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    Emerging risk factors and risk markers for cardiovascular disease: Looking beyond NCEP ATP III


    Cardiovascular disease (CVD) continues to be the leading cause of death in the United States. The current standard of care is to treat patients to a target low-density lipoprotein (LDL) cholesterol level, as recommended by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III. Unfortunately, despite treating patients to their respective LDL goals, many patients continue to suffer cardiovascular events. Evidence of risk factors for CVD beyond lipids is mounting in the literature. NCEP ATP III now recommends testing some patients for emerging cardiovascular risk factors, such as levels of C-reactive protein (CRP), fibrinogen, coronary artery calcification (CAC), homocysteine, lipoprotein(a), and small, dense LDL. Agents that may be used to ameliorate these emerging risk factors include statins, niacin, fibric acid derivatives, bile acid sequestrants, ezetimibe, thiazolidinediones, and aspirin. Selection of the most appropriate therapy requires an understanding of the function each emerging risk factor plays in atherosclerosis and the mechanisms of therapy. (Formulary. 2009;44:237–247.)

    Despite recent advances in the management of dyslipidemia, hypertension, and diabetes mellitus, cardiovascular disease (CVD) remains the leading cause of death in the United States.1 Current preventative strategies for CVD focus on treating patients to specific lipid goals as identified in the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III and its 2004 update.2,3 NCEP ATP III bases these goals on a patient's risk factor(s) for CVD, such as hypertension (HTN), low high-density lipoprotein (HDL) cholesterol levels, family history of premature CVD, age, and tobacco use. These risk factors are specified because of their well-established association with CVD.

    Current NCEP ATP III guidelines recommend a primary target of treating low-density lipoprotein (LDL) cholesterol levels to each patient's predetermined goal. Recommended targets for primary prevention are LDL <160 mg/dL for patients with 0 or 1 risk factor and <130 mg/dL for those with ≥2 risk factors and a Framingham risk score of <20%.2 Those patients who have documented CVD or who have a CVD risk equivalent such as diabetes mellitus, abdominal aortic aneurysm, peripheral arterial disease (PAD), carotid artery disease, or a Framingham risk of ≥20% are recommended to maintain an LDL cholesterol level <100 mg/dL; those patients who are considered at very high risk for a future CVD event should maintain an LDL level <70 mg/dL.2,3

    Figure 1: Risk mediator model (ie, inflammatory markers)
    Although most cardiovascular (CV) events can be attributed to ≥1 of the aforementioned major risk factors, there remains a significant proportion of the population who will experience an event in the absence of traditional risk factors. It has been estimated that up to 50% of all myocardial infarctions (MIs) and strokes occur in men and women with LDL levels below recommended goals.4 To effectively decrease the CV risk of such patients, the ATP III update recommends consideration of more aggressive lipid therapy in patients with "emerging risk factors" for CVD.3 NCEP ATP III identifies these emerging risk factors as lipoprotein(a) (Lp[a]), homocysteine, prothrombotic and proinflammatory factors, impaired fasting glucose, and evidence of subclinical atherosclerotic disease.2 Identification of these emerging risk factors also allows for further risk stratification of patients who may be at an intermediate risk of disease and thus may encourage more aggressive therapy.3,5

    Figure 2: Risk marker model (ie, inflammatory markers)
    Many CV risk factors have been proposed over the last decade, but for a risk factor to be considered clinically useful, it must be readily measurable, there must be considerable evidence linking the risk factor to CVD, and modifying treatment must be available.1,5 Additionally, as more evidence is published linking these emerging risk factors to CVD, it becomes important to determine whether the value is a risk mediator or a risk marker. In other words, the question is whether a phenomenon causes CVD or whether the phenomenon is noted because CVD is present. To be considered a risk mediator, the factor must not only show a strong correlation with an increased likelihood of CVD but must also directly contribute to the development of disease. A risk marker is likely elevated because of the existence of a disease state but does not contribute to disease progression (Figures 1 and 2).1 This review will focus on several of the most researched emerging risk mediators and markers. For the sake of being concise, these mediators and markers will be referred to throughout the article as risk factors (Table 1).3

