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1 National Medical Policy Subject: Policy Number: Cardiac Risk Assessment-Laboratory Tests NMP203 Effective Date*: February 2005 Updated: October 2015 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State s Medicaid manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link X National Coverage Determination (NCD) Lipid Testing (190.23): National Coverage Manual Citation X Local Coverage Determination (LCD)* B-Type Natriuretic Peptide (BNP) Testing: High Sensitivity C-Reactive Protein (hscrp) Testing: Non-Covered Services: Article (Local)* X Other Palmetto GBA. MolDX. Corus CAD Test Coding and Billing Guidelines (M0009). sf/docscat/moldx%20website~moldx~browse %20By%20Topic~Covered%20Tests~8WXQ5R5 416?open&navmenu=%7C%7C Palmetto GBA. Jurisdiction 11 Part B. CMS National Laboratory Coverage Determinations: s.nsf/docscat/providers~jurisdiction%2011%20 Part%20B~Browse%20by%20Topic~Lab?open& Cardiac Risk Assessment-Laboratory Tests Oct 15 1

2 Start=1&Count=50&Pg=1&navmenu=Browse% 5Eby%5ETopic%7C%7C Medicare Learning Matters Network. MLN Matters Number: MM5457. Related CR Release Date: January 26, 2007: Education/Medicare-Learning-Network- MLN/MLNMattersArticles/downloads/MM5457.pdf Medicare National Coverage Determinations (NCD) Coding Policy Manual and Change Report. January 2013: gegeninfo/downloads/manual pdf None Medicare Learning Matters Network. MLN Matters Number: Medicare Learning Matters Network. October 26, 2012: Education/Medicare-Learning-Network- MLN/MLNMattersArticles/downloads/mm4328.pd f Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement (Please see Health Net National Medical Policies on Carotid Intima-Media Thickness, and Pharmocogenetics) Health Net, Inc. considers high-sensitivity C-reactive protein (hs-crp) testing for the assessment of coronary artery disease (CAD) risk medically necessary when all of the following are met: 1. The patient has undergone previous noninvasive tests for cardiac risk stratification (e.g., stress EKG, exercise thallium, stress echocardiography, SPECT) and been found to be at intermediate risk (not high risk*) as evidenced by meeting all of the following: Cardiac Risk Assessment-Laboratory Tests Oct 15 2

3 LDL cholesterol levels between 100 to 130 mg/dl; and Patient has 2 or more coronary heart disease (CHD) major risk factors, such as: Hypertension (BP 140 mmhg or higher, or on antihypertensive medication) Low HDL cholesterol (< 40 mg/dl) Diabetes Family history of premature CHD (CHD in male first degree relative < 55 years; CHD in female first degree relative < 65 years) Age (men age 45 years or older; women age 55 years or older) Current cigarette smoking Global risk assessment using Framingham point scoring** reveals a 10 to 20% risk of CHD per 10 years, i.e., a Framingham risk score of 0-9; and * Note: hs-crp testing is not recommended in high risk patients because an impact on their treatment outcomes has not been shown. **References: 1. Estimate of 10-Year Risk for Coronary Heart Disease Framingham Point Scores. Accessed at: 2. Framingham Risk Assessment Tool for Estimating 10-year Risk of Developing Hard CHD (Myocardial Infarction and Coronary Death). Accessed at: Health Net Inc. considers any of the following tests investigational, to assess cardiac risk because the medical literature is inconclusive regarding the utility of these tests for screening, diagnosis or management of CHD: High-sensitivity C-reactive protein (hs-crp) as a screening test for the general population or for monitoring response to therapy Complete profiles of cardiac risk (e.g., Cardiarisk, AAL Reference Laboratories offers an Atherosclerosis Activity Evaluation, Great Smokies Diagnostic Labs offers a Comprehensive Cardiovascular Risk Profile, Profilir technology) Apolipoprotein A-I (apo AI) Apolipoprotein B (apo B) Apolipoprotein E (apo E) Lipoprotein remnants: intermediate density lipoproteins (IDL) and small density lipoproteins (NMR LipoProfile). High density lipoprotein (HDL) subclasses (LpAI, LpAI/AII and/or HDL3 and HDL2) Low density lipoprotein (LDL) subclasses (small and large LDL particles) Lipoprotein(a) enzyme immunoassay Cardiac Risk Assessment-Laboratory Tests Oct 15 3

4 Angiotensin gene (AGT) (CardiaRisk) Fibrinogen Lipoprotein-associated phospholipase A2 (Lp-PLA2) (PLAC) Noninvasive measurements of arterial elasticity by means of blood pressure waveforms (e.g., HDI PulseWave, CVProfilor) Post-challenge insulin, high Iron levels Serum uric acid VAP (Vertical Auto Profile) Cholesterol Test Corus CAD gene expression testing Measurement of B-type natriuretic peptides (BNP) Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will now include the preliminary ICD-10 codes in preparation for this transition. Please note that these may not be the final versions of the codes and that will not be accepted for billing or payment purposes until the October 1, 2015 implementation date. ICD-9 Codes (not all inclusive list) Pure hypercholesterolemia Pure hyperglyceridemia Mixed hyperlipidemia Hyperchylomicronemia Other and unspecified hyperlipidemia Intermediate coronary syndrome ICD-10 Codes E78.0- E78.9 Disorders of lipoprotein metabolism and other lipidemias I20.0- I20.9 Angina pectoris I24.0- I24.9 Acute ischemic heart disease I25.1- I25.10 Chronic ischemic heart disease I I Atherosclerotic heart disease of native coronary artery with angina pectoris I I25.9 Other forms of chronic ischemic heart disease Cardiac Risk Assessment-Laboratory Tests Oct 15 4

5 CPT Codes Apolipoprotein, each Lipoprotein (a) Lipoprotein-associated phosolipase A2 (Lp-PLA) Lipoprotein, Blood; Electrophoretic Separation And Quantitation Lipoprotein, Blood; High Resolution Fractionation And Quantitation Of Lipoproteins Including Lipoprotein Subclasses When Performed (Eg, Electrophoresis, Ultracentrifugation) Lipoprotein, Blood; Quantitation Of Lipoprotein Particle Numbers And Lipoprotein Particle Subclasses (Eg, By Nuclear Magnetic Resonance Spectroscopy Lipoprotein, direct measurement; high density cholesterol (HDL cholesterol) LDL cholesterol Natriuretic peptide Unlisted chemistry procedure C-reactive protein C-reactive protein; high sensitivity (hscrp) Unlisted cardiovascular service or procedure 0311T Non-invasive calculation and analysis of central arterial pressure waveforms with interpretation and report HCPCS Codes N/A Scientific Rationale Update October 2015 The 2014 Update of the 2007 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for carotid artery stenosis, has been completed. The USPSTF commissioned a systematic review to synthesize the evidence on the accuracy of screening tests, externally validated risk-stratification tools, the benefits of treatment of asymptomatic carotid artery stenosis with carotid endarterectomy (CEA) or carotid angioplasty and stenting (CAAS), the benefits from medications added to current standard medical therapy, and the harms of screening and treatment with CEA or CAAS. This recommendation applies to adults without a history of transient ischemic attack, stroke, or other neurologic signs or symptoms. The USPSTF recommends against screening for asymptomatic carotid artery stenosis in the general adult population. (D recommendation) The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without related signs or symptoms. It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment. The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms. In the most recently published 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Cardiac Risk Assessment-Laboratory Tests Oct 15 5

