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Homocysteine Testing in the Screening, Diagnosis, and Management of Cardiovascular Disease and Venous Thromboembolic Disorders Form

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Homocysteine Testing in the Screening, Diagnosis, and Management of Cardiovascular Disease and Venous Thromboembolic Disorders

Indications

(1) Does the request meet this criterion: individuals for cardiovascular disease? 
(2) Does the request meet this criterion: individuals with venous thromboembolism or risk of venous thromboembolism. Note: Laboratories are not allowed to obtain clinical authorization or participate in the authorization process on behalf of the ordering physician. Only the ordering physician shall be involved in the authorization, appeal? 

Effective Date

NA

Last Reviewed

NA

Original Document

  Reference



500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 01|01|2024 POLICY LAST REVIEWED: 02|18|2026 OVERVIEW Homocysteine is an amino acid that has been evaluated as a potential marker of cardiovascular disease (CVD) and as a potential risk marker for people with CVD and thrombotic disorders; the presence of this amino acid raises one’s risk of developing a blood clot. The association between homocysteine-lowering interventions and the risk of CVD or thrombotic events has been examined. MEDICAL CRITERIA Not applicable PRIOR AUTHORIZATION Not applicable POLICY STATEMENT Medicare Advantage Plans and Commercial Products
Measurement of plasma levels of homocysteine are not covered for Medicare Advantage Plans and not medically necessary for Commercial Products in the screening, evaluation and management of patients with the following indications due to the large amount of evidence that homocysteine-lowering interventions do not improve health outcomes: • individuals for cardiovascular disease • individuals with venous thromboembolism or risk of venous thromboembolism. Note: Laboratories are not allowed to obtain clinical authorization or participate in the authorization process on behalf of the ordering physician. Only the ordering physician shall be involved in the authorization, appeal or other administrative processes related to prior authorization/medical necessity.
In no circumstance shall a laboratory or a physician/provider use a representative of a laboratory or anyone with a relationship to a laboratory and/or a third party to obtain authorization on behalf of the ordering physician, to facilitate any portion of the authorization process or any subsequent appeal of a claim where the authorization process was not followed and/or a denial for clinical appropriateness was issued, including any element of the preparation of necessary documentation of clinical appropriateness. If a laboratory or a third party is found to be supporting any portion of the authorization process, BCBSRI will deem the action a violation of this policy and severe action will be taken up to and including termination from the BCBSRI provider network. If a laboratory provides a laboratory service that has not been authorized, the service will be denied as the financial liability of the participating laboratory and may not be billed to the member. Commercial Products Some genetic testing services are not covered and a contract exclusion for any self-funded group that has excluded the expanded coverage of biomarker testing related to the state mandate, R.I.G.L. §27-19-81 described in the Biomarker Testing Mandate policy. For these groups, a list of which genetic testing services are covered with prior authorization, are not medically necessary or are not covered because they are a contract exclusion can be found in the Coding section of the Genetic Testing Services or Proprietary Laboratory Analyses policies. Please refer to the appropriate Benefit Booklet to determine whether the member’s plan has customized benefit coverage. Please refer to the list of Related Policies for more information. Medical Coverage Policy | Homocysteine Testing in the Screening, Diagnosis, and Management of Cardiovascular Disease and Venous Thromboembolic Disorders

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 2 (401) 274-4848 WWW.BCBSRI.COM

COVERAGE Benefits may vary between groups and contracts. Please refer to the appropriate Benefit Booklet, Evidence of Coverage or Subscriber Agreement for applicable not medically necessary/not covered benefits/coverage.

BACKGROUND Homocysteine is a sulfur-containing amino acid that is rapidly oxidized in plasma into homocysteine and cysteine-homocysteine disulfide. Measurement of total plasma homocysteine is the sum of homocysteine and its oxidized forms.

Plasma levels of homocysteine have been actively researched as a risk factor for cardiovascular disease (CVD), initially based on the observation that patients with hereditary homocystinuria, an inborn error of metabolism associated with high plasma levels of homocysteine, had a markedly increased risk of CVD. Subsequently, prospective epidemiologic studies were conducted to determine if an elevated plasma level of homocysteine was an independent risk factor for CVD and could be used to improve current risk prediction models. Several case-control studies have also suggested that elevated homocysteine is a risk factor for venous thromboembolism (VTE; pulmonary embolism, deep vein thrombosis).

Interest in homocysteine as a potentially modifiable risk factor has been stimulated by the epidemiologic finding that levels of homocysteine inversely correlate with levels of folate. This finding has raised the possibility that treatment with folic acid might lower homocysteine levels and, in turn, reduce the risk of CVD and thrombotic events. Therefore, homocysteine has a potential utility both as a risk predictor and as a target of treatment.