    Table 1: Emerging risk factors for CVD
    As more data are published on these emerging risk factors, providers will begin to screen more patients for their presence, and eventually prescribing patterns and guidelines will likely change. Although statins have a favorable effect on LDL levels and high-sensitivity C-reactive protein (hs-CRP) values, they have little effect on LDL particle size or on the levels of Lp(a) or fibrinogen.1,5–7 Clinicians will likely use secondary lipid therapies, such as niacin and the fibric acids, more aggressively, and many patients will be managed with a multidrug regimen. Additionally, healthcare professionals may begin to see an increased use of supplements containing folate, vitamin B12, vitamin B6, and even thiazolidinediones (TZDs). Therefore, it is becoming increasingly important that clinicians understand the mechanics of these risk factors as mediators of CVD, as well as the agents used to manage these risks.


    Lipids (cholesterol esters and triglycerides) are transported through the body in complexes known as lipoproteins. Lipoproteins vary in size and density and are designated as LDL, HDL, and very low-density lipoprotein (VLDL). Laboratory-reported LDL concentration actually represents a measurement of not just one lipoprotein, but rather a spectrum of LDL particles ranging in size and density.6

    Table 2: Dyslipidemia: Pattern A versus Pattern B
    LDL cholesterol is divided into 4 major subtypes based on particle diameter: large LDL I (≥26 nm), medium LDL II (25.5–26 nm), small LDL III (24.2–25.6 nm), and very small LDL IV (≤24.2 nm).6,8,9 Two tests are widely available to determine LDL particle size: nuclear magnetic resonance (NMR) and vertical density-gradient ultracentrifugation.10 LDL size may be reported as an average diameter or as a concentration of each subtype reported in mg/dL. A patient's LDL profile can be further classified into 2 distinct patterns (A and B) based on average particle diameter or the LDL particle subtype with the highest concentration. Pattern A denotes larger average particle diameter (20.6–23 nm), whereas pattern B denotes smaller average particle diameter (18–20.5 nm).10 Pattern A and B patients also differ in other components of the lipid panel, as noted in Table 2.

    It has been well established that smaller, more dense LDL particles confer a greater CV risk, and that by altering LDL pattern, this risk may be reduced.6 These data support the idea that LDL quality (ie, size and density) may matter more than LDL quantity.8 The predominance of small, dense LDL (sdLDL) particles has been linked to a 3- to 7-fold increased risk of coronary artery disease (CAD) when compared with the risk associated with a preponderance of large LDL particles.8 A partial explanation may be that sdLDL particles are taken up more readily by the arterial tissue and are also more susceptible to oxidation than larger, more buoyant LDL particles.8,9

    The quintessential pattern B patient is the patient with insulin resistance, and this patient often presents with metabolic syndrome. Metabolic syndrome is a constellation of risk factors that increase a patient's risk for CVD and diabetes.2 Factors indicative of metabolic syndrome include abdominal obesity, high triglycerides (TG), low HDL, impaired fasting glucose, and HTN. This TG-rich lipoprofile is associated with an increase in sdLDL particles.8 sdLDL levels may also be significantly elevated in men, in postmenopausal women, and in patients with a genetic predisposition, increased age, or high-carbohydrate diet.8

    Table 3: Medications used to alter LDL pattern
    To convert sdLDL to larger, more buoyant particles, patients need to have a reduced availability of TG-rich particles. Accordingly, drugs that change LDL pattern most effectively include those that reduce TG levels most effectively, including fibric acids (fenofibrate, gemfibrozil) and niacin. Table 3 lists the agents demonstrated to be most effective at improving LDL pattern.8,9,11 Statins are believed to lower the levels of all LDL subtypes but will not shift the production of sdLDL to the production of larger, more buoyant varieties.8,9,11