6 Atherosclerotic Cardiovascular Risk in Adults, there is no recommendation of particle size in assessing risk or efficacy of treatments (Stone, 2014). Validated tools for linking levels of small dense LDL to clinical decision making, both in risk assessment and treatment response, are currently not available. Published data are inadequate to determine how such measurements should guide treatment decisions and whether these treatment decisions result in beneficial clinical outcomes. Other associated lipid parameters, such as triglycerides and HDL levels may be more useful than LDL size in assessing risk and treatment response. In the 2013 publication of the ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (Stone, 2013), only LDL-C, HDL-C and triglycerides are recommended as serum markers for assessing risk and managing disease. The guideline includes statements on treatments proven to reduce ASCVD events and do not include recommendations that include advanced lipoprotein testing. The guideline includes a critical question for future guidelines to determine "Whether on-treatment markers such as Apo B, Lp(a), or LDL particles are useful for guiding treatment decisions. Therefore, clinical application of these alternative serum markers for CVD risk remains undefined. In addition to the above guidelines, several meta-analyses, reviews and clinical studies have been published assessing the association of lipoprotein with CVD risk and events. Although consistently strong associations have been found between levels of lipoproteins and adverse cardiac health outcomes, evidence presented on the clinical utility of these measures continues to be inconsistent, conflicting and thus inconclusive. Clinical studies are ongoing to further assess and define the role and clinical utility of lipoprotein testing in CVD risk assessment, treatment and management. National Institute of Health Care Excellence (NICE, July 2014) has guidelines (CG181) on Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. However, these guidelines do not mention the laboratory testing for cardiac risks as noted in the policy statement. Studies Jonas et al. (2014) Approximately 10% of ischemic strokes are caused by carotid artery stenosis (CAS). Estimated prevalence of asymptomatic CAS is 1%. The purpose of this study was to evaluate evidence on screening and treating asymptomatic adults for CAS. The Study selection included good- or fair-quality trials of screening, carotid endarterectomy (CEA), or stenting compared with medical therapy or of intensification of medical therapy; systematic reviews; multi-institution studies reporting harms; and externally validated risk-stratification tools. No trials compared screening with no screening or stenting with medical therapy or assessed intensification of medical therapy, and no externally validated, reliable riskstratification tools were found. Given the specificity of ultrasonography (range, 88% to 94% for CAS 50% to 70%), its use in low-prevalence populations would yield many false-positive results. Absolute reduction of non-perioperative strokes was 5.5% (95% CI, 3.9% to 7.0%; 3 trials; 5223 participants) over approximately 5 years for CEA compared with medical therapy. The 30-day rates of stroke or death after CEA in trials and cohort studies were 2.4% (CI, 1.7% to 3.1%; 6 trials; 3435 participants) and 3.3% (CI, 2.7% to 3.9%; 7 studies; participants), respectively. Other harms of interventions included myocardial infarction, nerve injury, and hematoma. Trials may have overestimated benefits and used highly Cardiac Risk Assessment-Laboratory Tests Oct 15 6

7 selected surgeons. Medical therapy used in trials was outdated, and stroke rates have declined in recent decades. Harms may have been underreported. Current evidence does not establish incremental overall benefit of CEA, stenting, or intensification of medical therapy. Potential for overall benefit is limited by low prevalence and harms. Current evidence does not establish incremental overall benefit of CEA, stenting, or intensification of medical therapy. Potential for overall benefit is limited by low prevalence and harms. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. Classification of risk of ischemic stroke is important for medical care and public health reasons. Whether addition of biomarkers adds to predictive power of the Framingham Stroke Risk or other traditional risk factors has not been studied in older women. Wasserheil-Smoller et al. (2014) completed a a case-control study of blood biomarkers, assayed in 972 ischemic stroke cases and 972 controls, nested in the Women's Health Initiative Observational Study of 93, 676 postmenopausal women followed for an average of eight-years. This study known as The Hormones and Biomarkers Predicting Stroke Study evaluated additive predictive value of two commercially available biomarkers: C-reactive protein and lipoprotein-associated phospholipase A2 to determine if they added to risk prediction by the Framingham Stroke Risk Score or by traditional risk factors, which included lipids and other variables not included in the Framingham Stroke Risk Score. As measures of additive predictive value, the C-statistic was used, a net reclassification improvement, category-less net reclassification improvement, and integrated discrimination improvement index. Addition of C-reactive protein to Framingham risk models or additional traditional risk factors overall modestly improved prediction of ischemic stroke and resulted in overall net reclassification improvement of 6 3%, (case net reclassification improvement=3 9%, control net reclassification improvement =2 4%). In particular, high-sensitivity C-reactive protein was useful in prediction of cardioembolic strokes (net reclassification improvement=12 0%; 95% confidence interval %) and in strokes occurring in less than three-years (net reclassification improvement=7 9%, 95% confidence interval %). Lipoprotein-associated phospholipase A2 was useful in risk prediction of large artery strokes (net reclassification improvement=19 8%, 95% confidence interval %) and in early strokes (net reclassification improvement=5 8%, 95% confidence interval %). C-reactive protein and lipoprotein-associated phospholipase A2 can improve prediction of certain subtypes of ischemic stroke in older women, over the Framingham stroke risk model and traditional risk factors, and may help to guide surveillance and treatment of women at risk. Additional peerreviewed studies are necessary. Kara et al. (2014) evaluated serum high-sensitivity C-reactive protein (hs-crp) and lipoprotein-related phospholipase A2 (Lp-PLA2) in patients who had acute ischemic stroke. In 200 patients who presented to an emergency service (i.e., acute ischemic stroke, 102 patients; control with no stroke, 98 patients), stroke patients were evaluated with the Canadian neurological scale and diffusion-weighted magnetic resonance imaging, and all patients were evaluated with the Glasgow coma scale and their serum hs-crp level and Lp-PLA2 activity were assessed. The volume of stroke lesions was calculated from magnetic resonance images. Patients who had stroke had higher mean serum hs-crp level (stroke, 7±6 mg/dl; control, mean ± standard deviation 1±1 mg/dl; P 0.001) and Lp-PLA2 activity (stroke, mean ± standard deviation 113±86 nmol/min/ml; control, mean ± standard deviation 103±50 Cardiac Risk Assessment-Laboratory Tests Oct 15 7

