1. High-sensitivity C-reactive protein (hs-CRP):

   1. Aetna considers high-sensitivity C-reactive protein (hs-CRP) testing medically necessary for members who meet all of the following criteria: 1) member has 2 or more coronary heart disease (CHD) major risk factors*, and 2) member has low density lipoprotein (LDL) cholesterol levels between 100 to 130 mg/dL; and 3) member has been judged to be at an intermediate risk of cardiovascular disease by global risk assessment (i.e., 10 to 20 percent risk of CHD per 10 years using Framingham point scoring**).

      *Major risk factors include the following:

      1. Current cigarette smoking
      2. Hypertension (BP 140 mmHg or higher, or on antihypertensive medication)
      3. Low HDL cholesterol (less than 40 mg/dL)
      4. Family history of premature CHD (CHD in male first degree relative less than 55 years; CHD in female first degree relative less than 65 years)

      5. Age (men age 45 years or older; women age 55 years or older).

      **Note: Framingham risk scoring for men and women is presented in the Appendix below.

   2. Aetna considers hs-CRP testing experimental and investigational for all other indications, including use as a screening test for the general population and for monitoring response to therapy.

2. Apolipoprotein B (apo B):

   Measurement of apolipoprotein B (apoB) is considered medically necessary for use in high-risk persons with hypercholesterolemia to assess whether additional intense interventions are necessary when LDL cholesterol goals are reached (LDL cholesterol less than 70 mg/dL and non-LDL cholesterol less than 100 mg/dL in persons with known CVD or diabetes mellitus, or LDL-C less than 100 mg/dL and non-LDL cholesterol less than 130 mg/dL in persons with other risk factors). High risk persons are those with one or more of the following criteria:

   1. Known cardiovascular disease (CVD); or
   2. Diabetes mellitus; or

   3. Two or more of the following CVD risk factors:

      1. Current cigarette smoking; or
      2. Hypertension ((BP 140 mmHg or higher, or on antihypertensive medication); or
      3. Family history of premature CVD) (CHD in male first degree relative less than 55 years; CHD in female first degree relative less than 65 years).

   Aetna considers measurement of apolipoprotein B (apoB) experimental and investigational for all other indications.

3. Aetna considers any of the following tests for assessing CHD risk experimental and investigational:

   1. Apolipoprotein A-I (apo AI)
   2. Apolipoprotein E (apo E)
   3. Homocysteine testing
   4. Lipoprotein remnants: intermediate density lipoproteins (IDL) and small density lipoproteins
   5. HDL subspecies (LpAI, LpAI/AII and/or HDL3 and HDL2)
   6. LDL subspecies (small and large LDL particles)
   7. LDL gradient gel electrophoresis
   8. Lipoprotein(a) enzyme immunoassay
   9. Angiotensin gene (CardiaRisk AGT)
   10. Fibrinogen
   11. Lipoprotein-associated phospholipase A2 (Lp-PLA2) (PLAC)
   12. Measurement of long chain omega-3 fatty acids composition in red blood cell

   13. Interleukin 6 -174 g/c promoter polymorphism

   The medical literature does not support the utility of the above tests for screening, diagnosis, or management of CHD.

4. Aetna considers homocysteine testing experimental and investigational for assessing CHD or stroke risk. Homocysteine testing may be medically necessary for the following indications: 1) evaluating persons with homocystinuria (cystathionine beta synthase deficiency); 2)  evaluating persons with coagulation disorders (e.g., unexplained thrombotic disorders such as deep venous thrombosis or pulmonary embolism); 3) for evaluating women with recurrent pregnancy loss (see CPB 348 - Recurrent Pregnancy Loss); and 4) for evaluating persons with borderline vitamin B12 deficiency (see CPB 536 - Vitamin B-12 Therapy ). Homocysteine testing is considered experimental and investigational for all other indications.

5. Aetna considers measurement of carotid medial intima thickness experimental and investigational for assessing CHD risk.

6. Aetna considers non-invasive measurements of arterial elasticity by means of blood pressure waveforms (e.g., HDI PulseWave, CVProfilor) experimental and investigational for assessing CHD risk.

See also CPB 228 - Calcium Scoring for Evaluating Coronary Artery Disease; CPB 525 - Screening for Lipid Disorders.

Nontraditional risk factors for coronary heart disease (CHD) are used increasingly to determine patient risk, in part because of an assumption that many patients with CHD lack traditional risk factors (cigarette smoking, diabetes, hyperlipidemia, and hypertension).

Hackman & Anand (2003) summarized existing evidence about the connection between atherosclerotic vascular disease and certain nontraditional coronary heart disease (CHD) risk factors (abnormal levels of C-reactive protein, fibrinogen, lipoprotein(a), and homocysteine). The authors conclude that current evidence does not support the notion that nontraditional risk assessment adds overall value to traditional risk assessment. The authors explained  that “for each putative risk factor, there must be prospective controlled trials demonstrating that (1) targeting individuals with elevated levels of these risk factors for proven risk-reducing interventions offers advantages over current methods of targeting therapy (e.g. by cholesterol, diabetes, and blood pressure screening); or (2) selectively and specifically reducing the risk factor reduces hard cardiovascular end points, such as mortality, nonfatal myocardial infarction, and stroke.”

Recent large prospective studies support screening for traditional risk factors. In one study (Greenland, et al., 2003), researchers assessed major antecedent risk factors among patients who suffered fatal CHD or nonfatal myocardial infarction (MI) while enrolled in 3 prospective cohort studies involving nearly 400,000 patients (age range, 18-59). Follow-up ranged from 21 to 30 years. Major risk factors were defined as total cholesterol greater than or equal to 240 mg/dL (greater than or equal to 6.22 mmol/L), systolic blood pressure greater than or equal to 140 mm Hg, diastolic BP greater than or equal to 90 mm Hg, current cigarette smoking, and diabetes. Of patients age 40 to 59 at baseline who died of CHD during the 3 studies, 90%-94% of women and 87%-93% of men had at least 1 major CHD risk factor. In the 1 study that assessed nonfatal MI, at least 1 major risk factor was present in 87% of women and 92% of men age 40 to 59.

In another large study (Khot, et al., 2003), researchers analyzed data from more than 120,000 patients enrolled in 14 randomized clinical trials to determine the prevalence of baseline conventional risk factors among CHD patients. Of patients with CHD, 85% of women and 81% of men had at least 1 conventional risk factor.

As Canto & Iskandrian (2003) notes, these data challenge the assumption that "only 50%" of CHD is attributable to conventional risk factors and emphasize the importance of screening for these risk factors and aggressively treating patients who have them.