    In 1 study, immediate-release niacin (niacin IR) 3,000 mg/d (n=48) was studied versus atorvastatin 10 mg/d (n=53) in patients with total cholesterol levels >200 mg/dL and TG levels of 200 to 800 mg/dL.7 Both agents reduced sdLDL by a significant amount (44.3% with atorvastatin and 35.1% with niacin IR), but niacin IR increased the number of larger LDL particles by 75%, whereas atorvastatin reduced the number of these particles by 9.8%. Additionally, niacin IR shifted more patients from pattern B to pattern A than did atorvastatin (41% vs 12%, respectively). Another trial compared 120 men with baseline TG levels >190 mg/dL who were treated with either lovastatin 20 mg twice/d plus colestipol 10 g 3 times/d or lovastatin 20 mg twice/d plus niacin IR 4,000 mg/d.12 Patients treated with lovastatin plus niacin IR demonstrated a 20% increase in pattern A dyslipidemia versus a 6% increase in those patients treated with lovastatin plus colestipol.

    Fibrates have also been demonstrated to alter LDL particle size. In 1 study, healthy, nonobese patients with type IIA dyslipidemia were randomized to receive fenofibrate 200 mg/d (n=36) or pravastatin 20 to 40 mg/d (n=43) for 16 weeks.13 Fenofibrate-treated patients demonstrated a significant increase in LDL particle size. The proportion of fenofibrate-treated patients with sdLDL was reduced from 69.4% to 30.6% (P<.05), whereas the proportion of pravastatin-treated patients with sdLDL was reduced from 81.4% to 72.1% (not significant). A similar study compared fenofibrate 200 mg/d with atorvastatin 10 mg/d in patients with type 2 diabetes mellitus and mixed dyslipidemia.14 In this study, atorvastatin reduced LDL by 29% and lowered sdLDL but had no significant effect on increasing the number of larger, more buoyant LDL particles. Conversely, fenofibrate reduced LDL by 11% but also reduced sdLDL by 31% (P<.05) and increased intermediate-density LDL by 36%.


    The role of inflammation in CVD has been well documented over the past decade. Inflammation has been demonstrated to be involved in all stages of atherosclerosis, from initiation and growth to plaque rupture.15 hs-CRP levels are increased in patients with acute inflammatory events such as infection, autoimmune disorders, and the chronic inflammation caused by atherosclerotic plaque formation. The correlation between hs-CRP and CV events is so strong that hs-CRP retains an independent association with coronary events even after adjusting for age, total cholesterol (TC), HDL cholesterol, tobacco use, body mass index (BMI), diabetes, HTN, exercise level, and family history of CVD.5,15 It has been noted that CRP levels are up-regulated in the presence of atherosclerotic plaques, promoting LDL cholesterol uptake by macrophages and facilitating the recruitment of circulating monocytes to plaque sites, thus furthering atherogenesis.16

    Despite this strong evidence linking elevated hs-CRP to CVD, it remains unknown whether CRP is a risk mediator or a risk marker.1 One recent study by Elliot et al17 was undertaken to answer this question. This study investigated the association of genetic loci with CRP levels and the risk of CVD. The researchers identified a single-nucleotide polymorphism (SNP) in the CRP gene that was strongly associated with CRP levels, with each minor allele associated with a 21% decrease in CRP concentration. Despite a prediction of a 6% CVD risk reduction based on this decrease in CRP, this SNP was not associated with CVD. From these results, the authors concluded that although CRP is elevated in CVD, it does not appear to be a cause of CVD.