8 nmol/min/ml; P 0.001) than control patients who did not have stroke. The mean hs-crp level and Lp-PLA2 activity were higher in patients who had greater stroke severity (lower Canadian neurological scale score) and were higher in patients who had larger volume strokes. Higher hs-crp level and Lp-PLA2 activity are significantly associated with more severe neurologic impairment and larger infarct size in patients who have acute ischemic stroke. These biomarkers may be useful for rapid diagnosis and prediction of ischemic tissue volume in the early stage of ischemic stroke. These findings may be important for health care facilities that have limited access to emergency computed tomography scanning for the diagnosis of stroke. Lipoprotein-associated phospholipase A2 (LpPLA2) levels are associated with stroke, though whether this extends to all populations and stroke subtypes is unknown. Katan et al. (2014) Serum samples from stroke-free community participants in the Northern Manhattan Study were assayed for LpPLA2 mass and activity. Participants were followed annually for stroke. Cox-proportional-hazard models were fitted to estimate hazard-ratios and 95% confidence intervals (HR, 95% CI) for the association of LpPLA2 levels with ischemic stroke (IS), after adjusting for demographic and medical risk factors. Serum samples were available in 1946 participants, of whom 151 (7.8%) experienced a first IS during median follow-up 11 years. Mean age was 69 (SD 10), 35.6% were men, 20% non-hispanic Whites, 22% non-hispanic Blacks, and 55% Hispanics. LpPLA2 mass and activity levels were not associated with overall IS risk. LpPLA2 mass but not activity levels were associated with strokes due to large artery atherosclerosis (LAA; adjusted HR per SD 1.55, 95% CI ). There was a dose-response relationship with LAA (compared to first quartile, 2nd quartile HR=1.43, 95% CI ; 3rd quartile HR=4.47, 95% CI ; 4th quartile HR=5.07, 95% CI ). The associations between LpPLA2-mass and LAA-stroke risk differed by race-ethnicity (p=0.01); LpPLA2-mass was associated with increased risk of LAA among non-hispanic Whites (adjusted HR per SD 1.44, 95% CI ), but not other race-ethnic groups. CONCLUSION: LpPLA2-mass levels were associated with risk of atherosclerotic stroke among non- Hispanic White participants, but not in other race-ethnic groups in the cohort. Further study is needed to confirm these race-ethnic differences and the reasons for them. Scientific Rationale Update October 2014 O'Donoghue et al. ( J Am Coll Cardiol. 2014) completed a study to assess the prognostic utility of lipoprotein(a) [Lp(a)] in individuals with coronary artery disease (CAD). Data regarding an association between Lp(a) and cardiovascular (CV) risk in secondary prevention populations are sparse. Plasma Lp(a) was measured in 6,708 subjects with CAD from 3 studies; data were then combined with 8 previously published studies for a total of 18,978 subjects. Across the 3 studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (odds ratio [OR]: 1.03 per log-transformed SD, 95% confidence interval [CI]: 0.96 to 1.11) or by quintile (Q5:Q1 OR: 1.05, 95% CI: 0.83 to 1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR: 1.40, 95% CI: 1.15 to 1.71), but with significant between-study heterogeneity (p = 0.001). When stratified on the basis of low-density lipoprotein (LDL) cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was 130 mg/dl (OR: 1.46, 95% CI: 1.23 to 1.73, p < 0.001), whereas this relationship did not achieve statistical significance for studies with an average LDL cholesterol <130 mg/dl (OR: 1.20, 95% CI: 0.90 to Cardiac Risk Assessment-Laboratory Tests Oct 15 8

9 1.60, p = 0.21). Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear. Patel et al. (2014) completed a study in which the purpose was to compare the association between variants at the chromosome 9p21 locus (Ch9p21) and risk of first versus subsequent coronary heart disease (CHD) events through systematic review and meta-analysis. Ch9p21 is a recognized risk factor for a first CHD event. However, its association with risk of subsequent events in patients with established CHD is less clear. The authors searched PubMed and EMBASE for prospective studies reporting association of Ch9p21 with incident CHD events and extracted information on cohort type (individuals without prior CHD or individuals with established CHD) and effect estimates for risk of events. The authors identified 31 cohorts reporting on 193,372 individuals. Among the 16 cohorts of individuals without prior CHD (n = 168,209), there were 15,664 first CHD events. Ch9p21 was associated with a pooled hazard ratio (HR) of a first event of 1.19 (95% confidence interval: 1.17 to 1.22) per risk allele. In individuals with established CHD (n = 25,163), there were 4,436 subsequent events providing >99% and 91% power to detect a per-allele HR of 1.19 or 1.10, respectively. The pooled HR for subsequent events was 1.01 (95% confidence interval: 0.97 to 1.06) per risk allele. There was strong evidence of heterogeneity between the effect estimates for first and subsequent events (p value for heterogeneity = (-11)). We found no evidence for biases to account for these findings. Ch9p21 shows differential association with risk of first versus subsequent CHD events. This has implications for genetic risk prediction in patients with established CHD and for mechanistic understanding of how Ch9p21 influences risk of CHD. Scientific Rationale Update October 2013 The determination of the underlying etiology of symptoms suggestive of obstructive coronary artery disease (CAD), 50% stenosis in a major coronary artery, is a common clinical challenge. Usual care in low to medium risk patients often involves a family history, risk factor assessment, and then stress testing with or without noninvasive imaging. If positive, this is often followed by invasive coronary angiography (ICA). Despite extensive adoption of this usual protocol, more than 60% of patients referred for angiography do not have obstructive CAD. In order to try to identify those symptomatic patients without obstructive CAD, who can avoid subsequent cardiac testing and look elsewhere for the cause of their symptoms, a whole blood gene expression score, or Corus CAD test is being proposed. A Policy Statement from the American Heart Association (2012) discussed the role of genetics and cardiovascular disease treatment and diagnosis but did not address gene expression as is measured in the Corus CAD test. McPherson et al. (2013) completed the Clinical Trial on The IMPACT-Cardiology (i.e., Investigation of a Molecular Personalized Coronary Gene Expression Test on Cardiology Practice Pattern, which was done to assess the impact of Corus CAD use on clinical decision-making during the assessment of stable chest pain patients in the cardiology setting. The Clinical Trials.gov identifier is ClinicalTrials.gov Identifier: NCT and it was last updated in February The study included a prospective cohort of 83 patients eligible for analysis. These patients were referred to six cardiologists for evaluation of suspected CAD and were matched by clinical factors to patients in a historical cohort. The study protocol was designed to Cardiac Risk Assessment-Laboratory Tests Oct 15 9