An assessment by the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2005) provided a framework for the evaluation of the potential clinical utility putative risk factors for cardiovascular disease. The assessment explained that the strongest evidence of the value of such a test is direct evidence that its measurement to assess cardiovascular disease risk results in improved patient outcomes. In the absence of such evidence, the assessment of the potential clinical utility of a test lies in understanding a chain of logic and the evidence supporting those links in the chain. The potential for clinical utility of a test for assessing cardiovascular disease risk lies in following a chain of logic that relies on evidence regarding the ability of a measurement to predict cardiovascular disease beyond that of current risk prediction methods or models, and evidence regarding the utility of risk prediction to treatment of cardiovascular disease. In order to assess the utility of a test in risk prediction, specific recommendations regarding patient management based on the test results should be stated. The assessment notes that another factor that would be important to consider is the availability and reliability of laboratory measurements.

High sensitivity C-reactive protein (hs-CRP):

It has been theorized that certain markers of inflammation--both systemic and local--may play a role in the development of atherosclerosis. High sensitivity C-reactive protein (hs-CRP) is one systemic marker of inflammation that has been intensively studied and identified as an independent risk factor for coronary artery disease. Of current inflammatory markers identified, hs-CRP has the analyte and assay characteristics most conducive for use in practice. A Writing Group convened by the American Heart Association and the Centers for Disease Control and Prevention (Pearson, et al., 2003) endorsed the optional use of hs-CRP to identify persons without known cardiovascular disease who are at intermediate risk (10 to 20 percent risk of coronary heart disease over the next 10 years). For these patients, the results of hs-CRP testing may help guide considerations of further evaluation (e.g., imaging, exercise testing) or therapy (e.g., drug therapies with lipid-lowering, antiplatelet, or cardioprotective agents). The Writing Group noted, however, that the benefits of such therapy based on this strategy remain uncertain. High-sensitivity C-reactive protein testing is not necessary in high-risk patients who have a 10-year risk of greater than 20 percent, as these patients already qualify for intensive medical interventions. Individuals at low risk (less than 10 percent per 10 years) will be unlikely to have a high risk (greater than 20 percent) identified through hs-CRP testing. The Writing group recommended screening average risk (10-year risk less than 10 percent) for hs-CRP for purposes of cardiovascular risk assessment. The Writing Group stated that hs-CRP also may be useful in estimating prognosis in patients who need secondary preventive care, such as those with stable coronary disease or acute coronary syndromes and those who have underdone percutaneous coronary interventions. The Writing Group posited that this information may be useful in patient counseling because it offers motivation to comply with proven secondary preventive interventions. However, the Writing Group noted that the utility of hs-CRP in secondary prevention is more limited because current guidelines for secondary prevention generally recommend, without measuring hs-CRP, the aggressive application of secondary preventive interventions. The Writing Group recommends measurement of hs-CRP be performed twice (averaging results), optimally two weeks apart, fasting or non-fasting in metabolically stable patients. Patients with an average hs-CRP level greater than 3.0 mg/dL are considered to be at high relative risk of CHD. Patients with an average hs-CRP level less than 1 mg/L are at low relative risk, and patients with an hs-CRP level between 1.0 and 3.0 mg/L are at average relative risk. If hs-CRP level is greater than 10 mg/dL, the Writing Group recommends that testing should be repeated and the patient examined for sources of infections or inflammation. The Writing group recommended against the measurement of inflammatory markers other than hs-CRP (cytokines, other acute-phase reactants) for determination of coronary risk in addition to hs-CRP.

In an analysis of Women’s Health Study participants, including high-sensitivity CRP in CVD-risk prediction improved the predictive accuracy in nondiabetic women whose traditional 10-year CVD risk was at least 5%. Cook, et al.. (2006) compared risk-prediction models that include or do not include hs-CRP. The models were applied to 15,048 Women’s Health Study participants who were age 45 or older and free of cardiovascular disease and cancer at baseline. During a mean follow-up of 10 years, 390 women developed CVD. For accurately predicting CVD events, hs-CRP was outmatched only by older age, current smoking, and high blood pressure among traditional Framingham variables. Nondiabetic women were classified according to their 10-year risk for CVD in a model without CRP. Adding CRP to the model substantially improved predictive accuracy for women with an initial 10-year CVD risk of at least 5%. The gain in accuracy was greatest among women initially classified in the 5% to 9.9% risk range: 21.3% of those women were reclassified in a more accurate risk category when CRP was included in the risk-prediction model (11.9% moved down a risk category (to <5%) and 9.5% moved up a risk category (to 10%–19.9%)). Accounting for the predictive value of older age, smoking, and high BP lessened the predictive contribution of CRP but still left CRP ahead of any cholesterol parameter (total, LDL, or HDL).

In a nested, case-control study of 122 cases and 244 controls drawn from a cohort of Women's Health Study participants, Ridker, et al. (2000) assessed the risk for cardiovascular disease (CVD) according to levels of four inflammatory markers: high-sensitive C-reactive protein (hs-CRP), serum amyloid A, interleukin-6, and soluble intercellular adhesion molecule type-1 (sICAM-1). Homocysteine and several lipid and lipoprotein fractions (including apolipoprotein A-I, apolipoprotein B-100, lipoprotein(a), total cholesterol and HDL cholesterol) were measured. Outcomes included fatal coronary heart disease, nonfatal myocardial infarction, stroke, or coronary revascularization procedures. Overall, hs-CRP showed the strongest univariate association with all markers studied.  Although several other markers studies were univariate predictors of CVD, hs-CRP was the only novel plasma marker that predicted risk in multivariate analysis. Total cholesterol-to-HDL ratio also predicted risk in multivariate analysis.

Yeh (2005) noted that as a clinical tool for assessment of cardiovascular risk, hs-CRP testing enhances information provided by lipid screening or global risk assessment. While statin therapy and other interventions can reduce hs-CRP, whether or not such reductions can actually prevent cardiovascular events is being investigated. This is in agreement with the observation of Nambi and Ballantyne (2005) who stated that studies are now under way to evaluate if targeting patients with high CRP and low LDL cholesterol will have any impact on future cardiovascular events and survival and whether changes in CRP correlate to event reduction. The utility of CRP as a target of therapy remains to be proved, and these ongoing studies will likely provide us with guidance.

