Waiting for the National Cholesterol Education Program Adult Treatment Panel IV Guidelines, and in the Meantime, Some

Challenges and Recommendations

Seth S. Martin, MDa,*, Thomas S. Metkus, MDa, Aaron Horne, MD, MBAa, Michael J. Blaha, MD, MPHa, Rani Hasan, MDa, Catherine Y. Campbell, MDa, Omair Yousuf, MDa, Parag Joshi, MDa, Sanjay Kaul, MD, MPHb, Michael Miller, MDc, Erin D. Michos, MDa, Steven R. Jones, MDa, Ty J. Gluckman, MDd, Christopher P. Cannon, MDe, Laurence S. Sperling, MDf, and Roger S. Blumenthal, MDa
The National Cholesterol Education Program Adult Treatment Panel (ATP) has provided education and guidance for decades on the management of hypercholesterolemia. Its third report (ATP III) was published 10 years ago, with a white paper update in 2004. There is a need for translation of more recent evidence into a revised guideline. To help address the signicant challenges facing the ATP IV writing group, this statement aims to provide balanced recommendations that build on ATP III. The authors aim for simplicity to increase the likelihood of implementation in clinical practice. To move from ATP III to ATP IV, the authors recommend the following: (1) assess risk more accurately, (2) simplify the starting algorithm, (3) prioritize statin therapy, (4) relax the follow-up interval for repeat lipid testing, (5) designate <70 mg/dl as an ideal low-density lipoprotein cholesterol target, (6) endorse targets beyond low-density lipoprotein cholesterol, (7) rene therapeutic target levels to the equivalent population percentile, (8) remove misleading descriptors such as borderline high, and (9) make lifestyle messages simpler. In conclusion, the solutions offered in this statement represent ways to translate the totality of published reports into enhanced hyperlipidemia guidelines to better combat the devastating impact of hyperlipidemia on cardiovascular health. 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;xx:xxx) The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) has provided education and guidance for decades on the management of hypercholesterolemia. Its third report (ATP III) was published 10 years ago,1 with a white paper update in 2004.2 We continue to wait intently while the ATP IV writing group works to translate more recent evidence into a revised guideline. As the French proverb goes, People count up the faults of those who keep them waiting. This statement identies signicant challenges in moving from ATP III to ATP IV and aims to help address these challenges by providing balanced recommendations. We aim for simplicity to increase the likelihood of implementation in clinical practice. Recommendation 1: Assess Risk More Accurately Matching therapeutic intensity to estimated cardiovascular risk optimally balances benets and dose-dependent risks. ATP III recommends the Framingham risk score (FRS) to determine the 10-year risk for developing a myocardial infarction (MI) or death from coronary heart disease (CHD) on the basis of age, gender, total and high-density lipoprotein (HDL) cholesterol, smoking, and blood pressure (or antihypertensive treatment). However, this method limits the inputs (traditional risk factors only), outputs (point estimate risk for nonfatal MI and CHD death only), and time span (10 years only). A 50-year-old woman with a total cholesterol level of 250 mg/dl, an HDL cholesterol level of 60 mg/dl, untreated systolic blood pressure of 160 mm Hg, and no diabetes or tobacco use is estimated to carry a 2% cardiovascular risk over the next 10 years.3 However, the ATP FRS end point ignores noncoronary forms of occlusive atherosclerotic vascular disease and also overlooks lifetime risk, which is actually about 50% in this woman.3 Moreover, ATP III views her risk as the same even if she has metabolic syndrome, stage 2 chronic kidney disease, a strong family history of premature CHD, or a coronary artery calcium score of 400. Although ATP III recognizes that risk for CHD is inuenced by other factors [that] can modulate clinical judgment, these are not incorporated into the treatment algorithm. Unfortunately, most adults presenting with
www.ajconline.org

Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, Maryland; bCardiovascular Division, Cedars-Sinai Medical Center, Los Angeles, California; cCardiovascular Division, University of Maryland School of Medicine, Baltimore, Maryland; dProvidence Heart and Vascular Institute, Portland, Oregon; eCardiovascular Division, TIMI Study Group, Brigham and Womens Hospital, Boston, Massachusetts; and f Cardiovascular Division, Emory University School of Medicine, Atlanta, Georgia. Manuscript received March 3, 2012; revised manuscript received and accepted March 9, 2012. *Corresponding author: Tel: 410-955-7376; fax: 410-502-0231. E-mail address: smart100@jhmi.edu (S.S. Martin). 0002-9149/12/$ see front matter 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2012.03.023

The American Journal of Cardiology (www.ajconline.org)

Figure 1. Initial treatment algorithm. CAC coronary artery calcium; CKD stage 2 chronic kidney disease; CV cardiovascular; CVD cardiovascular disease (CHD, peripheral arterial disease, abdominal aortic aneurysm, or symptomatic carotid artery disease); DM diabetes mellitus; FHx family history of premature cardiovascular disease; FRS ATP III Framingham risk score; global risk DAgostino General Cardiovascular Disease Risk Prole for Use in Primary Care; MetS metabolic syndrome; RF risk factors (hyperlipidemia, hypertension, diabetes, and smoking); RRS Reynolds risk score. Most acknowledges that some patients (e.g., a young patient who recently developed disease) may be exceptions to the CHD risk equivalent rule. Table 1 Five Ps to consider when discussing personalized statin initiation in a patient at high lifetime risk Preference Precision Participation Potency Price What does the patient prefer? Is further testing for more precise risk stratication warranted? How motivated is the patient to improve lifestyle habits? What statin potency will likely be required to attain therapeutic targets? Can the patient afford the drug, and do the benets likely outweigh the risks?

their rst MIs were not considered candidates for statin therapy on the basis of their ATP IIIpredicted risk before having events.4 We recommend incorporating risk assessment tools beyond the ATP FRS into the treatment algorithm (Figure 1). More comprehensive risk assessment could enhance the efciency of statin therapy allocation, optimize the risk/ benet ratio, and ensure that more patients who may benet from therapy are not missed. Because statin trials did not randomize patients to treatment strategies on the basis of the ATP FRS, the scientic justication for this proposal is the same as for the Framingham tool itself: as estimated risk increases, more aggressive therapy provides greater absolute benet. There are a number of alternatives to assess cardiovascular risk beyond the ATP FRS. Two of the more common are the Reynolds risk score and the DAgostino General Cardiovascular Disease Risk Prole for Use in Primary Care.5 With the Reynolds risk score, C-reactive protein level and parental history of premature MI are added to FRS

ATP inputs. In contrast, the DAgostino tool can use either laboratory or clinical inputs, including body mass index, with easy estimation through a point system at the bedside. The Reynolds risk score and DAgostino tools address more comprehensive end points than the ATP FRS: MI, stroke, revascularization, or cardiovascular death in the Reynolds risk score and CHD, stroke, peripheral arterial disease, or heart failure in the DAgostino tool. If these tools and the ATP FRS were reported not only as point estimates of risk but also as 95% condence intervals, this would better acknowledge the uncertainty of risk estimation by these tools alone. Moving beyond risk factors closer to the atherosclerosis phenotype, noninvasive imaging of coronary artery calcium and carotid intima-media thickness are additional tools for risk stratication with class IIa indications (benets exceed risks) in intermediate-risk patients in the 2010 American College of Cardiology Foundation and American Heart Association guideline for the assessment of cardiovascular risk asymptomatic adults.6 Of the 2, coronary artery calcium scoring is more widely available and better standardized. Quantifying atherosclerosis burden, coronary artery calcium provides robust risk information and may be used to target patients expected to derive the most benet from statin treatment.7 The power of coronary artery calcium probably lies most in its ability to integrate known and unknown risk exposures and account for the total duration of risk exposure, an important factor not accounted for by current risk models. Recognizing that coronary artery calcium scoring delivers a small radiation dose on the order of mammography, and that indiscriminate use is not advised, at about $100, it should be especially considered in patients with