10 evaluate and compare the cardiologists diagnostic strategies before and after receiving the Corus CAD results for their patients. The pre-corus CAD assessment of patients CAD probability noted their preliminary management decision. This pre- Corus CAD assessment was compared to physicians assessment of CAD probability after The IMPACT-Cardiology protocol and this was designed to evaluate and compare the cardiologists diagnostic strategies before and after receiving the Corus CAD results for their patients. In this study following communication of Corus CAD results, a change in diagnostic testing (e.g. myocardial perfusion imaging, CTA and cardiac catheterization) was noted in 48 patients [58%, 95% CI (46%, 69%)]. More patients had a decreased versus increased level of testing (n=32 (39%) vs n=16 (19%), p=0.03). In particular, 91% (29 of 32) of patients with decreased testing had low Corus CAD ( 15), while 100% (16 of 16) of patients with increased testing had elevated Corus CAD (p<0.001). The most common change was among patients considered for referral to non-invasive imaging or invasive angiography prior to the Corus CAD test who were then referred to either no intervention or medical management after receiving a low Corus CAD score. In addition, none of the patients with low scores ( 15) saw an increase in testing. The IMPACT-CARD trial demonstrated that among patients with a low Corus CAD score, the management decisions led to a decrease in non-invasive cardiac imaging and invasive angiography. The study was sponsored by CardioDx. This study is limited by comparison with historical controls, which were not well-matched to the study population. In addition, the impact of management changes in this study is uncertain. There is no information provided on whether the management changes led to beneficial effects on outcome, and it is not possible to estimate the likelihood of benefit from the information given in this study. Therefore, it is not possible to conclude that the GES score leads to changes in management that improve outcomes. The Clinical Trial Personalized Risk Evaluation and Diagnosis In the Coronary Tree (PREDICT), with the ClinicalTrials.gov identifier NCT was terminated in The Clinical Trial on Coronary Obstruction Detection by Molecular Personalized Gene Expression (COMPASS) has been completed, with the CardioDxClinicalTrials.gov Identifier of NCT The sponsor of this study is CardioDx. The COMPASS study evaluated test performance in symptomatic patients (N=431) referred for myocardial perfusion imaging (MPI), a procedure used prior to angiography. The gold standard is a combination of either invasive angiography or CT-angiography, both determined in core laboratories, so that all patients independent of their MPI results, had gold standard data on their coronary anatomy. Obstructive CAD prevalence was only 15%. Positive MPI scans were seen in 11% of patients The primary endpoint of the area under the receiver-operating characteristics curve (AUC for ROC) analysis for discriminating patients with and without obstructive CAD (50% stenosis by quantitative angiography or core-lab CT-angiography) yielded AUCs of 0.79, (p<0.001). In the COMPASS study, the overall accuracy of the GES score in predicting cardiac events was superior to MPI in patients who were referred for MPI testing. However, in this study, the reported sensitivity of MPI was considerably lower than generally reported in the literature. Also, it is unclear from the COMPASS study whether patients with a positive MPI could safely forego further testing based on a low GES score. There is another Clinical Trial on A Registry to Evaluate Patterns of Care Associated with the Use of Corus CAD in Real World Clinical Care Settings (PRESET) with the Cardiac Risk Assessment-Laboratory Tests Oct 15 10

11 ClinicalTrials.gov Identifier of NCT This was last updated on August , and is currently recruiting participants. Though the diagnostic properties of Corus CAD have been evaluated in previous observational studies, there are limited data regarding how primary care clinicians are using the results of the test in the care and management of patients with angina. This registry is designed to examine the relationship between the Corus CAD score and patterns of care regarding diagnostic testing in real world clinical care settings. There is no estimated date of completion at this time. There is another Clinical Trial Primary Care Providers Use of a Gene Expression Test in Coronary Artery Disease Diagnosis (IMPACT-PCP) which is ongoing but not recruiting participants. The ClinicalTrials.gov Identifier is NCT , and was last updated in February This is a prospective, multi-center study examining the clinical impact of the Corus CAD assay in approximately 250 evaluable subjects with no history of obstructive coronary artery disease who now present with chest pain or anginal-equivalent symptoms to a primary care physician (PCP) for evaluation. The primary completion date is listed as February 2013, but this study is not completed at this time. There is another Clinical Trial Investigation of a Novel Gene Expression Test for the Diagnosis of Obstructive Coronary Artery Disease on Physician's Practice Pattern which is currently recruiting participants. The ClinicalTrials.gov Identifier is NCT and it was last verified in February The objective of this study is to collect data on the commercial use of CORUS (validated quantitative in vitro diagnostic test) Coronary Artery Disease (CAD) blood test to evaluate the clinical referral patterns of Primary Care Physicians after receipt of their patients' CORUS Score, and to better understand patient management patterns for clinicians ordering the test. The estimated primary completion date is March Although the results of the evaluation of the Corus CAD test are promising, its results should be interpreted carefully as patients with diabetes mellitus and chronic inflammatory or autoimmune disorders were excluded from test development and validation. Furthermore, this test was derived and tested in predominantly Caucasian patient populations. Given the known variations in the prevalence of CAD in different ethnic/racial backgrounds, results of this test in non-caucasian populations should be interpreted with caution. In summary, the data regarding Corus CAD are limited in reaching conclusions about its performance and value in patients being evaluated for obstructive CAD. While the available evidence suggests the test has a moderately high negative predictive value, additional evidence supporting the analytical validity, clinical validity, and clinical utility is necessary. Two of the Clinical Trials noted within this Scientific Rationale (i.e., IMPACT and COMPASS) were just completed this year (2013). Additional research is necessary to determine if a low CAD score (i.e., GES Score) and changes in the individual s care management leads to better long-term outcomes for the individual. It was also unclear from the COMPASS study if a positive myocardial perfusion imaging (MPI) could safely forego further testing based on a low GES score. Scientific Rationale Update June 2013 The ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults, has not been updated since Cardiac Risk Assessment-Laboratory Tests Oct 15 11