Apolipoprotein A-I, LDL gradient gel electrophoresis, and Lipoprotein (a) enzyme immunoassay:

The apolipoprotein A-I test, LDL gradient gel electrophoresis (GGE), and lipoprotein(a) (Lp(a)) enzyme immunoassay have been promoted as important determinants of coronary heart disease risk, and as a guide to drug and diet therapy in patients with established coronary artery disease. The measurement of subclasses of Lp(a) and LDL subclass patterns may be useful in elucidating possible atherogenic dyslipemia in patients who have no abnormalities in conventional measurement (total cholesterol, HDL, LDL, and triglycerides). However, the therapeutic usefulness of discovering such subclass abnormalities has not been substantiated.

Braunwald, et al. states “because Lp(a) measurement is not a widely available laboratory determination and the clinical significance of alterations in Lp(a) is not known, the NCEP [National Cholesterol Education Program] does not recommend the routine measurement of this lipoprotein at this time.”

Prospective studies that evaluated Lp(a) as a predictor of cardiovascular events have had conflicting results. Some studies suggested that Lp(a) was an independent risk factor for CHD (Bostom, et al., 1994; Bostom, et al., 1996; Schaefer, et al., 1994; Nguyen, et al., 1997; Wald, et al., 1994; Cremer, et al., 1994; Schwartzman, et al., 1998; Ariyo, et al., 2003; Shai, et al., 2003), while others showed no significant association (Coleman, et al., 1992; Ridker, et al., 1993; Jauhiainen, et al., 1991; Cantin, et al., 1998; Nishino, et al., 2000).

Hackam and Anand (2003) systematically reviewed the evidence for Lp(a) and concluded that “the use of Lp(a) as a screening tool has some limitations.” Although they identified moderate evidence for its role as an independent risk factor, they found minimal information on its incremental risk, and no prospective clinical outcome studies evaluating its role in management.

Although some studies have linked elevated serum levels of lipoprotein(a) to cardiovascular risk, the clinical utility of this marker has not been established. Suk Danik, et al. (2006) analyzed data available from a cohort of about 28,000 participants followed for 10 years in the Women’s Health Study. Blood samples that had been frozen at study entry were tested for lipoprotein(a), and incident cardiovascular events were documented during the follow-up period. A total of 26% of the women had lipoprotein(a) levels greater than 30 mg/dL, which is the level currently considered to confer increased cardiovascular risk. However, only the women in the highest quintile with respect to lipoprotein(a) level (greater than or equal to 44 mg/dL) were more likely to experience cardiovascular events than women in the lowest quintile (hazard ratio, 1.47); thus, a threshold effect was seen. Overall, women with the highest rates of cardiovascular disease were those who had lipoprotein(a) levels at or above the 90th percentile and LDL-C levels at or above the median. These findings indicate that routinely measuring lipoprotein(a) is of little benefit for most women. However, lipoprotein(a) testing might be helpful in the clinical management of women who are at particularly high risk or who have already experienced a cardiovascular event despite having few or no traditional risk factors. Since lipoprotein(a) is not decreased by lipid-lowering therapies, the mainstay of therapy for cardiovascular risk is still aggressive control of LDL-C levels with a statin or niacin, regardless of a woman’s lipoprotein(a) level.

A study by Ariyo, et al. (2003) of the predictive value of Lp(a) in the elderly (age greater than 65 years) found that lipoprotein(a) levels have prognostic value for stroke and death in men, but not for CHD in men or for any major vascular outcome in women. However, even the links for stroke and death in men were evident only in the highest compared with the lowest quintile, not in intermediate quintiles. Ariyo, et al. (2003) prospectively studied 3972 Cardiovascular Health Study participants (minimum age 65) who had Lp(a) measurements taken at baseline and did not have vascular disease. Overall, mean baseline Lp(a) levels were slightly higher among women (4.4 mg/dL) than among men (3.9 mg/dL). Median follow-up was 7.4 years. Study participants were placed into quintiles of Lp(a) level (lowest, 0.1-1.2 mg/dL; highest, 8.2-47.5 mg/dL). In analyses adjusted for other vascular-disease risk factors, elderly women in the highest Lp(a) quintile were no more likely to experience stroke, coronary heart disease (CHD), death from vascular causes, or death from any cause than were elderly women in the lowest quintile. However, compared with elderly men in the lowest Lp(a) quintile, elderly men in the highest quintile were significantly more likely to experience stroke (hazard ratio, 2.92), death from vascular causes (HR, 2.09), and death from any cause (HR, 1.60), but not CHD. The authors concluded that, overall, these results do not appear to support routine measurement of Lp(a) levels in elderly persons.

In a nested case-control study, lipoprotein(a) was found to add little to standard lipid measures and C-reactive protein in predicting development of peripheral arterial disease. Ridker, et al. (2001) had access to baseline plasma samples from 14,916 healthy men from the Physicians' Health Study. Samples from 140 cases who developed symptomatic peripheral arterial disease (PAD) during 9-year follow-up were compared with samples from 140 controls (matched by age, smoking status, and length of follow-up) who did not develop PAD. Eleven standard and novel biomarkers were analyzed.  Most biomarkers were significant independent predictors of peripheral arterial disease. Ratio of total cholesterol (TC) to HDL cholesterol was the strongest lipid predictor (adjusted relative risk, 3.9; 95 percent CI, 1.7-8.6); CRP was the strongest nonlipid predictor (adjusted RR, 2.8; 95 percent CI, 1.3-5.9). In a separate analysis of which novel biomarkers would enhance the predictive power of standard lipid measures (TC and TC/HDL ratio), the inflammatory markers (fibrinogen and CRP) were the only ones to add to it significantly (CRP even more than fibrinogen). As expected, lipoprotein(a) and homocystine added little, as  did LDL cholesterol, apolipoprotein A-1, and apolipoprotein B-100.

No universally accepted, standardized method for determination for Lp(a) exists, although recently, a working group of the International Federation of Clinical Chemistry demonstrated the inaccuracy of Lp(a) values determined by methods sensitive to apo(a) size and recommended the widespread implementation of a proposed reference material for those Lp(a) assays that are validated to be unaffected by apo(a) size heterogeneity. Lipoprotein(a) concentrations are unaffected by most available lipid-lowering therapies, with the exception of high-dose nicotinic acid, which is often poorly tolerated. This has made it difficult to demonstrate that Lp(a) plays a direct role in vascular disease, since large-scale controlled intervention studies examining the reduction of Lp(a) and hard cardiovascular end points have not been performed. Last, the incremental predictive value of Lp(a) measurement additive to that of traditional screening methods for global risk assessment has not been formally studied.

A consensus statement by the American College of Cardiology (ACC) and the American Diabetes Association (ADA) (Brunzell, et al., 2008) concluded that the clinical utility of routine measurement of Lp(a) is unclear, although more aggressive control of other lipoprotein paramters may be warranted in those with high concentrations of Lp(a).