    Other studies, however, have demonstrated that hs-CRP levels may have prognostic value for predicting a cardiovascular event in patients with acute coronary syndrome (ACS), those undergoing coronary revascularization procedures using percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), and, most robustly, in patients with no known history of CVD.1,4,15,18 One of the first studies to link hs-CRP to increased CVD risk was the Physicians' Health Study.16 This study divided patients into quartiles by baseline hs-CRP, with ≤0.55 mg/L as the lowest level and ≥2.11 mg/L as the highest level. The Physicians' Health Study indicated that patients with hs-CRP levels in the highest quartile are at 2 times the risk of stroke, 3 times the risk of MI, and 4 times the risk of peripheral arterial disease compared with those with hs-CRP levels in the lowest quartile. These findings were strengthened by data from the Women's Health Study, which demonstrated that women with LDL <130 mg/dL but with hs-CRP levels in the highest tertile ( >3 mg/L) have 3 times the risk of experiencing coronary events in the future.19 More recently, a cohort of 5,067 patients without CVD underwent testing to determine if CRP was predictive of CV and coronary events after a mean of 12.8 years.20 The authors observed that the strongest association between CV events and a single biomarker was the association between these events and CRP, which demonstrated a multivariable-adjusted HR of 1.19 (95% CI, 1.07-1.32) for each standard deviation increment in CRP. Another recent publication demonstrating the correlation between CVD and hs-CRP is the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study.4 The JUPITER study enrolled 17,802 patients with a normal LDL (<130 mg/dL) but an elevated hs-CRP (>2 mg/L) and compared treatment with rosuvastatin 20 mg/d versus placebo. The study was halted after 1.9 years of follow-up. Treatment with rosuvastatin produced a 44% decrease in the composite risk of MI, stroke, arterial revascularization, hospitalization for unstable angina, and death from CV causes, further demonstrating that hs-CRP is closely related to CVD.

    Table 4: Characteristics/conditions affecting hs-CRP concentration
    hs-CRP is a nonspecific marker of inflammation. In adults, normal hs-CRP is <1 mg/L. Levels of hs-CRP have been divided into tertiles, which correlate with Framingham risk scores: low risk (<1.0 mg/L), moderate risk (1–3 mg/L), and high risk (>3 mg/L).15 It is necessary to perform 2 separate measurements to accurately classify a patient's risk. If the initial hs-CRP is >10 mg/L, it should be discarded and the test should be repeated in 2 weeks to allow for the resolution of acute inflammation.15

    Table 5: Medications used to lower hs-CRP
    As noted in Table 4, hs-CRP may be reduced or increased by several patient characteristics and conditions.5 Diabetes, tobacco use, obesity, HTN, metabolic syndrome, acute illness, and inflammation have all been demonstrated to increase hs-CRP. There is also a direct relationship between the extent of reduction in hs-CRP and the reduction in LDL. Medications that reduce hs-CRP include statins, ezetimibe, fibrates, niacin, colesevelam, TZDs, and aspirin (Table 5).1,19,21–31 It is important to note that hs-CRP levels should be used clinically only as a marker for predicting CVD risk, not as evidence of the effectiveness of a particular drug therapy. Therefore, following serial hs-CRP concentration is not necessary and not recommended.5,15


    Fibrinogen has been identified as an emerging risk factor for CVD.2 Like hs-CRP, fibrinogen is an acute phase reactant. The conversion of fibrinogen to fibrin, which is triggered in response to vascular or tissue injury, is the final step in the clotting cascade. Fibrinogen has also been linked to CVD through other mechanisms, such as decreasing blood viscosity; increasing platelet aggregation; causing vasoconstriction at sites of vessel wall injury; and increasing cell adhesion, chemotaxis, and proliferation.5 However, there are no therapies that have been demonstrated to lower fibrinogen concentrations enough to reduce CV risk.5,32,33

    Fibrinogen antigen is measured by immunonephelometry, a test normally used to diagnose dysfibrogenemias, which may lead to bleeding disorders. A fibrinogen antigen level >350 mg/dL is considered elevated. Because fibrinogen is an acute phase reactant, levels should not be tested in patients with active bleeding, those with acute infection, or those who have received blood transfusions in the previous 4 weeks.10