12 The American Heart Association/American Stroke Association Council recommendations were last updated in The guideline states that measurement of inflammatory markers such as Lp-PLA2 in patients without cardiovascular disease may be considered to identify patients who may be at increased risk of stroke, although their effectiveness (i.e. usefulness in routine clinical practice) is not well established. Additional well-designed clinical trials are necessary to establish the clinical utility of Lp-PLA2 for cardiovascular risk assessment and to determine the role of Lp-PLA2 as a potential adjunct to traditional risk assessment in the overall management of stroke in adults. The European Guidelines on Cardiovascular Disease Prevention in Clinical Practice were updated in Fibrinogen may be measured as part of refined risk assessment in patients with an unusual or moderate CVD risk profile. Recommendation was IIb B Weak (Fibrinogen should not be measured in asymptomatic low-risk individuals and high-risk patients to assess 10-year risk of CVD. (European 2012). While advanced lipoprotein analysis detects elevated or reduced levels of lipoproteins, there is lack of agreement on how this information would be used in clinical decision-making. In addition, while the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III identifies lipoprotein (a) and apolipoprotein analysis as emerging technologies, it does not recommend their routine use in identifying persons at risk for cardiovascular disease or ischemic stroke. Some experts continue to argue that apo B is superior to LDL cholesterol, and that the apo B/apo A-I ratio is superior to the LDL/HDL ratio, as predictors of cardiovascular risk, and that these apolipoprotein measures should supplement or replace traditional lipid measures. A publication from the American Diabetes Association and the American College of Cardiology Foundation (2009) included specific recommendations for incorporating apo B testing into clinical care for highrisk patients. This expert panel stated, ApoB and LDL particle number also appear to be more discriminating measures of the adequacy of LDL lowering therapy than are LDL cholesterol or non-hdl cholesterol. Therefore, they recommend that for patients with metabolic syndrome who are being treated with statins, both LDL cholesterol and apo B should be used as treatment targets, with an apo B target of less than 90mg/dl. Treatment should be intensified for patients with apob above this level even if target LDL has been achieved. However, the evidence suggests that any incremental improvement in predictive ability over traditional measures is likely to be small and of uncertain clinical significance. In addition, none of the major lipid treatment guidelines, such as The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP), have yet to formally incorporate the measurement of apolipoproteins into their recommendations. This creates difficulties in interpreting and applying the results of apo B and/or apo B/apo A-I measurements to routine clinical care. Therefore, it does not appear likely that apolipoprotein measures will replace traditional lipid measurements for cardiovascular risk prediction in routine clinical care, at this time. A large body of research has focused on the correlation between lipid levels and the underlying apolipoprotein E (apo E) genotype. Other studies have focused on the relationship between genotype and clinical disease. Clinical evidence suggests that apo E is not clinically useful in providing additional information on risk for CAD when compared with other established and emerging risk factors. None of the studies reviewed provide adequate data to suggest that apo E genotype improves outcomes when used in clinical care. Cardiac Risk Assessment-Laboratory Tests Oct 15 12

13 Retrospective cross-sectional studies have suggested that the protective effect of HDL was associated primarily with the HDL-2 subclass. However, these studies could not determine whether decreased HDL-2 preceded the development of cardiovascular disease or was its result. A number of large, prospective studies designed to answer this question have reported mixed results. A nonprofit independent licensee of the BlueCross BlueShield Association, notes that subclassification information on risk assessment for CAD, has not been reported consistently in all studies. HDL subclassification has not been incorporate into quantitative risk assessment models or treatment guidelines, such as the Adult Treatment Panel (ATP III) that can be used in clinical practice. Intermediate density lipoprotein (remnant-like particles). An immunoseparation assay has received approval from the U.S. Food and Drug Administration (FDA) for the direct measurement of intermediate density lipoprotein. While measurement of intermediate-density lipoproteins (IDLs) has emerged as an important research tool in evaluating cardiac risk factors and understanding how different components of plasma triglycerides contribute to cardiac risk, it is unclear how the management of IDLs can be used in the management of the patient. The majority of publications focus on the pathophysiology and basic science aspects of IDL, with a smaller number of research studies reporting data with potential clinical relevance. There are no prospective, large-scale cohort studies that evaluated IDLs as a predictor of cardiovascular risk, nor are there any large diagnostic studies that evaluated the utility of IDLs in diagnosing type III hyperlipidemia. None of the available studies provide guidance on the clinical use of IDL measurements, nor does this evidence suggest that health outcomes are improved as a result of measuring IDL level. Low density (small) lipoprotein particle size. Small LDL size is one component of an atherogenic lipid profile that also includes increased triglycerides, increased apolipoprotein B, and decreased HDL. Some studies have reported that LDL size is an independent risk factor for CAD, and others have reported that a shift in LDL size may be useful marker of treatment response. A relatively small number of published articles contain clinically relevant evidence on the utility of measuring the concentration of small, dense LDL (or LDL particle size). The available publications primarily focus either on the use of these measures as a predictor of cardiovascular risk, or the effect of pharmacologic treatment on small, dense LDL. Studies predicting cardiac risk were cross-sectional studies that evaluated the association of small, dense LDL with a variety of cardiovascular outcomes. There are a paucity of large, prospective cohort studies that evaluate the predictive ability of small, dense LDL for future cardiovascular events. The studies of treatment effect examined the impact of diet and/or pharmacologic agents on small, dense LDL and other LDL subclasses. These studies generally confirmed that small, dense LDL is impacted preferentially by fibrate treatment, and possibly also by statin therapy. However, the studies do not demonstrate that preferentially targeting small, dense LDL leads to improved outcomes, as compared to using the standard LDL targets that are widespread in clinical care. These newly published studies do not provide evidence that measurement of small, dense LDL leads to improved clinical outcomes. Tools for linking concentration of LDL particles to clinical decision making, both in risk assessment and treatment response, are currently not available. Scientific Rationale Update September 2012 The Palmetta GBA site notes: "Palmetto GBA has completed the Corus CAD Gene Expression technical assessment and determined that the test meets criteria for analytical and clinical validity, and clinical utility as a reasonable and necessary Cardiac Risk Assessment-Laboratory Tests Oct 15 13