Editorial/ATP IV Recommendations

Figure 2. Ideal cardiovascular (CV) health. *Ideal cholesterol denition modied from the American Heart Association denition.

family histories of premature CHD or metabolic syndrome who are not already classied at high 10-year risk. ATP IIIs assertion that testing is relatively expensive and not widely available is no longer true. The CHD risk equivalent is an important ATP construct that simplies risk categorization. In addition to diabetes mellitus, we recommend introducing stage 2 chronic kidney disease as a CHD risk equivalent.8 The term most in Figure 1 acknowledges that risk is modied by other factors,8 including age and disease duration, and so, for instance, a young patient who recently developed disease may be one common exception to the CHD risk equivalent rule. In addition to diabetes and chronic kidney disease, providers need greater ATP guidance on managing other special populations, including patients with end-stage renal disease on hemodialysis, congestive heart failure, human immunodeciency virus, and autoimmune diseases such as systemic lupus erythematosus, as is done in the European guidelines.8 ATP guidelines should be further enhanced by introducing lifetime risk as a framework for patients who are estimated to carry low to intermediate short-term risk3,5 (see Figure 1 and the following discussion). The published research denes high lifetime risk as a 39% lifetime chance of developing cardiovascular disease, which is roughly equivalent to reaching 50 years of age with 1 major risk factor (hyperlipidemia, hypertension, smoking, diabetes),3 providing another simple risk classication system.

Recommendation 2: Simplify the Adult Treatment Panel III Algorithm, Which Is Overly Complex For patients not perceived as at high risk, the ATP III process begins with (1) exclusion of secondary causes of dyslipidemia, (2) risk factor counting, (3) FRS calculation, (4) determination of the baseline low-density lipoprotein (LDL) cholesterol cut point at which therapeutic lifestyle changes are indicated, (5) denition of a separate baseline LDL cholesterol cut point at which drug therapy is warranted, and (6) setting the LDL cholesterol goal. Therefore, recommendations are prioritized by baseline LDL cholesterol and treatment goals, not by therapy itself, creating a convoluted path between risk assessment and therapy. The level of evidence for this scheme will vary by the therapy used to get to goal. We recommend directly linking risk with therapy as the rst priority in the algorithm (Figure 1), a more evidencebased and simpler process. This proposal is consistent with ATP III logic: A basic principle of prevention is that the intensity of risk-reduction therapy should be adjusted to a persons absolute risk. Nonetheless, this picture is currently clouded by LDL cholesterol serving as the middleman, although the NCEP ATP 2004 white paper acknowledges, Persons with low [LDL cholesterol] have the same absolute risk [because of other risk factors] as those with high [LDL cholesterol], [and thus] the same absolute benet is attained for a given milligram-per-deciliter lowering of

The American Journal of Cardiology (www.ajconline.org) Table 2 Therapeutic targets LDL Cholesterol (mg/dl) Ideal Satisfactory 70 100 Non-HDL Cholesterol (mg/dl) 90 120 Apolipoprotein B (mg/dl) 60 80