There is inadequate evidence that LDL subclassification by electrophoresis improves outcomes of patients with cardiovascular disease. According to the guidelines of the National Cholesterol Education Program, electrophoretic methods “cannot be recommended as procedures of choice for measuring LDL-cholesterol.”

An ACC/ADA consensus statement (Brunzell, et al., 2008) concluded that measurements of apoA1 appears to provide little clinical value beyond measurements of HDL cholesterol.

Measurement of apolipoprotein A-I, LDL GGE, and Lp(a) have not been established as clinically useful tests at this time. They are not useful in determining therapy for patients with coronary artery disease or dyslipemia.

Apo [Apolipoprotein] B testing:

Each LDL particle has one molecule of apo B per particle. Therefore the apo B concentration is an indirect measurement of the number of LDL particles, in contrast to LDL cholesterol, which is simply a measure of the cholesterol contained within the LDL. Because apo B is a marker for LDL particle number, the greater or higher the apo B level suggests an increased level of small, dense LDL particles which are thought to be especially atherogenic.

Guidelines from the American College of Cardiology and the American Diabetes Association recommend the use of apoB in persons at elevated cardiometabolic risk to assess whether additional intense interventions are necessary when LDL cholesterol goals are reached (Brunzell, et al., 2008). According to these guidelines, high risk persons are those with known cardiovascular disease (CVD), diabetes, or multiple CVD risk factors (i.e., smoking, hypertension, family history of premature CVD).

Apo B testing has not been validated as a tool for risk assessment in the general population. A recent study found that measuring apo B and apo A-I, the main structural proteins of atherogenic and antiatherogenic lipoproteins and particles, adds little to existing measures of CAD risk assessment and discrimination in the general population.  van der Steeg, et al. (2007) measured apolipoprotein and lipid levels for 869 cases (individuals who developed fatal or nonfatal coronary artery disease) and 1511 matched controls (individuals who remained CAD-free) over a mean follow-up of 6 years. Upon enrollment, participants were 45–79 years old and apparently healthy. Occurrence of CAD during follow-up was determined using a regional health authority database (hospitalizations) and U.K. Office of National Statistics records (deaths). The apo B:apo A-I ratio was associated with future CAD events independent of traditional lipid values, including total cholesterol:HDL cholesterol ratio (adjusted odds ratio, 1.85), and independent of the Framingham risk score (OR, 1.77). However, the apo B:apo A-I ratio did no better than lipid values in discriminating between individuals who would and would not develop CAD, and it added little to the predictive value of the Framingham risk score. In addition, this ratio incorrectly classified 41% of cases and 50% of controls.

A large, population-based, cohort study suggests that the apo B:apo A-1 ratio has little clinical utility in predicting incident CHD in the general population, and that measuring total cholesterol and HDL appears to suffice to determine heart disease risk (Ingelsson, et al., 2007). Investigators used a variety of techniques to evaluate the relative utility of apo B, apolipoprotein A-1 (apo A-1), serum total cholesterol, HDL cholesterol, LDL cholesterol, non-HDL cholesterol, and three lipid ratios in determining risk for CHD, as well as the relative ability of these measures to reclassify CHD risk. More than 3300 middle-aged, white participants in the Framingham Offspring Study without cardiovascular disease were followed for a median of 15 years. A total of 291 first CHD events occurred, 198 of them in men. In men, elevations in non-HDL cholesterol, apo B, total cholesterol:HDL ratio, LDL:HDL ratio, and apo B:apo A-1 ratio were all significantly associated with increased CHD risk to a similar degree. Elevated apo A-1 and HDL were likewise associated with reduced CHD risk. Women had results similar to those in men except that decreased apo A-1 was not significantly associated with incident CHD. In sex-specific analyses, elevated LDL and total cholesterol were not significantly associated with increased CHD risk in either men or women, perhaps owing to the lack of statistical power of these substudies. In men, total cholesterol:HDL and apo B:apo A-1 ratios both improved reclassification of 10-year risk for CHD; however, the difference between the two was not significant. In women, neither lipid ratio improved CHD risk reclassification.

Further study is needed to determine the usefulness of apolipoprotein B measurement as an adjunct to risk evaluation by routine lipid measurements in the general population.

Apolipoprotein E (apo E) testing:

Apolipoprotein E (apo E) is one of the major apolipoproteins of VLDL. Apo E has been studied for many years for its involvement in cardiovascular disease. In addition, one allele of the apoE gene (E4) is being investigated as a potential risk factor for Alzheimer's disease and stroke. Apo E polymorphisms have functional effects on lipoprotein metabolism, and has been studied in disorders associated with elevated cholesterol levels and lipid derangements.

The literature on apo E and cardiovascular disease was reviewed by Eichner, et al. (2002); the investigators concluded that the apo E genotype yields poor predictive values when screening for clinically defined atherosclerosis despite positive, but modest associations with plaque and coronary heart disease outcomes. The value of apo E testing in the diagnosis and management of CHD needs further evaluation.

Available evidence indicates that apo E genotype is a poor predictor of ischemic stoke. Sturgeon and colleagues examined whether apo E genotype alters the risk for ischemic stroke, as previous studies examining whether apo E genotype alters the risk for stroke have yielded conflicting results. In this study, 14,679 individuals in the Atherosclerosis Risk in Communities (ARIC) study were genotyped for apo E. During more than 183,569 person-years of follow-up, 498 participants had an ischemic stroke. After stratifications by sex and race and adjustments for nonlipid risk factors for stroke, no significant relation between apo E genotype and stroke was identified, except for a lower risk associated with APOE-epsilon-2 compared with APOE-epsilon -3 in black women only. The investigators concluded that the apo E genotype is at most a weak factor for ischemic stroke

Homocysteine testing:

Homocysteine is an amino acid that is found normally in the body. Studies suggest that high blood levels of this substance may increase a person's chance of developing heart disease, stroke, and reduced blood flow to the hands and feet. It is believed that high levels of homocysteine may damage arteries, may make blood more likely to clot, and may make blood vessels less flexible. It is also suggested that treatment consisting of high doses of folic acid, vitamins B6 and B12 decreases a patient's homocysteine levels and thus decreases their risk of cardiovascular disease. However, published study results in the medical literature are conflicting; therefore the usefulness of homocysteine testing in reducing cardiovascular disease risk and improving patient outcomes has not been demonstrated. ATP III noted the uncertainty about the strength of the relation between homocysteine and CHD, a lack of clinical trials showing that supplemental B vitamins will reduce risk for CHD, and the relatively low prevalence of elevated homocysteine in the U.S. population.