14 Medicare benefit. Effective January 1, 2012, Palmetto GBA will reimburse services for Corus CAD. To report a Corus CAD service, submit the following claim information: CPT code Unlisted chemistry procedure". CardioDX has a press release dated August 8, 2012, which notes the following: "CardioDx, Inc., announced Palmetto GBA, a national contractor that administers Medicare benefits, has established coverage for the company s Corus CAD gene expression test for the evaluation of patients presenting with typical and atypical symptoms suggestive of coronary artery disease. Corus CAD is promoted to assess whether or not a stable non-diabetic patient s symptoms are due to obstructive coronary artery disease (CAD), enabling many patients to avoid unnecessary invasive testing and exposure to imaging-related radiation risks or imaging agent intolerance. The test has been validated in patient cohorts, including two prospective, multicenter U.S. trials, PREDICT and COMPASS. Per CardioDX, a retrospective, multicenter chart review study and the prospective IMPACT trial at Vanderbilt University demonstrated that Corus CAD use yielded significant and clinically relevant changes in patient management decisions in both primary care and cardiology settings. Corus CAD is the first gender-specific test for obstructive CAD accounting for critical biological differences between men and women. Corus CAD is not intended for use in patients who are diabetic, have been diagnosed with prior myocardial infarction (MI) or have had a previous revascularization procedure, or are currently taking steroids, immunosuppressive agents or chemotherapeutic agents. The Corus CAD test measures the RNA levels of 23 genes. Because peripheral blood cell RNA levels are altered when obstructive coronary artery disease is present, the Corus CAD score aids clinicians in assessing whether an individual patient s symptoms may be due to obstructive coronary artery disease. Effective 6/22/12 Revisions in Medicare Coverage: " Coverage for all Medicare members when one Medicare A/B Administrative Contractor (MAC) processes all of the claims for a particular Medicare covered item or service for all Medicare beneficiaries around the country. This generally occurs when there is only one supplier of a particular item, medical device or diagnostic test (e.g., certain pathology and lab tests furnished by independent laboratories). In this situation, Medicare Advantage (MA) plans must follow the coverage requirements OR LCD of the MAC that enrolled the supplier and processes all of the Medicare claims for that item, test or service". (Effective , Medicare CMS Manual, Transmittal 107, Chapter 90.2, Available at: Guidance/Guidance/Transmittals/Downloads/R107MCM.pdf Elashoff et al. (2011) Alterations in gene expression in peripheral blood cells have been shown to be sensitive to the presence and extent of CAD. A non-invasive blood test that could reliably assess obstructive CAD likelihood would have diagnostic utility. Microarray analysis of RNA samples from a 195 patient Duke CATHGEN registry case: control cohort yielded 2,438 genes with significant CAD association (p < 0.05), and identified the clinical/demographic factors with the largest effects on gene expression as age, sex, and diabetic status. RT-PCR analysis of 88 CAD classifier genes confirmed that diabetic status was the largest clinical factor affecting CAD associated gene expression changes. A second microarray cohort analysis limited to non-diabetics from the multi-center PREDICT study (198 patients; 99 case: control pairs matched for age and sex) evaluated gene expression, clinical, and cell population predictors of CAD and yielded 5,935 CAD genes (p < 0.05) with an intersection of 655 genes with the CATHGEN results. Biological pathway (gene ontology and literature) and statistical analyses (hierarchical clustering and logistic Cardiac Risk Assessment-Laboratory Tests Oct 15 14

15 regression) were used in combination to select 113 genes for RT-PCR analysis including CAD classifiers, cell-type specific markers, and normalization genes.rt-pcr analysis of these 113 genes in a PREDICT cohort of 640 non-diabetic subject samples was used for algorithm development. Gene expression correlations identified clusters of CAD classifier genes which were reduced to meta-genes using LASSO. The final classifier for assessment of obstructive CAD was derived by Ridge Regression and contained sex-specific age functions and 6 meta-gene terms, comprising 23 genes. This algorithm showed a cross-validated estimated AUC = 0.77 (95% CI ) in ROC analysis. The authors have developed a whole blood classifier based on gene expression, age and sex for the assessment of obstructive CAD in non-diabetic patients from a combination of microarray and RT-PCR data derived from studies of patients clinically indicated for invasive angiography. Clinical Trial Registration Information: PREDICT, Personalized Risk Evaluation and Diagnosis in the Coronary Tree, NCT However, the Clinical Trial noted in the paragraph above, with the ID number of NCT , was terminated and last updated on June 4, The purpose of this prospective, multi-center, observational study, was to develop and validate a diagnostic blood assay for atherosclerotic CAD. The Assay will use quantitative realtime PCR (RT-PCR) to quantify the expression of multiple genes from circulating peripheral blood cells to assess the presence of clinically significant CAD in a patient. The study was divided into four sequential segments with unique subjects and goals: gene discovery (segment 1), Assay development (segment 2), Assay validation (segment 3), and additional Assay testing (segment 4). The primary analysis will be performed during the third segment of the study using a subset of the enrolled subjects ("primary subjects"). Primary subjects will be defined by additional eligibility criteria beyond the general eligibility criteria required for enrollment in the overall study. The additional, post-enrollment eligibility criteria will be based on clinical and demographic factors that are found during the course of the study to affect the expression of genes used in the Assay. Such factors will be identified during gene discovery and algorithm development. The post-enrollment eligibility criteria will be defined prior to the beginning of the Assay validation segment of the study. In addition, three substudies are planned and will enroll up to 1500 subjects. The first substudy will include subjects undergoing cardiac CT angiography (CTA) and aims to determine how gene expression correlates with total coronary atheroma burden, as measured by CTA. The second substudy examines sample handling and shipping conditions and does not affect the treatment of the subjects. The third substudy will focus on additional algorithm development and validation in a non-diabetic female patient population. However, since this trial was terminated, it does not seem that any of the substudies or post studies would be done. There is another Clinical Trial on 'Coronary Obstruction Detection by Molecular Personalized Gene Expression (COMPASS)', also noted above, which is ongoing, but not recruiting participants. This was last updated on March 16, 2012 with the ClinicalTrials.gov Identifier of NCT The purpose of this trial was to validate the use of Corus CAD blood assay in subjects who are referred for the work-up of CAD. The study will evaluate the clinical utility of a gene expression test (Corus CAD) in subjects referred for myocardial perfusion imaging (MPI) work-up for suspected obstructive atherosclerotic coronary artery disease (CAD). The Corus CAD is a gene expression test that quantify the expression of multiple genes from circulating peripheral blood cells to detect the presence of clinically significant obstructive CAD in patients with chest pain. Cardiac Risk Assessment-Laboratory Tests Oct 15 15