[LDL cholesterol]. Indeed, the Cholesterol Treatment Trialists meta-analysis of 170,000 participants in 26 randomized trials conrmed the benet of statins independent of baseline cholesterol.9 Therefore, withholding therapy because of baseline LDL cholesterol runs contrary to current science. Statins are an important adjunct to the rst line of therapy: lifestyle changes. Potent statin therapy is warranted in most patients at high short-term risk. In other patients, lifetime risk should factor into decision making. If high, this may help motivate patients to make lifestyle changes. In addition, many patients with high lifetime risk may benet from statin therapy, which should be discussed and strongly considered (Table 1). Patients at low short-term and lifetime risk can focus on maintenance of ideal cardiovascular health (Figure 2).10 Therefore, at least with regard to the broad conceptual construct of allocating statin therapy, we agree that the rst priority should be to treat risk, not LDL cholesterol.11 The most directly evidence based, but likely too insular, approach is to treat only patients who met eligibility criteria for randomized statin trials with the drugs and dosages used in the trials. We submit that matching therapy to risk is a reasonable extension of the data with more widespread clinical utility. Recommendation 3: Prioritize Statins Over Other Drug Classes In addition to prioritizing LDL cholesterol goals over therapy, in the Progression of Drug Therapy in Primary Prevention, ATP III recommends starting a statin or bile acid sequestrant or nicotinic acid. However, statins have a higher maximal magnitude of therapeutic effect and have been studied more extensively than other lipidlowering drug classes in randomized controlled trials. As summarized by the ATP,1,2 there are randomized data for statins in primary and secondary CHD prevention. In addition, randomized trials have demonstrated the efcacy of statins in patients with stroke, peripheral arterial disease, and chronic kidney disease.8 When the totality of evidence is viewed in aggregate in 170,000 patients, statins demonstrate a consistent benet across a broad array of patient subgroups.9 Statins have an excellent safety prole,9,12 with generics yielding attractive costeffectiveness.13 Consistent with this evidence, American Heart Association and American College of Cardiology Foundation secondary prevention guidelines,14,15 and guidelines outside the United States,8,16 we recommend prioritizing statins over other drug therapies. If a patient does not tolerate initial statin therapy, one can try a lower dose, an alternative dosing schedule, or a different statin before switching to another drug class.12 Given variability in metabolism, patients not tolerating one statin may tolerate another.12 ATP IV should address toxicity concerns (e.g., diabetes) that have emerged since ATP III while emphasizing that benets of therapy still generally outweigh risks.17

Recommendation 4: Relax the Follow-Up Interval for Repeat Lipid Testing Per ATP III, when drug therapy is initiated, the patient is asked to return in 6 weeks for a repeat LDL cholesterol measurement. If above goal, the patient is asked to follow up in 6 weeks for a repeat level. Referral to a lipid specialist is suggested if LDL cholesterol still remains above goal. Instead, we recommend relaxing follow-up testing. It can be personalized to the patient. Some might prefer to return for repeat laboratory testing as early as 6 weeks, seeking encouragement from lipid number improvement. Other patients may nd early follow-up inconvenient and, in addition to drug effect, prefer the opportunity to also see the added response to several more months of important lifestyle changes. These 2 approaches are reasonable, and neither is clearly superior on the basis of scientic evidence. Thus, a personalized plan can be put in the hands of the patient and his or her provider. For patients who do not initially attain therapeutic targets, the ATP recommendation to return again in 6 weeks and involve a lipid specialist can be considered, but alternative strategies can also lead to success. For example, a primary care clinic initiative treating patients with lipidlowering action plans at follow-up intervals of 3 to 4 months converted a considerable number of patients to ATP therapeutic attainers at a low cost.18 Recommendation 5: Designate <70 mg/dl as an Ideal Low-Density Lipoprotein Cholesterol Target The 2004 ATP white paper states that an LDL cholesterol level of 70 mg/dL seems preferable for high-risk patients compared with a level of 100 mg/dL. At present, however, [the Heart Protection Study] and [the Pravastatin or Atorvastatin Evaluation and Infection Therapy trial] cannot be taken as nal word on the benet of reducing [LDL cholesterol] levels to well below 100 mg/dL. Setting the routine target at 100 mg/dl discourages treatment if the baseline LDL cholesterol level is 100 mg/dl, although such patients benet from therapy. Moreover, some of the highest risk patients, such as those with diabetes, have biologically lower LDL cholesterol levels because LDL particles are small and dense.19 With data from additional trials and meta-analyses supporting LDL cholesterol levels 70 mg/dl,9 we recommend this as an ideal therapeutic target. Indeed, the European Society of Cardiology and the European Atherosclerosis Society recently adopted this goal for patients with atherosclerosis.8 In patients who have baseline LDL cholesterol levels 70 mg/dl, we concur with the Canadian guideline recommendation to aim for LDL cholesterol lowering of