    Table 6: Characteristics/conditions affecting fibrinogen concentration
    The Coronary Artery Risk Development in Young Adults (CARDIA) study was a population-based, observational study of 1,396 men and women aged 18 to 30 years.34 Patients were divided into quartiles based on fibrinogen level, with 108 to 220 mg/dL constituting Quartile 1, 221 to 254 mg/dL constituting Quartile 2, 255 to 298 mg/dL constituting Quartile 3, and levels >299 mg/dL constituting Quartile 4. This study demonstrated that elevated levels of fibrinogen are associated with an increased risk of subclinical CVD in the next decade of life. Those patients in the highest quartile demonstrated a change in carotid intima-media thickness (CIMT) score of +0.204 versus a change of –0.136 among patients in the lowest quartile (P<.001). Despite this possible link, the usefulness of fibrinogen as a marker of CVD is debatable, as there is a paucity of data supporting therapy for patients with high fibrinogen levels. For example, 1 trial demonstrated a 13% reduction in fibrinogen in patients taking bezafibrate but failed to demonstrate a reduction in the primary end point of CV events or stroke.32 Another study comparing the effects of extended-release niacin with the effects of gemfibrozil on lipids and emerging CV risk factors demonstrated that niacin reduced fibrinogen levels, but this reduction was not linked to a reduction in pertinent clinical end points, such as CV morbidity or mortality.33 The most effective treatment for elevated fibrinogen appears to be lifestyle modification, such as smoking cessation, moderate alcohol intake, and exercise (Table 6).5,35


    Lp(a) is an LDL-like particle. The protein constituent consists of lipo-protein(a), or Apo(a), linked to apolipoprotein B, the standard lipoprotein of the LDL particle.5 The Lp(a) particle is similar in composition and density to a normal LDL particle, but has an added deleterious effect because of its structural similarity to plasminogen.36 In addition to having thrombotic properties, Lp(a) is also 40% cholesterol by mass; therefore, it also has the ability to cause atherosclerosis.5

    Levels of Lp(a) are classified into quartiles, which correlate to increasing risk for CVD. An Lp(a) level <20 mg/dL is considered desirable, whereas a level of 20 to 30 mg/dL is borderline, 31 to 50 mg/dL is high risk, and >50 mg/dL is very high risk. Lp(a) is measured by enzyme-linked immunosorbent assay (ELISA) testing and may vary based on ethnicity, with Asian and Caucasian patients having the highest levels.10

    Of the currently known emerging CV risk factors, Lp(a) seems to have the strongest hereditary link, but not all studies have demonstrated an increased risk of CVD associated with increased Lp(a).5,37,38 A meta-analysis of 27 prospective studies that included >5,400 patients with CVD demonstrated that patients with Lp(a) measurements in the top third of the population are at a 70% increased risk of death from CVD versus those with measurements in the bottom third.39 In contrast, the Genetic Epidemiology Network of Arteriopathy (GENOA) study included 765 men and women and demonstrated no correlation between Lp(a) and coronary calcification, with correlation coefficients of 0.055 (P=.33) and 0.052 (P=0.27) in men and women, respectively.38 Beyond the fact that data seem to be conflicting regarding the importance of Lp(a) as a risk factor for CVD, there are also currently no good treatment options for elevated Lp(a) levels.

    Table 7: Characteristics/conditions affecting Lp(a) concentration
    Whereas statins have not been demonstrated to reduce Lp(a) levels, extended-release niacin (niacin ER) may be effective when administered at high doses. Pan et al40 studied 46 diabetic patients with pattern B dyslipidemia and an Lp(a) level >25 mg/dL. The study was undertaken to ascertain if niacin ER could reduce Lp(a) in patients with diabetes and what dose would be needed to decrease these patients' Lp(a) levels to <25 mg/dL. All patients took niacin ER 500 to 750 mg once/d initially, with dose titration to achieve a target Lp(a) <25 mg/dL. A total of 22% of the enrolled patients withdrew because of adverse reactions. The mean dose of niacin ER needed for patients to reach the Lp(a) goal was 2,819821 mg/d, which is above the maximum daily dose approved for this medication. By study termination, the mean baseline Lp(a) had been reduced from 3710 mg/dL to 2310 mg/dL (P<.001). Oral estrogens have also been demonstrated to reduce Lp(a) levels, but the risks associated with hormone replacement therapy, such as CVD, invasive breast cancer, pulmonary embolism, and stroke, outweigh the benefit. Hence, oral estrogens are not recommended for this use (Table 7).41–43