16 A Clinical Trial on 'Investigation of a Molecular Personalized Coronary Gene Expression Test on Cardiology Practice Pattern (IMPACT-CARD), is also ongoing, but not recruiting participants. This was last updated on March 16, 2012 with the ClinicalTrials.gov Identifier of NCT The purpose of this study was to investigate whether the use of Corus CAD blood assay changes the diagnostic testing pattern in patients referred to a cardiologist for the evaluation of chest pain or anginal equivalent symptoms. Lansky et al. (American Heart Journal 2012) summarizes the PREDICT trial as noted above. It also notes that this test has not yet been studied to predict the risk of future cardiovascular events. In addition, beyond only a subset of the cohort having MPIs, there is a significant referral bias inherent in the analysis because patients with negative MPI were probably less likely to be referred to diagnostic catheterization, therefore impacting the reported negative predictive value of MPI. Irrespective of these limitations, the comparative validation study applies equally to both MPI and GES, and the positive predictive value should not be greatly impacted by the referral bias because patients with positive MPIs are likely to be referred to diagnostic catheterization given current practice patterns. It also notes that the use of a bloodbased GES may be particularly helpful in the assessment of obstructive CAD in nondiabetic patients and, in particular, women for whom the use of symptoms and functional testing has proven unreliable. However, further studies are needed to validate whether this test or other methods that use individualized genomic data will help promote more efficient and appropriate use of coronary angiography in women. (7/13/2002) Palmetto GBA has determined APOLIPOPROTEIN (Apo) E genotype testing, developed to assess the risk of cardiovascular disease, has insufficient evidence to support reasonable and necessary criteria for Medicare reimbursement. Therefore, Palmetto GBA will deny ApoE test services. Medicare does not cover High-sensitivity C-reactive protein (hscrp) testing as a screening test for the general population or for monitoring response to therapy. The clinical value for these uses has not been established. Homocysteine testing, the measurement of 12-hour fasting levels of homocysteine in plasma, can be used as part of an overall assessment of patient risk for cardiovascular disease (CVD). It has been suggested that homocysteine testing can provide information regarding CVD risk in addition to that provided by more common lipoprotein tests, such as total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. Homocysteine testing may also aid in treatment decisions, based on the assumption that there is a health benefit associated with lowering elevated homocysteine levels. Although there is evidence from epidemiologic studies for an association between high plasma homocysteine levels and increased cardiovascular disease (CVD) risk, not all prospective studies have supported such a relationship. In addition, there is no consensus on target levels or safe levels of total homocysteine, and there is a paucity of evidence in relation to women and racial minorities. Moreover, it remains to be proven whether reduction of plasma homocysteine levels has a positive effect on the risk or progression of CVD. Therefore, at the present time, there is insufficient evidence to support the use of homocysteine testing for screening, diagnosis, or management of CVD in healthy, atrisk, or diagnosed patient populations. The aim of the 2012 guidelines from the Fifth Joint Task Force (JTF) of the European Societies on Cardiovascular Disease Prevention in Clinical Practice is to give an Cardiac Risk Assessment-Laboratory Tests Oct 15 16

17 update of the present knowledge in preventive cardiology. The following has been noted: Because apob (the main apoprotein of atherogenic lipoproteins) levels have so frequently been measured in outcome studies in parallel with LDL cholesterol, apob can be substituted for LDL cholesterol, but it does not add further to the risk assessment. There is still not sufficient scientific evidence for any high density lipoprotein (HDL) cholesterol value to be considered as a goal of therapy, although HDL cholesterol,1.0 mmol/l (40 mg/dl) in men and,1.2 mmol/l (45 mg/dl) in women may be regarded as a marker of increased risk. Lipoprotein(a) is a low-density lipoprotein (LDL) to which is attached an additional protein called apolipoprotein(a). High concentrations of Lp(a) are associated with increased risk of CHD and ischaemic stroke, although there is no randomized intervention showing that reducing Lp(a) decreases CVD risk. There is no justification for screening the general population for Lp(a) at present, and no evidence that any value should be considered as a target. Apolipoprotein A1 (apoa1) is the major apoprotein of HDL. It is beyond doubt that the apob:apoa1 ratio is one of the strongest risk markers. However, it is still not established whether this variable should be used as a treatment goal. As the measurement of apolipoproteins is not available to all physicians in Europe, is more costly than currently used lipid variables, and does not add more information, its use is not as yet generally recommended. Fibrinogen should not be measured in asymptomatic low-risk individuals and high-risk patients to assess 10-year risk of CVD. High-sensitivity CRP has shown consistency across large prospective studies as a risk factor integrating multiple metabolic and low-grade inflammatory factors underlying the development of unstable atherosclerotic plaques, with a magnitude of effect matching that of classical major risk factors. This marker was used in individuals showing a moderate level of risk from clinical assessment of major CVD risk factors. However, several weak points exist when including this biomarker for highrisk assessment: 1. Multiplicity of confounders: dependence on other classical major risk factors. 2. Lack of precision: narrow diagnostic window for hscrp level and risk of CVD. 3. Lack of specificity: similar level of risk for other noncardiovascular causes of morbidity and mortality (e.g. other low-grade inflammatory diseases). 4. Lack of dose effect or causality relationship between changes in hscrp level and risk of CVD. 5. Lack of specific therapeutic strategies or agents targeting circulating CRP and showing reduction in CVD incidence. Statements numbered 1-5 above are also noted for fibrinogen. Homocysteine has shown precision as an independent risk factor for CVD. The magnitude of effect on risk is modest, and consistency is often lacking, mainly due to nutritional, metabolic (e.g. renal disease), and lifestyle confounders. In addition, intervention studies using B vitamins to Cardiac Risk Assessment-Laboratory Tests Oct 15 17

18 reduce plasma homocysteine have proven inefficient in reducing risk of CVD. LpPLA2 has recently emerged as a marker with high consistency and precision as an independent risk factor for plaque rupture and atherothrombotic events. The magnitude of effect on risk remains modest at the level of the general population; study limitations or bias are present. Studies Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a recently identified and potentially useful plasma biomarker for cardiovascular and atherosclerotic diseases. However, the correlation between the Lp-PLA2 activity and carotid atherosclerosis remains poorly investigated in patients with metabolic syndrome (MetS). Gong et al. completed a study aimed to evaluate the potential role of Lp-PLA2 as a comprehensive marker of metabolic syndrome in individuals with and without carotid atherosclerosis. The authors documented 118 consecutive patients with MetS and 70 age and sex matched healthy subjects served as controls. The patients were further divided into two groups: 39 with carotid plaques and 79 without carotid plaques to elucidate the influence of Lp-PLA2 on carotid atherosclerosis. The plasma Lp-PLA2 activity was measured by using ELISA method and carotid intimal-media thickness (IMT) was performed by ultrasound in all participants. Lp-PLA2 activity was significantly increased in MetS subgroups when compared with controls, and was higher in patients with carotid plaques than those without plaques (P < 0.05). significant difference was found in Lp-PLA2 that was obtained between patients with three and four disorders of metabolic syndrome (P < 0.01). Age (β = 0.183, P = 0.029), LDL-cholesterol (β = 0.401, P = 0.000) and waist-hip ratio (β = 0.410, P = 0.000) emerged as significant and independent determinants of Lp-PLA2 activity. Multiple stepwise regression analysis revealed that LDL-cholesterol (β = 0.309, P = 0.000), systolic blood pressure (β = 0.322, P = 0.002) and age (β = 0.235, P = 0.007) significantly correlated with max IMT, and Lp-PLA2 was not an independent predictor for carotid IMT. Lp-PLA2 may be a modulating factor for carotid IMT via age and LDL-cholesterol, but not an independent predictor in the pathophysiological process of carotid atherosclerosis in patients with MetS. Additional peer reviewed studies with long-term outcomes are necessary. Constantinides et al. (2011) completed a recent meta-analysis which showed that both plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2) ) mass and activity may independently predict cardiovascular events. Lp-PLA(2) activity but not mass was found to be a determinant of cardiovascular outcome in type 2 diabetes mellitus. We questioned whether relationships of carotid intima media thickness (IMT), a measure of subclinical atherosclerosis, with Lp-PLA(2) mass differ between diabetic and nondiabetic subjects. Relationships of IMT with plasma Lp-PLA(2) mass (turbidimetric immunoassay) were compared in 74 patients with type 2 diabetes and in 64 nondiabetic subjects. IMT was increased (P=0 016), but plasma Lp-PLA(2) mass was decreased in patients with diabetes compared to nondiabetic subjects (277±66 vs. 327±62ΜgL(-1), P<0 001). In nondiabetic subjects, IMT was correlated positively with Lp-PLA(2) (r=0 325, P<0 009); multiple linear regression analysis confirmed an independent association of IMT with Lp-PLA(2) (ß=0 192, P=0 048). In contrast, IMT was unrelated to Lp-PLA(2) in patients with diabetes (r=0 021, P=0 86), and the relationship of IMT with Lp-PLA(2) was different in diabetic and control subjects (P<0 001). The relationship of Lp-PLA(2) with the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio also differed between diabetic and nondiabetic subjects (P<0 001). Plasma Lp-PLA(2) may relate to early Cardiac Risk Assessment-Laboratory Tests Oct 15 18

