Hyperlipidemia: How to Optimize Risk While Waiting for NCEP ATP IV Guidelines

The National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III guidelines on the management of hypercholesterolemia¹ were published more than a decade ago, with a white paper update in 2004. The ATP IV guidelines, due out soon, will translate for us the advances in science and clinical evidence that, as I see things, should already be changing the way we treat our patients.

In the meantime, I worked with an expert group of physicians to develop a set of actionable recommendations for the ATP update. Following is a 10-point summary of those recommendations, written to specifically address primary care practice. They are, by design, as straightforward as possible to make implementation easier in the clinic.

Recommendation #1: Assess risk more accurately.
     • The Framingham Risk Score for hard coronary heart disease (CHD) is the global risk measure in ATP III.
        » Limitations:
             • A powerful tool, but limits inputs (traditional risk factors only), outputs (nonfatal MI and CHD death only), and time span (10 years only)
             • Underestimates risk in many patients, particularly women
             • Ignores factors like kidney disease and a family history of CHD
             • Risk scoring does not include stroke, known to be preventable by statins
             • Most adults with first MI were not ATP III candidates for statins

        » Two common alternatives (more comprehensive, but still imperfect):
             • Both address more comprehensive end-points, including stroke
                  • Reynolds risk: adds C-reactive protein (CRP) level and parental history of premature MI to Framingham traditional risk factors
                  • Framingham global cardiovascular disease (CVD) risk: uses lab or clinical inputs; easy estimation using bedside point system; gives “heart age”
             • Expect updated risk calculators in the near future

     • Providers in a busy primary care clinic may not always calculate a risk score
        » The CHD risk equivalent allows a provider to quickly classify risk:
             • CHD risk equivalent: ≥20% 10-yr risk of MI or death from CHD
             • Diabetes mellitus (DM) is a CHD risk equivalent in ATP III
             • We recommend stage ≥2 chronic kidney disease as a CHD risk equivalent
             • Other factors modify risk (eg, age, disease duration), so a young patient with newly diagnosed diabetes may be a common exception to the CHD risk equivalent rule

        » Lifetime risk is also a quick way to classify risk
             • A viable conceptual framework for patients estimated to carry low-to- intermediate 10-yr risk
             • High lifetime risk: ≥39% lifetime chance of developing CVD
                  • Roughly equivalent to reaching age 50 with 1 major risk factor

     • Risk scores yield point estimates; in reality, there is a 95% CI around this estimate, which highlights the uncertainty of risk estimation by these tools alone. When more precise risk estimation is needed, consider referral for noninvasive atherosclerosis imaging, such as coronary artery calcium scanning, especially for patients with family histories of CHD or metabolic syndrome.

Recommendation #2: Simplify the starting algorithm.
     • Current starting algorithm: Risk assessment → Baseline LDL-C → LDL-C goal
        » LDL-C cut-points for lifestyle changes and drugs are different, which is confusing
        » Baseline LDL-C is a “middle man”
             • However,  per ATP III, “When persons with low LDL-C have the same absolute risk (because of other risk factors) as those with high LDL-C, the same absolute benefit is attained for a given mg/dL lowering of LDL-C.”

     • Our suggested simplified starting algorithm: Risk assessment → Therapy
        » More evidence-based, easier to follow, and in line with ATP III logic above
        » Focus on healthy lifestyle is important for all; don’t need LDL-C cut-points
        » Low short-term and lifetime-risk patients: focus on AHA ideal CV health
        » High short-term risk (CHD risk equivalent): potent statin therapy typically
        » Then there are those in the middle (ie, patients with CV risk factors)
        » Many high-lifetime risk patients benefit from statin therapy, which should be discussed
             • Five Ps to consider when discussing a statin:
                  • Preference: What does the patient prefer?
                  • Precision: Need further testing for more precise risk stratification?
                  • Participation: Is the patient motivated to improve lifestyle habits?
                  • Potency: What statin potency will likely be required?
                  • Price: Can the patient afford the drug, and do the benefits likely outweigh the risks?

Recommendation #3: Prioritize statin therapy.
ATP III recommends starting a “statin or bile acid sequestrant or nicotinic acid”
     • However, statins have more effect and much more data
     • Statins should be first-line; guidelines from the AHA/ACC² explicitly state this
     • If a patient does not tolerate initial statin therapy, try a lower dose, alternative dosing schedule, or a different statin before switching to another drug class

Recommendation #4: Relax the follow-up interval for repeat lipid testing.
When a drug is started, ATP III recommends that we repeat the LDL-C in 6 weeks: if the level is not at goal, repeat the measurement 6 weeks later
     • Not an evidence-based, practical, or cost-effective approach to care
     • In fact, some experts believe we should blindly titrate statins and not retest lipids
     • However, patients and doctors like knowing the numbers and this allows greater personalization of care, as well as additional risk stratification
     • We recommend relaxing follow-up testing and individualizing the interval to the patient
        » Some might be encouraged early in treatment by lipid number improvement
        » Others may find testing inconvenient and want to wait longer to assess response to important lifestyle changes, in addition to drug effect

Recommendation #5: Designate <70 mg/dL as an “ideal” LDL-C target. 
Currently, a LDL-C <70 mg/dL is only a therapeutic option for “very high-risk patients”
     • With data from additional trials (TNT,³ IDEAL,⁴ JUPITER⁵) and meta-analyses supporting LDL-C levels <70 mg/dL, we view this as “ideal”
     • Indeed, the ESC/EAS⁶ joint task force on management of dyslipidemia recently adopted this as a routine goal for patients with atherosclerosis