    One of the most hotly debated risk factors for CVD continues to be homocysteine. Homocysteine is formed as a by-product of the metabolism of the essential amino acid methionine and is then remetabolized by multiple enzymes that use folic acid, cobalamin (vitamin B12), and pyridoxine (vitamin B6) as substrates.5 Although homocysteine has no known biologic function, it is a highly reactive amino acid that can increase CVD risk if levels are elevated. One meta-analysis calculated an odds ratio of 1.7 (95% CI, 1.5–1.9) for CAD in patients with elevated homocysteine levels.44 Several mechanisms have been described to explain the correlation between elevated homocysteine and CVD. Homocysteine is thought to injure endothelial cells, alter platelet activity, inhibit vasodilation, and cause thrombogenesis.45,46 Increased homocysteine levels likely increase CVD risk when augmented by other well-established risk factors (eg, smoking, HTN, elevated LDL) but may not increase risk when not associated with these other risk factors.5 One of the most common causes of hyperhomocysteinemia is a gene mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme, which is responsible for metabolizing homocysteine. This genetic abnormality can lead to a 25% increase in homocysteine levels, especially in the setting of low folate intake.5

    Plasma homocysteine is measured by competitive immunoassay and should be tested when patients are in the fasting state, as higher levels are noted after eating. Levels >10 mcmol/L are thought to place patients at higher risk of CVD. Very high homocysteine levels (>100 mcmol/L) are typically caused by homozygous cystathionine-beta-synthase (CS) deficiency, which occurs in 1 per 300,000 live births. Patients with the MTHFR variant will likely have moderate elevations in homocysteine levels (16–30 mcmol/L).10

    Table 8: Characteristics/conditions affecting homocysteine concentration
    Although there continues to be debate regarding the use of homocysteine as an independent CV risk factor, there does seem to be support for the treatment of elevated homocysteine (>10 mcmol/L) in patients with other risk factors. Treatment may consist of a modified diet rich in folate-containing foods or supplemental vitamins containing folic acid 0.4 mg, vitamin B6 2 mg, and vitamin B12 6 mcg per day (Table 8).5,45 A meta-analysis of published trials confirmed that folic acid, cyanocobalamin, and pyridoxine may be used in combination at various doses to lower homocysteine levels.46 This analysis demonstrated that folic acid 0.5 to 5 mg and vitamin B12 0.5 mg can be expected to reduce homocysteine levels by approximately one-third; unfortunately, these trials did not assess CVD outcomes associated with a reduction in homocysteine levels.46 The effect of lowering homocysteine levels on the outcome of carotid plaque progression was demonstrated in an observational study of 101 patients with CVD who were stratified by homocysteine level (<14 mcmol/L and >14 mcmol/L).47 These patients received folic acid 2.5 mg, vitamin B6 25 mg, and vitamin B12 250 mcg once/d. Carotid plaque was measured using a 2-dimensional ultrasound. The rate of plaque progression among patients with homocysteine levels >14 mcmol/L was 0.210.41 cm2/y before treatment and –0.0490.24 cm2/y after treatment (P=.0001). Although patients in this study had improvement in plaque progression regardless of baseline homocysteine levels, the most robust improvement was observed in those patients with the highest baseline levels of homocysteine.

    Conversely, another trial assigned 5,522 patients with documented vascular disease or diabetes to treatment with folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg or placebo.48 The occurrence of death from CV causes, MI, or stroke was 18.8% in the treatment group and 19.8% in the placebo group (P=.41). Patients in both groups had a mean baseline homocysteine level of 12.2 mcmol/L; the treatment group demonstrated a decrease from baseline of 2.4 mcmol/L in plasma homocysteine level.