In a structured evidence review, Hackam and Anand (2003) found moderate evidence that homocystine is an independent risk predictor of coronary heart, cerebrovascular and peripheral vascular disease. However, the authors found only minimal evidence that homocystine contributes incrementally to risk prediction. The authors also stated that it is unclear whether elevated homocysteine is causal or simply a marker of atherosclerotic vascular disease. The authors found few, if any, controlled studies to evaluate risk-reduction strategies for these four factors.   Hackman and Anand (2003) stated “[w]hether homocysteine is causative in the pathogenesis of atherosclerosis, is related to other confounding cardiovascular risk factors, or is a marker of existing vascular disease will have to await the completion of a number of large, randomized controlled trials studying the effect of homocysteine-lowering vitamins on cardiovascular end points.”

An assessment by the Institute for Clinical Systems Improvement (ICSI, 2003) concluded that “[t]he relevance of studies of [plasma homocysteine] as a risk factor for cardiovascular disease is unclear given the decreasing [plasma homocysteine] levels as a result of mandatory folic acid supplementation. It remains unproven whether lowered [plasma homocysteine] levels will result in reduced morbidity and mortality from cardiovascular disease.”

Prospective clinical studies have failed to demonstrate beneficial effects of homocysteine lowering therapy on cardiovascular disease. An international randomized trial involved 5522 patients with histories of documented vascular disease (coronary, cerebrovascular, or peripheral) or with diabetes plus another risk factor. Patients received either a combination pill (containing folic acid, vitamin B6, and vitamin B12 or placebo daily (HOPE 2 Investigators, 2006). After 5 years, mean homocysteine levels were about 25% lower in the vitamin group than in the placebo group. However, no significant difference was found between groups in the primary endpoint of myocardial infarction, stroke, or cardiovascular death (18.8 percent versus 19.8 percent; p = 0.41) or in various secondary outcomes. Importantly, vitamin B supplementation did not benefit patients with the highest baseline homocysteine levels or patients from countries without mandatory folate fortification of food.

In a secondary prevention randomized trial from Norway (Bønaa, et al., 2006), 3749 patients with myocardial infarction during the preceding 7 days received vitamin B supplements or placebo. During an average follow-up of 3 years, vitamin supplementation conferred no benefit for any clinical outcome.

These results are consistent with earlier randomized controlled trials of homocysteine lowering therapy for cardiovascular disease. In a multicenter double-blind randomized study, Toole, et al. (2004) enrolled 3680 patients with nondisabling, nonembolic ischemic strokes and total homocysteine levels above the 25th percentile for the North American stroke population. Patients received either high doses of homocysteine-lowering vitamins (2.5 mg folic acid, 25 mg pyridoxine, and 0.4 mg cobalamin) or low doses that would not be expected to lower homocysteine significantly (20 µg, 200 µg, and 6 µg, respectively). During 2 years of follow-up, mean total homocysteine decreased from 13.4 µmol/L to about 11 µmol/L in the high-dose group and changed only minimally in the control group. However, no reductions were noted in rates of recurrent stroke, coronary events, or death. Even in the subgroup with the highest homocysteine levels, high-dose therapy was ineffective.

In an open-label, prospective trial from the Netherlands, Liem, et al. (2003) randomized 593 consecutive outpatients with coronary-artery disease to folic acid or to standard care. All had been taking statins for at least 3 months. The two groups had similar baseline characteristics, including mean plasma homocysteine levels of 12 µmol/L. By 3 months, homocysteine levels had decreased among folic-acid recipients (by 18%) but not among controls. By a mean follow-up of 24 months, clinical vascular events (i.e., death, myocardial infarction, stroke, invasive coronary procedures, vascular surgery) had occurred at similar rates in folic-acid (12.3%) and standard-care (11.2%) recipients; the similarity also was evident among patients in the highest quartile of baseline homocysteine level (greater than 13.7 µmol/L). In multivariate analysis, poor creatinine clearance was a more important cardiovascular risk factor than elevated homocysteine level was.

Routine testing for homocysteine is also not supported in persons with venous thromboembolism. In a secondary analysis of a previously published multinational randomized controlled trial designed to assess the effect of homocysteine-lowering therapy on the risk for arterial disease (Ray, et al, 2007), investigators studied whether daily folate (2.5 mg) and vitamins B6 (50 mg) and B12 (1 mg) affected the risk for symptomatic deep venous thrombosis or pulmonary embolism. Subjects were 5522 adults (age 55 years and older) with arterial vascular disease, diabetes, and at least one other cardiovascular disease risk factor. During a mean follow-up of 5 years, homocysteine levels decreased more in the vitamin-therapy group than in the placebo group. However, the incidence of venous thromboembolism did not differ between the vitamin-therapy and placebo groups, both overall and among the quartile with the highest homocysteine levels (i.e., greater than 13.8 µmol /L) at baseline.

These results were similar to an earlier secondary prevention trial of homocysteine for venous thromboembolism. In the first randomized trial of homocystine therapy to prevent recurrent venous thromboembolism,  den Heijer, et al. (2007) enrolled 701 patients with recent venous thromboembolism (either proximal deep-vein thrombosis or pulmonary embolism), but without major predisposing risk factors such as recent surgery or immobilization. At baseline, half the patients had hyperhomocysteinemia (mean, 15.5 µmol/L), and half had normal levels (mean, 9.0 µmol/L). Patients were randomized to receive a B-vitamin supplement (5 mg folic acid, 0.4 mg B12, and 50 mg B6) or placebo, in addition to standard anticoagulation. During 2.5 years of follow-up, the overall incidence of recurrent VTE was not significantly different in the B-vitamin and placebo groups (5.4 percent versus. 6.4 percent). In hyperhomocysteinemic patients, the incidence of recurrent venous thromboembolism was nonsignificantly higher in B-vitamin recipients than in placebo recipients (6.7 percent vs. 6.0 percent); in those with normal homocysteine, the incidence of recurrent VTE was nonsignificantly lower in B-vitamin recipients (4.1 percent versus 7.0 percent). The authors note that their study might have been underpowered to detect a small beneficial effect. However, they also speculate that homocysteine's observed epidemiologic association with venous thromboembolism might in fact be mediated by some other thrombophilic factor that is correlated with homocysteine.