Editorial/ATP IV Recommendations

50% because, again, this group benets equally from effective lipid lowering.16 Recommendation 6: Endorse Lipid Targets Beyond Low-Density Lipoprotein Cholesterol Level ATP III restricts itself to high blood cholesterol in its title and is LDL-centric, considering LDL cholesterol as the single primary therapeutic target. Although cholesterol levels have been used as part of the eligibility criteria for randomized controlled trials, they were not the point of randomization; that is, no trials have randomized patients to different cholesterol targets. Cholesterol targets are justied by their role in the biology of atherosclerosis, epidemiologic studies linking elevated cholesterol levels to atherosclerosis, the ability to measure cholesterol concentrations accurately in practice, and observations in multiple randomized trials that lowering cholesterol levels correlates with improved outcomes. A similar scientic basis exists for other parameters. Each atherogenic lipoprotein particle (LDL, intermediate-density lipoprotein, very low density lipoprotein, chylomicrons, and lipoprotein[a]) is composed of a core of cholesterols and triglycerides surrounded by a single copy of apolipoprotein B.20 In a gradient-driven process, apolipoprotein B containing particles enter the arterial wall and are retained, providing the building block for plaque formation.20 When apolipoprotein B recognizes binding sites on proteoglycans, oxidative and inammatory responses ensue, and atherosclerosis progresses.20 Epidemiologic data suggest that atherosclerosis risk tracks with atherogenic particle number (e.g., apolipoprotein B) atherogenic cholesterol (non-HDL cholesterol) LDL cholesterol.19,21,22 At a given LDL cholesterol level, there will be more atherogenic particles in a patient with a small dense LDL (pattern B) phenotype compared to one with larger, more buoyant particles. As a result, risk in patients with discordantly elevated particles may be underestimated by solely measuring cholesterol. The Centers for Disease Control and Preventions Lipid Standardization Program helps laboratories measure lipids and lipoproteins with the level of accuracy and precision needed to implement the NCEP recommendations. Accuracy-based standards are available for total cholesterol, triglycerides, HDL cholesterol, apolipoprotein A-I, and apolipoprotein B, but the NCEPs primary therapeutic target, LDL cholesterol, is not on this list. This is because LDL cholesterol is not routinely measured but is instead calculated using the Friedewald formula, which can introduce a magnied underestimation bias when LDL cholesterol levels are lower than the calibrated range of the original data set.23 As with LDL cholesterol, there are data from multiple randomized controlled trials that as non-HDL cholesterol and apolipoprotein B levels decrease, so does cardiovascular risk.16 After investing decades educating physicians and patients about LDL cholesterol, we do not recommend abandoning it. Tempering any clinical therapeutic recommendations for targets in general, or one target over another, is the lack of trial data primarily examining treat-to-target strate-

