pharmacologic Therapy:



  • Statins are drug of choice for LDL-C reduction
  • Fibrates for treatment of TG>500 mg/dL
  • Niacin for reducing TG and LDL-C, and increasing HDL-C
  • Bile acid sequestrants for reducing LDL-C and apoB; may increase TG
  • Cholesterol absorption inhibitors for reducing LDL-C and apoB in combination with statins
National Lipid Association (NLA) [26] 2014 N/A Low Risk: Non-HDL-C ≥190 mg/dL; LDL-C ≥160 mg/dL



Moderate Risk: Non-HDL-C ≥160 mg/dL; LDL-C ≥130 mg/dL



High Risk: Non-HDL-C ≥130 mg/dL; LDL-C ≥100 mg/dL



Very High Risk: Non-HDL-C ≥100 mg/dL; LDL-C ≥70mg/dL



Primary:



Low, Moderate, or High Risk:



Non-HDL-C <130 mg/dL



LDL-C <100 mg/dL



Very High Risk:



Non-HDL-C <100 mg/dL



LDL-C <70 mg/dL



Low to Moderate Risk;



First-line lifestyle changes should be monitored for 6-12 months; pharmacologic treatment can be added if levels remain elevated



High to Very High Risk:



Pharmacologic therapy should be initiated with lifestyle changes;



Lifestyle changes:



Nutrition counseling, physical activity, smoking cessation and weight loss.



Pharmacologic Therapy:



Moderate to high intensity statin; if very high TG ≥500mg/dL, TG lowering drug to prevent pancreatitis



Department of Veterans Affairs/Department of Defense (VA/DOD) [27] 2014 10-year risk calculator (ie, FRS-CVD, ACC/AHA-ASCVD) 10-year CVD risk ≥12%;



Consider pharmacologic intervention in patients with 10-year CVD risk ≥6% and <12%;



Patients with established ASCVD risk



CVD risk reduction Pharmacologic Therapy:



Moderate intensity statin; high intensity only for select patient populations (e.g., recurrent CVD events while on moderate-intensity statins)



Lifestyle changes:



Nutrition counseling, physical activity, smoking cessation and weight loss.



For patients unable to tolerate statin therapy, consider fibrates or bile acid sequestrants (BAS), but recommends against non-statin lipid lower drugs as monotherapy or in combination with statins for patients able to tolerate statin therapy



International Atherosclerosis Society (IAS) [5] 2014 Lifetime-FRS (preferred) or QRISK2 Non-HDL-C ≥130 mg/dL; LDL-C ≥100 mg/dL LDL-C <100 mg/dL



Non-HDL-C <130 mg/dL is an alternative target



Lifestyle changes(First line):



Nutrition counseling, physical activity, smoking cessation and weight loss.



Pharmacologic Therapy in addition to lifestyle changes:



Moderate to high intensity statin adjusted to absolute risk



European Society of Cardiology/ European Atherosclerosis Society (ESC/EAS) [28] 2011 SCORE Moderate Risk: LDL-C >115 mg/dL



High Risk:  LDL-C >100 mg/dL



Very High Risk:  LDL-C >70 mg/dL



Primary:



Moderate Risk: LDL-C <115mg/dL



High Risk: LDL-C <100mg/dL



Very High Risk: LDL-C <70 mg/dL or 50% reduction



Secondary: Non-HDL-C or apoB in patients with metabolic syndrome, diabetes, or chronic kidney disease



Lifestyle changes:



Nutrition counseling, physical activity, smoking cessation and weight loss.



Pharmacologic Therapy:



Statins up to the highest recommended and/or tolerable dose;



BAS, niacin or cholesterol absorption inhibitor may be given in combination with statin if target level not reached;



BAS and niacin in cases of statin intolerance; cholesterol absorption inhibitor may be considered as monotherapy or in combination with BAS or niacin



apoB=Apolipoprotein B; ASCVD=Atherosclerotic cardiovascular disease; CVD=Cardiovascular disease; FRS=Framingham Risk Score; HDL-C=High-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; TG=Triglycerides

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