An American Heart Association Science Advisory (Malinow, et al., 1999) has concluded: "Although there is considerable epidemiological evidence for a relationship between plasma homocyst(e)ine and cardiovascular disease, not all prospective studies have supported such a relationship …. Until results of controlled clinical trials become available, population-wide screening is not recommended…. Such treatment (supplemental vitamins) is still considered experimental, pending results from intervention trials showing that homocyst(e)ine lowering favorably affects the evolution of arterial occlusive diseases."

A consensus statement from the American College of Cardiology and the American Diabetes Association (Brunzell, et al., 2008) reported that homocysteine testing has been evaluated to determine its prognostic significance in cardiovascular disease. However, the independent predictive value of homocysteine testing and its clinical utility are unclear.

Intermediate and small density lipoproteins:

The National Cholesterol Education Program Adult Treatment Panel III (ATPIII) Guidelines (2002) state that lipoprotein remnants, including intermediate density lipoproteins (IDLs), as well as very-low-density lipoproteins (VLDL) and small density lipoproteins, have been shown to be atherogenic through several lines of evidence. According to ATPIII, “prospective studies relating various measures to CHD risk are limited, and measurement with specific assays cannot be recommended for routine practice.” The ATPIII panel concluded, however, that the most readily available method of measuring atherogenic triglyceride-rich lipoproteins is measurement of VLDL. A consensus statement by the American College of Cardiology and the American Diabetes Association (Brunzell, et al., 2008) noted that, although small dense LDL has been shown to be particularly atherogenic, the association of small LDL and cardiovascular disease may simply reflect the increased number of LDL particles in patients with small LDL.

HDL subspecies:

HDL comprises several components and subfractions that also have been related to CHD risk. While HDL cholesterol is the risk indicator most often used, HDL subfractions (lipoprotein AI (LpAI) and lipoprotein AI/AII (LpAI/AII) and/or HDL3 and HDL2) have also been used for risk prediction. ATPIII concluded, however, that the superiority of HDL subspecies over HDL cholesterol has not been demonstrated in large, prospective studies. Consequently, ATPIII did not recommend the routine measurement of HDL subspecies in CHD risk assessment. A consensus statement by the American College of Cardiology and the American Diabetes Association (Brunzell, et al., 2008) state that measurements of HDL subfractions appear to provide little clinical value beyond measurements of HDL cholesterol.

LDL subspecies (LDL particle sizes) and LDL particle number:

A number of studies have reported that both larger low-density lipoprotein (LDL) particle size and smaller LDL particle sizes are more atherogenic than intermediate-sized particles, and these particles at the extremes of LDL size may be associated with coronary heart disease (CHD) risk. It is thought that LDL subspecies at both extremes of LDL size and density distribution have a reduced LDL receptor affinity.

ATPIII stated that although the presence of small LDL particles has been associated with an increased risk of CHD, the extent to which small LDL particles predict CHD independent of other risk factors is “controversial.” It has been argued by Campos, et al. (2002), based on epidemiologic evidence, that the relationship between small LDL and CHD found in some studies is probably due to its correlation with other lipoprotein risk factors, and that small LDL is not an independent risk factor for CHD.

Campos, et al. (2002) demonstrated in a prospective cohort study that large LDL size is a potential statistically significant predictor of coronary events. Large LDL particles are thought to be large because of high cholesterol ester content. However, Campos reported that the relationship between LDL particle size and coronary events was not present among members of the cohort who were treated with pravastatin, perhaps because pravastatin acts by reducing the size of LDL particles. The author concluded that identifying patients on the basis of LDL size may not be useful clinically, since effective treatment for elevated LDL cholesterol concentrations also effectively treats risk associated with large LDL.

Commenting on LDL particle size, a consensus statement from the American College of Cardiology and the American Diabetes Association stated: "The size of LDL particles can also be measured. As small dense LDL particles seem to be particularly atherogenic, assessment of particle size has intuitive appeal. Both LDL particle concentration and LDL size are important predictors of CVD. However, the Multi-Ethnic Study of Atherosclerosis suggested that on multivariate analyses, both small and large LDL were strongly associated with carotid intima-media thickness [citing Mora, et al., 2007], while the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) showed that both were significantly related to coronary heart disease (CHD) events [citing Otvos, et al., 2006]. The association of small LDL and CVD may simply reflect the increased number of LDL particles in patients with small LDL. Hence, it is unclear whether LDL particle size measurements add value to measurement of LDL particle concentration" (Brunzell, et al., 2008).

The ACC/ADA consensus statement recommended ApoB measurement over measurement of particle number with NMR (Brunzell, et al., 2008): "Limitations of the clinical utility of NMR measurement of LDL particle number or size include the facts that the technique is not widely available and that it is currently relatively expensive. In addition, there is a need for more independent data confirming the accuracy of the method and whether its CVD predictive power is consistent across various ethnicities, ages, and conditions that affect lipid metabolism."

Angiotensin gene:

Angiotensin gene polymorphisms have been associated with cardiovascular disease risk and certain forms of hypertension. Certain AGT polymorphisms have been associated with responsiveness of blood pressure to sodium restriction and ACE inhibitors, so that analysis of the AGT gene may have the potential to help individualize therapy by predicting patients' responsiveness to certain antihypertensive interventions. CardiaRisk AGT from Myriad Genetics Laboratories is a laboratory test that analyzes the angiotensinogen gene. The value of analyzing angiotensin gene polymorphisms in altering the management and improving outcomes of patients has not been demonstrated in prospective clinical studies.

Fibrinogen:

Fibrinogen is a circulating glycoprotein that acts at the final step in the coagulation response to vascular and tissue injury, and epidemiological data support an independent association between elevated levels of fibrinogen and cardiovascular morbidity and mortality.

In a structured evidence review, Hackman and Anand (2003) found moderate evidence that fibrinogen is an independent risk predictor for atherosclerotic disease (coronary heart disease, cerebrovascular disease, and peripheral vascular disease). However, they found minimal evidence that fibrinogen is an incremental risk predictor. Hackam and Anand (2003) identified only one study that examined the additive yield of screening for fibrinogen. The authors noted that precise and validated tests are not available for fibrinogen. In addition, they concluded that it is unclear whether fibrinogen is causal or are simply markers of atherosclerotic vascular disease. The investigators found, few, if any, controlled studies evaluating risk-reduction strategies for fibrinogen or any of the other novel risk factors that they evaluated. The investigators concluded that “clinical trials are necessary before it can be determined whether fibrinogen has a causal role in atherothrombosis or is merely a marker of the degree of vascular damage taking place.”