gies.11 Nevertheless, after rst prioritizing the coupling of therapeutic intensity to risk, like we use glycosylated hemoglobin levels to guide adjustments in diabetes therapies, it makes sense to further personalize lipid therapy on the basis of levels of lipids and lipoproteins. The therapeutic response to a set dose of a given statin will vary in individual patients on the basis of multiple factors, such as adherence level, concurrent medications, and genetics, so assessing the adequacy of therapy and further risk stratifying with blood tests adds information. On the basis of the multiple lines of evidence presented here, non-HDL cholesterol and apolipoprotein B can be considered for this purpose. A simple message may be not to stop at LDL cholesterol, particularly in high-risk patients. Currently, ATP III deemphasizes non-HDL cholesterol by rating it a secondary target for only select patients with hypertriglyceridemia. As such, non-HDL cholesterol is not standard in laboratory reports and has not successfully disseminated into clinical practice.24 Non-HDL cholesterol adds zero cost to testing and can be measured in a nonfasting state.25 Although non-HDL cholesterol can be easily calculated by practitioners, advising routine laboratory reporting of non-HDL cholesterol could validate its importance and increase awareness. Apolipoprotein B can also be measured in a nonfasting state, and its cost is similar to a standard lipid panel.25 If the NCEP ATP were to acknowledge apolipoprotein B as a therapeutic target, this would be in line with existing European8 and Canadian16 guidelines and statements from the American College of Cardiology and American Diabetes Association19 and the National Lipid Association.24 Barriers to making apolipoprotein B a routine target are provider unfamiliarity, less well dened target levels, and greater cholesterol than apolipoprotein B lowering with statins.25 Patients especially likely to benet from apolipoprotein B testing include higher risk patients with hypertriglyceridemia and/or diabetics with dyslipidemia. If a patient has attained his or her LDL cholesterol and non-HDL cholesterol goals, then the next time testing is pursued, apolipoprotein B might be measured instead. Whether measurement of particle concentration by nuclear magnetic resonance should be routinely considered remains an open question in the absence of widespread clinical trial data and standardization. Ultimately, there is a lot left to learn about therapeutic targets for lipid-modifying therapy. Although we focus on targets of lipid-lowering therapy, large trials of HDL cholesterolraising therapies are ongoing. In ATP IV and future iterations of ATP guidelines, the NCEP has the opportunity to take a leadership role in educating practitioners about common limitations of LDL cholesterol and more broadly address potential roles of emerging alternatives. Recommendation 7: Rene Target Levels to the Equivalent Population Percentile According to ATP III, the goal for non-HDL cholesterol in persons with high serum triglycerides can be set at 30 mg/dL higher than that for LDL cholesterol on the premise that a [very low density lipoprotein] cholesterol level of 30 mg/dL is normal. However, with this approach, non-

The American Journal of Cardiology (www.ajconline.org)

HDL cholesterol goals are higher than the equivalent population percentile for an equivalent LDL cholesterol goal. Ideal and satisfactory targets listed in Table 2 represent about the 10th and 40th population percentiles in the National Health and Nutrition Examination Survey (NHANES) 2007 to 2008.26 At low LDL cholesterol levels, the equivalent non-HDL cholesterol target is about 20 mg/ dl, not 30 mg/dl, higher. An apolipoprotein B target 80 mg/dl is the equivalent population percentile for LDL cholesterol 100 mg/dl, while the ideal apolipoprotein B per population percentiles is 60 mg/dl, but this may be impractical in many patients. Recommendation 8: Remove Descriptors ATP III uses descriptors in association with LDL cholesterol ranges; a level of 130 to 159 mg/dl is labeled borderline high. Nature, however, would argue that this is a false characterization, as LDL cholesterol levels range from 50 to 70 mg/dl in native hunter-gatherers, healthy human neonates, free-living primates, and other wild mammals, groups free from atherosclerosis.27 Thus, an LDL cholesterol level of 150 mg/dl is two- to threefold higher than humans evolved to have. Characterizing such a level as borderline high may provide false reassurance and is not evidence based. We recommend removing the current descriptors and framing United States adult lipid levels in the context of evolutionarily normal levels. Although this reveals widespread abnormality, allocation of pharmacotherapy should be based on comprehensive risk assessment, not solely cholesterol. Recommendation 9: Make Lifestyle Messages Simpler For diet, the ATP III executive summary highlights information on recommended nutrient composition in a way that is less than ideal when communicating with patients. We doubt many providers nd it effective to say to a patient, up to 10% of your total calories should be from polyunsaturated fat, up to 20% from monounsaturated fat, and so on. We submit that patients will achieve more consistent diet and exercise patterns in response to simpler, userfriendly take-home messages. Rather than nutrient percentages, we recommend emphasizing a dietary pattern. Patients can be encouraged to follow a Dietary Approaches to Stop Hypertension (DASH) like diet, which parallels a Mediterranean-style diet28 and is 1 component of ideal cardiovascular health. The key components of this diet can be efciently discussed in the clinic: increased consumption of fresh fruits, vegetables, whole grains, low-fat dairy, oily sh, poultry more than red meat, modest amount of nuts and beans, herbs and spices in place of salt, and limited added fats with olive oil in place of butter and margarine. Patients can engage in the learning process at home by using cookbooks written for the lay public that follow a DASH-like eating pattern. Indeed, those who follow this dietary pattern benet from reduced cardiovascular and all-cause mortality.28 Exercise is equally important and easily communicated by encouraging patients to wear pedometers, with a goal of