    Whereas the aforementioned tests may have some predictive value for CVD, the presence of coronary calcium indicates that CVD is present and can be used to predict the risk of a CV event. Coronary artery calcification (CAC) is virtually absent in normal arteries. CAC occurs early in atherosclerotic plaque formation in the second and third decades of life and progresses with further growth of the plaque. CAC seems to be most useful in identifying higher-risk asymptomatic individuals with an intermediate CVD risk based on family history and Framingham risk score.49,50 CAC is predictive of death or MI at 3 to 5 years and is independently predictive when controlling for standard risk factors.49

    CAC is measured using an electron-beam computed tomography (EBCT) scan, which allows for the acquisition of 1.5- to 3-mm sections. Each identified lesion is assigned a score of 1 to 4 based on the size of the lesion; the largest plaques receive a score of 4. The total coronary calcium score is then determined by adding up each lesion score for all sequential slices. CAC scores <100 are associated with a low probability (0.4%) of annual death or MI, whereas scores of 100 to 399 indicate that a moderate amount of plaque is present (annual risk of death or MI, 1.3%).50 A CAC score ≥400 puts a patient at a similar risk to that associated with diabetes or PAD, 2 well-known coronary heart disease risk equivalents.2 Because CAC is a marker of plaque formation, there is no treatment directed to reduce CAC. Rather, the occurrence of a high CAC score would result in a recommendation to be more aggressive in other methods to decrease plaque (eg, lipid-lowering therapy), as this high score indicates that CVD is already present.50


    With the availability of new tests and accumulating literature support regarding the importance of these emerging risk factors, providers and healthcare systems may be tempted to consider screening everyone for these risk factors. Additionally, as the results of these trials reach the lay press, educated patients may begin to request testing for emerging risk factors. Universal screening is not cost-effective, however, and it does not add clinical benefit in all situations.

    Table 9: Average cost of testing and Medicare reimbursement
    In assessing these emerging risk factors for CVD, cost also must be considered. The average cost of a fasting lipid panel including TC, TG, and HDL with a calculated LDL is $20 to $25 (Medicare reimbursement, $18). Costs for emerging risk factor testing are higher, based mostly on the technology used to obtain results. By far the most expensive test is an EBCT scan to measure CAC score, which costs approximately $2,200 because of the multiple factors involved, including imaging, contrast dye, injection of contrast dye, professional interpretation, and electrocardiogram (ECG) monitoring. The cost of the CT alone is approximately $400. Other tests range in cost from $18 to $100, depending on the test type and geographical location of the processing laboratory (Table 9).51

    Table 10: Screening for emerging risk factors
    All of the above emerging risk factors are useful when determining appropriate therapy for patients with an intermediate Framingham risk category (10-year risk, 10%–20%), and some of these risk factors may be beneficial for predicting risk of a second CV event (Table 10).1,3–5,35,42,45,49,50 It is also important to remember that screening a patient already known to be at high risk for CVD (10-year risk, >20%) will add little clinical value, as these patients will already warrant aggressive treatment. The most appropriate role for the use of emerging risk factors is in the determination of aggressiveness of therapy and the most advantageous medication for patients with intermediate Framingham risk, a family history of premature CVD without traditional risk factors, or CVD in the absence of traditional risk factors.


    CVD remains the leading cause of mortality in the United States despite advances in lipid management. Although a reduction in LDL cholesterol remains the major therapeutic target, it is important to remember that high LDL is not the only cause of CVD. Searching for nontraditional risk factors may be clinically useful in a certain subset of patients. The risk:benefit ratio of emerging risk factor testing and therapy must be evaluated on a case-by-case basis, and the importance of patient education and medication adherence must be stressed. Look for prescribing patterns to change as more data are published on these important risk factors.

    Dr Hoffmann and Dr Tucker are clinical pharmacists, Blanchard Valley Medical Associates, Findlay, Ohio. Dr Parker is an assistant professor of pharmacy practice, College of Pharmacy, University of Findlay, Ohio.

    Acknowledgment: The authors would like to thank Dr David Meier and Dr Catherine Waggoner-Meier for their assistance in preparing this manuscript.

    Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.


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