A consensus statement from the American College of Cardiology and the American Diabetes Association (Brunzell, et al., 2008) stated that the independent predictive power and clinical utlity of fibrinogen measurement is unclear.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) (PLAC):

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that can hydrolyze oxidized phospholipids to generate lysophosphatidylcholine and oxidized fatty acids, which have proinflammatory properties (Ballantyne, et al., 2004). Based on a 510(k) premarket notification, the U.S. Food and Drug Administration has cleared for marketing the PLAC Test (diaDexus, Inc., South San Francisco, CA), an enzyme immunoassay for the quantitative determination of Lp-PLA2 in plasma.

Some large prospective clinical studies have found lipoprotein-associated phospholipase A2 (Lp-PLA2) to be an independent risk factor for coronary artery disease (Packard, et al., 2000; Blake, et al., 2001; Ballantyne, et al., 2004), although another large study (Women's Health Study) found that the predictivity of Lp-PLA2 was no longer statistically significant after adjustment for other risk factors (Blake, et al., 2001).

In a prospective U.S. cohort study (Cook, et al, 2006), researchers assessed whether adding measurements of Lp-PLA2 or any of 18 other novel risk factors to traditional risk factors (age, race, sex, HDL and total cholesterol levels, systolic BP, use of antihypertensive agents, and smoking and diabetes status) improved prediction of incident coronary heart disease among nearly 16,000 adults (age 45 years or older). The authors found that, although Lp-PLA2 showed a statistically significant increase in predictive value compared with traditional risk factors only, this increase was not clinically important. The accompanying editorialist commented that, given that only one in three people with elevated blood pressure or cholesterol levels achieves adequate control, clinician should focus on treatment and control of traditional risk factors. For now, routine screening of Lp-PLA2 levels seems unwarranted.

There is insufficient evidence that Lp-PLA2 is useful in evaluating stroke risk. Ballantyne et al. (2005) evaluated the ability of Lp-PLA2 and C-reactive protein to predict stroke cases in a manner that is statistically independent from traditional risk factors. The authors use data from the Atherosclerosis Risk in Communities (ARIC) Study, a high-quality prospective follow-up of healthy U.S. adults with standardized risk factor measurements as well as stored blood samples that facilitated analysis of the potential new risk predictors. As expected from prior research on stroke risk, race, hypertension, diabetes, systolic and diastolic blood pressure, and triglyceride and HDL-C levels were each individually associated with higher stroke risk. The investigators reported an association of higher Lp-PLA2 and CRP levels with increased stroke risk in statistical models adjusted for the major traditional risk factors. In the highest tertile, CRP level was associated with higher stroke risk by about 2-fold, although confidence intervals were wide. For Lp-PLA2 levels in the top tertile, with adjustment for traditional risk factors and CRP, stroke risk was higher by about 2-fold as well. Thus, the investigators found that the Lp-PLA2 level was a moderately strong stroke risk predictor, and its association with stroke in this study was statistically independent of traditional risk factors as well as the inflammatory marker CRP. In unadjusted analyses, apparently healthy middle-aged people with high levels of both CRP and Lp-PLA2 (highest tertiles of both) had a stroke risk 11-fold higher than people with low levels of both. The authors speculated that Lp-PLA2 and CRP levels may be complementary to traditional risk factors for identifying middle-aged individuals at increased risk for stroke.

The accompanying editorialists explained, however, that from the Ballantyne et al. study, it is unclear how useful CRP or Lp-PLA2 level will be for improving risk prediction versus traditional risk factors alone (Greenland & O'Malley, 2005). The editorialists explained that, simply showing statistical independence is not adequate for demonstrating clinical utility for risk prediction. "Hazard ratios and p values are useful for demonstrating statistical associations, but they fail to show whether the new marker is truly capable of making a major impact on risk prediction or risk discrimination." The editorialists explained that one helpful way to determine additive utility of a new test is through the use of receiver operating characteristic (ROC) curves and area under the curve (AUC) information.  The editorialist noted that, unfortunately, Ballantyne et al did not report AUC or ROC information. However, based on statistical analytic findings reported elsewhere, individual tests with relative risks of only 2.0 to 3.0 "are simply not capable of increasing the AUC to a clinically significant degree."  The editorial concluded that "[t]o date, this search for new cardiovascular risk markers has not led to any test that can be recommended as a routine measurement beyond that of traditional risk factors."

There is a lack of evidence from prospective clinical studies that incorporation of Lp-PLA2 testing in cardiovascular risk assessment improves clinical outcomes. ATPIII guidelines do not include a recommendation for Lp-PLAC testing in assessment of coronary artery disease risk.

Carotid medial intima thickness:

Carotid ultrasonography measurement of the intimal medial thickness of the carotid arteries has been used to assess the atherosclerotic plaque burden. ATPIII reports that the extent of carotid atherosclerosis correlates positively with the severity of coronary atherosclerosis, and that some studies have shown that severity of intimal medial thickness independently correlates with risk for major coronary events. ATPIII states, however, that the predictive power of carotid medial intima thickness for persons without multiple risk factors has not been determined in prospective studies. ATPIII concluded that “its expense, lack of availability, and difficulties with standardization preclude a current recommendation for its use in routine risk assessment for the purpose of modifying intensity of LDL-lowering therapy.”

A consensus statement from the American Diabetes Association and the American College of Cardiology observed that measurements of carotid intima media thickness, as well as measurement of coronary calcification and ankle-brachial index, can detect the presence of so-called subclinical vascular disease, and that patients with documented subclinical atherosclerosis are at increased cardiovascular disease risk and may be considered candidates for more aggressive therapy. The consensus statement concluded, however, that it is unclear whether such tests improve prediction or clinical decision making in patients with cardiometabolic risk (Brunzell, et al., 2008).

Measurement of arterial elasticity:

Arterial elasticity has been shown to decrease with aging and with vascular disease. A number of studies have demonstrated loss of arterial elasticity in persons with coronary artery disease, heart failure, hypertension and diabetes. Hypertension Diagnostics, Inc. (HDI, Eagan, MN) has developed a method of analyzing blood pressure waveforms to noninvasively measure the elasticity (compliance) of arteries and arterioles. The HDI CVProfilor and the HDI PulseWave graphs the blood pressure waveform (“pulse contour analysis”) and calculates the elasticity (flexibility) of large and small arteries and arterioles. The CVProfilor obtains blood pressure and waveform data by use of a blood pressure cuff placed on the left upper-arm and a piezoelectric-based, direct contact, acoustical transducer placed over the right radial artery near the wrist. A computer performs a pulse contour analysis of blood pressure waveform data, and generates a report which includes a large artery elasticity index (a measure of capacitative compliance) and a small artery elasticity index (a measurement of oscillatory or reflective compliance). The CVProfilor also provides measurements of standard blood pressure values (systolic, diastolic and mean arterial pressure), heart rate, body surface area (BSA) and body mass index (BMI). Arterial elasticity has been investigated as an early marker of vascular disease in patients without standard risk factors for cardiovascular disease. Several studies have examined the impact of various factors on arterial elasticity, and have examined the question of whether arterial elasticity is an independent risk factor for cardiovascular disease. However, there is inadequate evidence from prospective clinical studies demonstrating that noninvasive measurements of arterial elasticity using the CVProfilor alters patient management and improves clinical outcomes. Current guidelines from leading medical professional organizations do not include a recommendation for use of pulse waveform analysis in cardiovascular disease risk assessment.