10,000 steps/day. Such an intervention is associated with increased physical activity and improved health.29 Pedometers can quantify activity across a broad range of activities, including walking, jogging, running, and sports, such as tennis. If a patient uses a stationary bike or stair-stepping machine, or swims, such activity can be quantied separately. Summary of Recommendations The concepts and solutions offered in this statement represent ways to translate the totality of the published research into enhanced hyperlipidemia guidelines. We are proponents of an ABCs30 approach to risk reduction that can be adapted to include our proposed revisions to the ATP guidelines: (1) assessment of risk: use a more comprehensive, accurate approach; (2) algorithm: directly link risk to therapy; (3) biology: educate on particles versus cholesterol and evolutionarily normal levels; (4) cholesterol: deemphasize baseline cholesterol as a starting point in treatment algorithms; (5) drug classes: prioritize statins; (6) descriptors: remove them; (7) diet: convey a simpler message (e.g., a DASH-like or Mediterranean diet); (8) exercise: convey a simpler message (e.g., 10,000 steps/day); and (9) follow-up: relax it.
1. Executive summary of the 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). JAMA 2001;285:2486 2497. 2. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. J Am Coll Cardiol 2004;44:720 732. 3. Lloyd-Jones DM, Leip EP, Larson MG, DAgostino RB, Beiser A, Wilson PW, Wolf PA, Levy D. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006;113:791798. 4. Go AS, Iribarren C, Chandra M, Lathon PV, Fortmann SP, Quertermous T, Hlatky MA. Statin and beta-blocker therapy and the initial presentation of coronary heart disease. Ann Intern Med 2006;144:229 238. 5. Berger JS, Jordan CO, Lloyd-Jones D, Blumenthal RS. Screening for cardiovascular risk in asymptomatic patients. J Am Coll Cardiol 2010; 55:1169 1177. 6. Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, Foster E, Hlatky MA, Hodgson JM, Kushner FG, Lauer MS, Shaw LJ, Smith SC Jr, Taylor AJ, Weintraub WS, Wenger NK, Jacobs AK, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Nishimura R, Ohman EM, Page RL, Stevenson WG, Tarkington LG, Yancy CW. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2010;56:e50 e103. 7. Blaha MJ, Budoff MJ, DeFilippis AP, Blankstein R, Rivera JJ, Agatston A, OLeary DH, Lima J, Blumenthal RS, Nasir K. Associations between C-reactive protein, coronary artery calcium, and cardiovascular events: implications for the JUPITER population from MESA, a population-based cohort study. Lancet 2011;378:684 692. 8. Catapano AL, Reiner Z, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D. 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.