19 stages of atherosclerosis development. In diabetes mellitus, in contrast, the association of IMT with plasma Lp-PLA(2) mass is abolished, which could be partly attributed to redistribution of Lp-PLA(2) mass from apolipoprotein B-containing lipoproteins towards HDL. These findings raise questions about the usefulness of plasma Lp-PLA(2) mass measurement as a marker of subclinical atherosclerosis in type 2 diabetes mellitus. Additional peer-reviewed studies are necessary The American College of Cardiology (ACC), and the American Heart Association (AHA) Task Force recommendations on assessing cardiovascular risk in asymptomatic adults by (Greenland et al., 2010), have not been updated since this time. The American Heart Association, the American College of Cardiology and the National Cholesterol Education Program Adult Treatment Panel guidelines (ATP III) have not issued formal recommendations for many of these laboratory tests. Further peer-reviewed evidence based literature is needed to establish the assessment of risk factors in determining coronary artery disease. Scientific Rationale Update July 2012 Serum CRP Screening In a review of over 15,000 individuals from the third National Health and Nutrition Examination Survey (NHANES) in the United States, high serum CRP (>3 mg/l) was rare in the absence of any borderline or abnormal coronary risk factor (4.4 percent in men and 10.3 percent in women). The likelihood of a high serum CRP was largely attributable to the presence of other risk factors (78 percent in men and 67 percent in women). It was concluded that serum CRP may have limited clinical utility as a screening tool beyond other known cardiovascular risk factors. Similar findings were noted in the ARIC study, which assessed the association of 19 novel risk markers, including serum CRP, with incident CHD in nearly 16,000 adults followed for up to 15 years. The CRP level did not add significantly to the basic riskfactor model (age, sex, total and high-density lipoprotein cholesterol levels, systolic blood pressure, antihypertensive medication use, smoking status, and diabetes) as assessed by the change in area under receiver operating characteristic curves. In total, these studies suggest that, while serum CRP does appear to act as an independent predictor of cardiovascular disease, the predictive value added to that determined by screening for other coronary risk factors in the general population is small. Instead, serum CRP appears to add the greatest predictive value in a subset of patients with intermediate CHD risk as determined by other measures such as the Framingham Risk Score. Screening for Coronary Heart Disease Although screening appears to identify patients at increased risk, there is a paucity of evidence that such screening actually improves outcomes. Some data suggest that medical therapy or revascularization in selected patients with silent ischemia may improve outcomes. MRFIT and the Atenolol in Silent Ischemia Study demonstrated benefit from risk factor reduction and atenolol, respectively. A benefit from revascularization was suggested by results from the NIH-sponsored Asymptomatic Cardiac Ischemia Pilot (ACIP) trial, which randomly assigned 558 patients to one of three treatment strategies: angina-guided medical therapy; ischemia-guided medical therapy; or revascularization with coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI). At two years, total mortality was significantly lower with revascularization compared to ischemia-guided Cardiac Risk Assessment-Laboratory Tests Oct 15 19

20 or angina-guided medical therapy (1.1 versus 4.4 and 6.6 percent). The composite end point of death, MI, or recurrent cardiac hospitalization was also reduced. The only appropriate indication for revascularization in asymptomatic patients is to improve prognosis since revascularization cannot improve symptoms. The choice of revascularization and of the procedure is dependent upon coronary anatomy, left ventricular function, and the presence or absence of diabetes. Apoproteins (Apolipoproteins) Lipids, such as cholesterol and triglycerides, are insoluble in plasma and circulating lipid is carried in lipoproteins that transport the lipid to various tissues for energy utilization, lipid deposition, steroid hormone production, and bile acid formation. The lipoprotein consists of esterified and unesterified cholesterol, triglycerides, and phospholipids, and protein. The protein components of the lipoprotein are known as apolipoproteins (apo) or apoproteins. The different apolipoproteins serve as cofactors for enzymes and ligands for receptors. There are five major lipoproteins, each of which has a different function: Chylomicrons are very large particles that carry dietary lipid. They are associated with a variety of apolipoproteins, including A-I, A-II, A-IV, B-48, C-I, C-II, C-III, and E. Intermediate density lipoprotein (IDL) carries cholesterol esters and triglycerides. It is associated with apolipoproteins B-100, C-III, and E. Low density lipoprotein (LDL) carries cholesterol esters and is associated with apolipoprotein B-100. Very low density lipoprotein (VLDL) carries endogenous triglycerides and to a lesser degree cholesterol. The major apolipoproteins associated with VLDL are B-100, C-I, C-II, C-III, and E. High density lipoprotein (HDL) also carries cholesterol esters. It is associated with apolipoproteins A-I, A-II, C-I, C-II, C-III, D, and E. Understanding the major functions of the different apolipoproteins is important clinically, because defects in apolipoprotein metabolism lead to abnormalities in lipid handling. Apolipoproteins are usually measured by immunoassay or immunonephelometry. These techniques rely on measurement of the turbidity caused by apolipoprotein antibody complexes. A potential limitation of this method stems from the inherent turbidity of lipemic samples or even nonlipemic samples after repeated freezing and thawing. To some extent, automated systems can correct for such turbidity. Lipoprotein concentrations have been measured and described in several ways. Some of these measurements, including particle mass and mass concentration (the mass of each lipoprotein particle as solute per liter of solution), are not easily applied for screening or routine clinical purposes. Lipoprotein-associated phospholipase A2 (LP-PLA2) Cardiac Risk Assessment-Laboratory Tests Oct 15 20

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