Recommendation #6: Endorse targets beyond LDL-C. 
We have no clinical trial data that primarily examine treat-to-target strategies, a fact that should temper any clinical therapeutic recommendations for targets in general, or one over another  
     • LDL-C goals are justified by the biology of atherosclerosis, epidemiologic studies that link high LDL-C to atherosclerosis, and data from multiple RCTs that show a correlation between lowering LDL-C and improved outcomes
     • ATP III identifies HDL-C only as a secondary target; however, multiple lines of evidence cited within the guideline’s cholesterol-based framework support non-HDL-C as the preferred  target
     • Non-HDL-C can be measured in a nonfasting state and adds no cost to testing
     • There is a similar scientific basis for measurement of the number of cholesterol particles (eg, apolipoprotein B [apoB]) rather than their cholesterol content
     • At a given LDL-C, there are more atherogenic particles when there is a small dense LDL-C pattern (eg, in DM); risk may be underestimated by cholesterol measurement alone
     • Measurement of apoB is standardized by the WHO,⁷and endorsed by the ADA/ACC⁸ and in guidelines from Europe⁶ and Canada⁹   
     • A simple message: do not stop at LDL-C, particularly in high-risk patients

Recommendation #7: Refine therapeutic target levels to the equivalent population percentile.
ATP III set non-HDL-C goals 30 mg/dL higher than LDL-C goals
     • With this approach, non-HDL-C goals are higher than the equivalent population percentile for an equivalent LDL-C goal.
     • Equivalent goals based on population percentiles are:
        » LDL-C <70 mg/dL = non-HDL-C <90 mg/dL = apoB <60 mg/dL
        » LDL-C <100 mg/dL = non-HDL-C <120 mg/dL = apoB <80 mg/dL

Recommendation #8: Remove misleading descriptors such as “borderline high.”
ATP III labels a LDL-C of 130 to 159 mg/dL as “borderline high”
     • Consider: Average LDL-C levels range from 50 to 70 mg/dL in groups naturally free of atherosclerosis (these include native hunter-gatherers, healthy human neonates, free-living primates, and other wild mammals)
     • The value range described as “borderline high” is 2 to 3 times higher than humans have evolved to have, is not evidence-based, and provides false reassurance to patients whose LDL-C is actually dangerously high; either the ranges or descriptors need reassessment
     • We recommend removing the misleading descriptors or reframing lipid levels in the context of normal levels by evolutionary, rather than modern American, standards  

Recommendation #9: Make lifestyle messages simpler, “user-friendly.”
Try telling a patient: “Up to 10% of your total calories should be from polyunsaturated fat, up to 20% from monounsaturated fat,” and so on. Not effective communication.
     • Here are lifestyle messages that are evidence-based and that we find helpful in clinic:
        » Diet
             • Rather than nutrient percentages, emphasize a dietary pattern
             • Encourage patients to follow a DASH–like (Mediterranean-style) diet¹⁰ 
                  • Associated with reduced cardiovascular and all-cause mortality
                  • Easy to discuss with a patient: increase consumption of fresh fruits, vegetables, whole grains, low-fat dairy, oily fish, poultry over red meat; eat a modest amount of nuts and beans, herbs and spices in place of salt, and limit added fats (eg, olive oil in place of butter and margarine)
             • Patients can use cookbooks following a DASH-like eating pattern
     • Exercise
             • Advise patients to wear a pedometer with a goal of 10,000 steps/day
             • This intervention is linked with increased exercise and improved health

Recommendation #10: Adopt an ABCDE approach in clinic.
     • Optimizing risk reduction in a busy primary care clinic is as easy as ABC, D, and E!
        » A: Assessment of risk, Aspirin/antiplatelet therapy, Affordability, ACE-I/ARB, Apnea
        » B: Blood pressure, Beta-blocker
        » C: Cholesterol, Cigarette smoking
        » D: Diet, Diabetes
        » E: Exercise  
    

 • As a nod to this approach, here are our ATP IV recommendations, summarized in ABDCE format:
        » A: Assessment of risk - use a more comprehensive, accurate approach
        » A: Algorithm - directly link risk to therapy; relax/personalize follow-up testing
        » B: Biology - consider particles vs. cholesterol, use evolutionarily normal lipid levels
        » C: Cholesterol - deemphasize baseline cholesterol as a starting point in algorithms
        » D: Drug classes - prioritize statins
        » D: Descriptors - remove them; they are misleading
        » D: Diet - convey a simpler message (eg, a DASH-like or Mediterranean diet)
        » E: Exercise - convey a simpler message (eg, 10 000 steps/day)

Scroll down for References

References:

References 1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).: Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421.  

2. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction.Circulation.2007;116:e148-e304.

3. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. NEJM. 2005;352:1425-1435.

4. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437-2445.

5.Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. NEJM. 2008;359:2195-2207.

6. Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias; the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011;217:3–46.

7. Marcovina SM, Albers JJ, Kennedy H, et al. International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. IV. Comparability of apolipoprotein B values by use of international reference material. Clin Chem. 1994;40:586-592.

8. Brunzell JD, Davidson M, Furberg CD,et al; American Diabetes Association; American College of Cardiology Foundation. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008;31:811-822.

9. Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult-2009 recommendations. Can J Cardiol. 2009;25:567–579.

10. Parikh P, McDaniel MC, Ashen MD, et al. Diets and cardiovascular disease: an evidence-based assessment. J Am Coll Cardiol. 2005;45:1379 –1387.

Other very important papers, on lifetime risk:
Lloyd-Jones DM, Leip EP, Larson MG, et al.. Prediction of lifetime risk for cardiovascular
disease by risk factor burden at 50 years of age. Circulation 2006;113:791–798

Berry JD, Dyer A, Cai X, et al. Lifetime risks of cardiovascular disease.  N Engl J Med. 2012;366:321-329.