Editorial/ATP IV Recommendations 9. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efcacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376: 1670 1681. 10. Lloyd-Jones DM, Hong Y, Labarthe D, Mozaffarian D, Appel LJ, Van Horn L, Greenlund K, Daniels S, Nichol G, Tomaselli GF, Arnett DK, Fonarow GC, Ho PM, Lauer MS, Masoudi FA, Robertson RM, Roger V, Schwamm LH, Sorlie P, Yancy CW, Rosamond WD. Dening and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Associations strategic impact goal through 2020 and beyond. Circulation 2010;121:586 613. 11. Hayward RA, Krumholz HM. Three reasons to abandon low-density lipoprotein targets: an open letter to the Adult Treatment Panel IV of the National Institutes of Health. Circ Cardiovasc Qual Outcomes 2012;5:25. 12. Mancini GB, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, Gupta M, Hegele RA, Ng D, Pope J. Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian Working Group Consensus Conference. Can J Cardiol 2011;27:635 662. 13. Mihaylova B, Briggs A, Armitage J, Parish S, Gray A, Collins R. Lifetime cost effectiveness of simvastatin in a range of risk groups and age groups derived from a randomised trial of 20,536 people. BMJ 2006;333:15. 14. Kushner FG, Hand M, Smith SC Jr, King SB III, Anderson JL, Antman EM, Bailey SR, Bates ER, Blankenship JC, Casey DE Jr, Green LA, Hochman JS, Jacobs AK, Krumholz HM, Morrison DA, Ornato JP, Pearle DL, Peterson ED, Sloan MA, Whitlow PL, Williams DO. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54:22052241. 15. Wright RS, Anderson JL, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Jneid H, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP, Antman EM, Califf RM, Chavey WE II, Hochman JS, Levin TN. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. J Am Coll Cardiol 2011;57:e215 e367. 16. Genest J, McPherson R, Frohlich J, Anderson T, Campbell N, Carpentier A, Couture P, Dufour R, Fodor G, Francis GA, Grover S, Gupta M, Hegele RA, Lau DC, Leiter L, Lewis GF, Lonn E, Mancini GB, Ng D, Pearson GJ, Sniderman A, Stone JA, Ur E. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult2009 recommendations. Can J Cardiol 2009;25:567579. 17. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marsi RM, Maggioni AP, Tavazzi L, Tognoni G,

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Cleareld MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735742. Coodley GO, Jorgensen M, Kirschenbaum J, Sparks C, Zeigler L, Albertson BD. Lowering LDL cholesterol in adults: a prospective, community-based practice initiative. Am J Med 2008;121:604 610. Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008;51:15121524. Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007;116:18321844. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J, Furberg CD. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes 2011;4:337345. Barter PJ, Ballantyne CM, Carmena R, Castro Cabezas M, Chapman MJ, Couture P, de Graaf J, Durrington PN, Faergeman O, Frohlich J, Furberg CD, Gagne C, Haffner SM, Humphries SE, Jungner I, Krauss RM, Kwiterovich P, Marcovina S, Packard CJ, Pearson TA, Reddy KS, Rosenson R, Sarrafzadegan N, Sniderman AD, Stalenhoef AF, Stein E, Talmud PJ, Tonkin AM, Walldius G, Williams KM. Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. J Intern Med 2006;259:247258. Scharnagl H, Nauck M, Wieland H, Marz W. The Friedewald formula underestimates LDL cholesterol at low concentrations. Clin Chem Lab Med 2001;39:426 431. Davidson MH, Ballantyne CM, Jacobson TA, Bittner VA, Braun LT, Brown AS, Brown WV, Cromwell WC, Goldberg RB, McKenney JM, Remaley AT, Sniderman AD, Toth PP, Tsimikas S, Ziajka PE, Maki KC, Dicklin MR. Clinical utility of inammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol 2011;5:338 367. Ramjee V, Sperling LS, Jacobson TA. Non-high-density lipoprotein cholesterol versus apolipoprotein B in cardiovascular risk stratication: do the math. J Am Coll Cardiol 2011;58:457 463. Centers for Disease Control and Prevention. NHANES 2007 - 2008: laboratory les. Available at: http://www.cdc.gov/nchs/nhanes/ nhanes2007-2008/lab07_08.htm. Accessed December 21, 2011. OKeefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol 2004;43:21422146. Parikh P, McDaniel MC, Ashen MD, Miller JI, Sorrentino M, Chan V, Blumenthal RS, Sperling LS. Diets and cardiovascular disease: an evidence-based assessment. J Am Coll Cardiol 2005;45:1379 1387. Bravata DM, Smith-Spangler C, Sundaram V, Gienger AL, Lin N, Lewis R, Stave CD, Olkin I, Sirard JR. Using pedometers to increase physical activity and improve health: a systematic review. JAMA 2007;298:2296 2304. Gluckman TJ, Baranowski B, Ashen MD, Henrikson CA, McAllister M, Braunstein JB, Blumenthal RS. A practical and evidence-based approach to cardiovascular disease risk reduction. Arch Intern Med 2004;164:1490 1500.