In a clinical trial, Woodman, et al. (2005) reported that large and small artery compliance, and stroke volume/pulse pressure (measured by HDI/PulseWave CR-2000), and systemic arterial compliance show poor agreement with central pulse wave velocity, an established measure of central arterial stiffness.

Measurement of long chain omega-3 fatty acids in red blood cell membranes:

Higher palmitic and lower long-chain omega-3 fatty acids (e.g., alpha-linolenic, eicosapentaenoic and docosahexaenoic acids) in serum are correlated with higher incidence of coronary heart disease (CHD) in middle-aged men at high risk for cardiovascular disease (Simon, et al., 1995). Improvements in plasma fatty acids and vitamins E and C were the only factors found related to improvements in life expectancy and 70 % lowering of heart disease in a study population (Renaud et al, 1995).

Harris (2004) stated that consumption of between 450 and 1000 mg/day of long-chain omega-3 fatty acids (fish or fish oil) is recommended for those without and with known CHD, respectively. Based on animal and isolated cell studies, these fatty acids were presumed to have anti-arrhythmic effects. It has been proposed that red blood cell (RBC) fatty acids composition, which is an index of long-term intake of eicosapentaenoic plus docosahexaenoic acids, can be considered a new, modifiable, and clinically relevant risk factor for death from CHD.

However, there is a lack of scientific evidence regarding how measurements of RBC omega-3 fatty acids composition would affect management of individuals at risk for or patients with CHD. Large randomized controlled studies are needed to ascertain the clinical value of RBC omega-3 fatty acids composition in the management of CHD.

Interleukin 6 -174 g/c promoter polymorphism:

Inflammation plays an important role in the pathogenesis of atherosclerosis. Interleukin 6 (IL-6) has many inflammatory functions, and the IL-6 -174 g/c promoter polymorphism appears to influence IL-6 levels. Previous findings on the relation between this polymorphism and risk of cardiovascular diseases are inconsistent. Sie and colleagues (2006) examined this polymorphism in relation to risk of CHD in a population-based study and meta-analysis. Subjects (n = 6434) of the Rotterdam Study were genotyped. Analyses on the relation between genotype and CHD were performed using Cox proportional hazards tests, and the association between genotype and plasma levels of IL-6 and CRP was investigated. All of the analyses were adjusted for age, sex, and common cardiovascular risk factors. A meta-analysis was performed, using a random effects model. No association between genotype and risk of CHD was observed. The polymorphism was not associated with IL-6 levels, but the C-allele was associated with higher CRP levels (p < 0.01). This meta-analysis did not show a significant association between the genotype and risk of CHD. The authors concluded that the polymorphism is not a suitable genetic marker for increased risk of CHD in persons aged 55 years or older.

Other Risk Factors:

Nontraditional risk markers have been shown to have statistically significant independent associations with incident CHD, but Folsom, et al. (2006) found that they do very little to improve the predictive value of traditional risk-factor assessment. Using a series of case-cohort studies, the prospective Atherosclerosis Risk in Communities (ARIC) Study assessed the association of 19 novel risk markers with incident coronary heart disease in 15,792 adults followed up since 1987-1989 (Folsom, et al., 2006). Novel markers included measures of inflammation (C-reactive protein, LpPLA2, interleukin 6, D-dimer), endothelial function (intracellular adhesion molecule-1), fibrin formation (plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase-1, soluble thrombomodulin, E-selectin), fibrinolysis (matrix metalloproteinase-1, plasminogen, tissue plasminogen activator), B vitamins (leptin, homocysteine, folate, vitamin B6), and antibodies to infectious agents (Chlamydia IgG positivity, cytomegalovirus antibody, herpes simplex virus-1 antibody). Change in the area under the receiver operating characteristic curve (AUC) was used to assess the additional contribution of novel risk markers to CHD prediction beyond that of traditional risk factors. The investigators found that the basic risk factor model, which included traditional risk factors (age, race, sex, total and high-density lipoprotein cholesterol levels, systolic blood pressure, antihypertensive medication use, smoking status, and diabetes), predicted coronary heart disease well, as evidenced by an AUC of approximately 0.8. The other risk factors did not add significantly to the AUC. Among the novel risk factors, the greatest contribution to AUC was C-reactive, protein, with an increase in AUC of 0.003.  The authors concluded that routine measurement of these novel markers is not warranted for risk assessment. These findings also reinforced the utility of major, modifiable risk factor assessment to identify individuals at risk for coronary heart disease for preventive action. The accompanying editorialists explained that these novel markers should not be used for basic risk factor assessment because they do not meaningfully reduce misclassification by traditional risk scoring (Lloyd-Jones & Tian, 2006).

Lloyd-Jones and Tian (2006) explained that statistical association of a novel marker with CVD that is "independent" of traditional risk factors is necessary but far from sufficient to demonstrate utility in the prediction of CVD. Rather, predictive utility requires demonstration of improvement in test characteristics, predictive values, AUCs (or C statistics), or likelihood ratios at given cutoff values when a novel marker is added to the existing risk score.  They explained that, from a decision-making point of view, the "ultimate" measure of a novel screening test is its ability to reclassify individuals. In other words, a new marker is useful only when it corrects a substantial portion of misclassification by the old test (the existing risk score).

Appendix: Framingham Risk Scoring

Framingham risk scoring for men and women below is adapted from Appendix A of the Executive Summary of the ATPIII Report, available at the following web site: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf.

Risk assessment for determining the 10-year risk for developing CHD is carried out using Framingham risk scoring (Table 1 for men and Table 2 for women). The 10-year risk for myocardial infarction and coronary death is estimated from total points, and the person is categorized according to absolute 10-year risk as indicated in the tables.

Table 1: Estimated 10-Year Risk for Men (Framingham Point Scores)

Table 2: Estimated 10-Year Risk for Women (Framingham Point Scores)