Response to Comments for MolDX: Biomarkers in Cardiovascular Risk Assessment

Judicious Use of Biomarkers Comment: A commenter indicates there are occasions when it is necessary to accurately gauge a patient’s overall CV risk, and simple screening tests (lipids and CRP) are inadequate in capturing the majority of subjects at increased risk. Specifically: LDL particles – (yields the same info as apoB) - may help to persuade for more intensive lipid lowering intervention beyond traditional goals; Lipoprotein subclasses - LDL subclass - may help to persuade more intensive lipid lowering intervention beyond traditional goals; Intermediate density lipoproteins - Limit to high TG subjects. High density lipoprotein AI9LpAI and AI/AII – Occasionally apoAI or apoAII levels is helpful, particularly where HDL- c is markedly elevated and one wants to make sure there are actually increased levels of HDL particles Lipoprotein(a) - typically limited to consult patient when assessing global risk,or when patient has a thrombotic event history without an eliciting risk factor. It is undeniable that LPa elevation predicts incident increased CVD event risk incremental to traditional RF, lipid profile levels and CRP. Apolipoprotein B (Apo B), apo A-I and apo E – occasionally helpful apoB (when TG levels are markedly elevated making LDL-c calculation less accurate) and apoAI levels are helpful. ApoE or apoE isoforms – not used in our institution Lipoprotein-associated phospholipase A2 (Lp-PLA2) - to better gauge global CVD risks and to assess level of intensity of preventive efforts. BNP - NT-proBNP presumably – help identify those at increased risk for CVD incremental to traditional risk factors; helpful in heart failure subjects or subjects with complaint of SOB; to better gauge global CVD risks; as with microalbumin, helps making decision of what type of BP medication to intensify sometimes. Cystatin - elevated levels help identify increased risk for CKD development. Thrombogenic/hematologic factors - Factor V Leiden, Protein C, anti-cardiolipin Antibodies, etc - very rarely used; maybe unexplained thrombotic event. Interleukin-6 (IL-6), tissue necrosis factor- a (TNF- a) , plasminogen activator inhibitor-1 (PAI-1) and IL-6 promoter polymorphism – not used Free fatty acids – rarely used Visfatin, angiotensin-converting enzyme 1 (ACE2) and serum amyloid A – rarely used Microalbumin – used to gauge overall global CVD risks on initial consult; to assess for early evidence of renal issues; as withBNP, may help in BP medication to intensify Myeloperoxidase (MPO) – occasionally at initial consult to gauge overall global CVD and thrombotic risks and to assess level of intensity of preventive efforts. Homocysteine and methylenetetrahydrofolate reductase (MTHFR) mutation testing - rarely used HCys is associated with incident CVD event risk and premature atherosclerotic heart disease; HCys appropriate in patient with premature thrombotic event of unclear etiology; In subjects with CKD, elevated HCys is very strong predictor of incident CVD risks and mortality risks; when elevated, intensification of global CVD risk reduction efforts If dramatically elevated, triggers search for specific vitamin deficiencies. Uric acid – some physicians under certain conditions use this to help identify those at increased risk for major adverse CV event risk incremental to traditional risk factors. The following are not used for CV risk assessment Vitamin D White blood cell count Long-chain omega-3 fatty acids in red blood cell membrane Gamma-glutamyltransferase (GGT) Genomic profiling including CardiaRisk angiotensin gene Leptin, ghrelin, adiponectin and adipokines, retinol binding protein 4 (RBP4) and resistin Inflammatory markers including VCAM-1, P-selectin (PSEL) and E-selectin (ESEL) Cardiovascular risk panels Response: The commenter and others confirm that, aside from lipids and CRP, biomarker testing is specific for a specific clinical condition/disease, or as in the latter group, not clinically indicated for CV risk assessment at all. General CV risk assessment panels, consisting of various combinations of biochemical, immunologic, hematologic, and molecular tests, constitutes patient screening, and are not a Medicare benefit. Medicare coverage for CV risk assessment is limited to the basic lipid panel under NCD (90.1). Under this policy, Medicare does cover the use of specific biomarkers (not as a broad risk panel) to characterize a given lipid abnormality or disease (e.g., diabetes), to determine a treatment plan or to assist with intensification of therapy. Comment: Another commenter writes “we share your view that biomarkers reviewed in this LCD lack compelling data for use in aiding CV risk assessment beyond conventional measures." Response: Generally agree. Coverage ApoB and LDL Particle Number Comment: Another commenter agrees with the LCD policy which views “non-traditional lipid markers” as well as other non-lipid biomarkers, as investigational for use in cardiovascular (CV) risk assessment. The commenter presents a thorough discussion for the role of LDL particle number and ApoB in high-risk populations to aid CV risk management . In brief, LDL particle number (NMR LDL-P), rather than LDL size or subclass, has been shown to be significantly associated with CV risk independent of traditional lipid and established risk factors. The American Association of Clinical Endocrinologists (AACE), the National Lipid Association (NLA), the American Diabetes Association (ADA) in conjunction with the American College of Cardiology (ACC), and the American Association of Clinical Chemistry (AACC) have developed consensus position statement on lipoprotein particle management in individuals at risk for CVD. Due to the prevalence of discordantly elevated LDL-P despite achieving low LDL-C and non-HDL-C values, each endorses use of LDL particle number to evaluate LDL response and aid decision making regarding potential adjustment of therapy. The 2013 AACE Comprehensive Diabetes Management Algorithm, as well as the 2015 joint AACE/American College of Endocrinology Clinical Practice Guidelines for Comprehensive Diabetes Mellitus Care, advocate specific LDL particle number goals for statin treated diabetic patients at high CV risk. The commenter presents a summary table of recommendations from expert societies advocating use of LDL particle number measure in CV risk management , and respectfully request coverage of LDL particle number and apoB for use in high-risk populations to aid CV risk management. Response: CGS and the MolDx contractor sincerely appreciates the comprehensive review of current data to support LDL particle number and apoB for high-risk populations. CGS and the MolDX contractor recognizes the role of LDL particle number, apoB and other individual biomarkers as clinically indicated in the management and treatment of CV disease. This policy is directed towards CV screening panels that exceed the basic lipid panel as specified in the NCD.