Determination of homocysteine concentration may be offered as a component of a comprehensive cardiovascular risk assessment that may include evaluation of small-density lipoproteins, subclassification of high-density lipoproteins, evaluation of lipoprotein (a), high-sensitivity C-reactive protein, and genotyping of apolipoprotein E. Determination of homocysteine concentration may also be offered as part of the risk assessment for patients at high-risk of VTE events or who have experienced idiopathic VTE, recurrent VTE, thrombosis occurring at a young age, or thrombosis at an unusual site.

For individuals who are asymptomatic with the risk of CVD or individuals with CVD who receive homocysteine testing, the evidence includes observational studies and RCTs of homocysteine-lowering interventions. Relevant outcomes are changes in disease status and morbid events such as CV events, including MI, stroke, and CV death. Evidence from RCTs evaluating homocysteine-lowering interventions does not support the hypothesis that lowering homocysteine levels with folate and/or B vitamins improves CV outcomes. Numerous large RCTs and meta-analyses of these trials have consistently reported that homocysteine-lowering treatment is ineffective in reducing major CV events. A Cochrane systematic review found that homocysteine-lowering treatment reduced the risk of stroke. However, the investigators considered the results weak, and the clinical significance of this reduction is still unknown. Given a large amount of evidence from placebo-controlled, randomized trials that homocysteine-lowering interventions do not improve health outcomes, it is unlikely that routine homocysteine testing has the potential to change management that improves health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with the risk of VTE or individuals who have experienced VTE events who receive homocysteine testing, the evidence includes observational studies and RCTs of homocysteine- lowering interventions. Relevant outcomes are change in disease status and morbid events such as VTE occurrence. Evidence from RCTs evaluating homocysteine-lowering interventions does not support the hypothesis that lowering homocysteine levels with folate and/or B vitamins reduces the risk of VTE. Only a single RCT was designed to test for VTE as a primary outcome. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 3 (401) 274-4848 WWW.BCBSRI.COM

CODING Medicare Advantage Plans and Commercial Products
The following CPT code(s) is not covered for Medicare Advantage Plans and not medically necessary for Commercial Products: 83090 Homocysteine

RELATED POLICIES Biomarker Testing Mandate
Genetic Testing Services

PUBLISHED Provider Update, April 2026 Provider Update, March 2025
Provider Update, March 2024
Provider Update, March/November 2023 Provider Update, April 2022

REFERENCES

  1. Veeranna V, Zalawadiya SK, Niraj A, et al. Homocysteine and reclassification of cardiovascular disease risk. J Am CollCardiol. Aug 30 2011; 58(10): 1025-33. PMID 21867837
  2. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.JAMA. Oct 2002; 288(16): 2015-22. PMID 12387654 3.
  3. Shoamanesh A, Preis SR, Beiser AS, et al. Circulating biomarkers and incident ischemic stroke in the FraminghamOffspring Study. Neurology. Sep 20 2016; 87(12): 1206-11. PMID 27558379
  4. Han L, Wu Q, Wang C, et al. Homocysteine, Ischemic Stroke, and Coronary Heart Disease in Hypertensive Patients: APopulation-Based, Prospective Cohort Study. Stroke. Jul 2015; 46(7): 1777-86. PMID 26038522
  5. Shi Z, Guan Y, Huo YR, et al. Elevated Total Homocysteine Levels in Acute Ischemic Stroke Are Associated With Long-Term Mortality. Stroke. Sep 2015; 46(9): 2419-25. PMID 26199315
  6. Wang C, Han L, Wu Q, et al. Association between homocysteine and incidence of ischemic stroke in subjects withessential hypertension: a matched case-control study. Clin Exp Hypertens. 2015; 37(7): 557-
  7. PMID 25992490
  8. Park CS, Ihm SH, Yoo KD, et al. Relation between C-reactive protein, homocysteine levels, fibrinogen, and lipoproteinlevels and leukocyte and platelet counts, and 10-year risk for cardiovascular disease among healthy adults in the USA.Am J Cardiol. May 01 2010; 105(9): 1284-8. PMID 20403480
  9. Martí-Carvajal AJ, Solà I, Lathyris D, et al. Homocysteine-lowering interventions for preventing cardiovascular events.Cochrane Database Syst Rev. Aug 17 2017; 8(8): CD006612. PMID 28816346
  10. Martí-Carvajal AJ, Solà I, Lathyris D, et al. Homocysteine-lowering interventions for preventing cardiovascular events.Cochrane Database Syst Rev. Jan 31 2013; (1): CD006612. PMID 23440809
  11. Martí-Carvajal AJ, Solà I, Lathyris D. Homocysteine-lowering interventions for preventing cardiovascular events. CochraneDatabase Syst Rev. Jan 15 2015; 1: CD006612. PMID 25590290
  12. Park JH, Saposnik G, Ovbiagele B, et al. Effect of B-vitamins on stroke risk among individuals with vascular disease whoare not on antiplatelets: A meta-analysis. Int J Stroke. Feb 2016; 11(2): 206-11. PMID 26783312
  13. Yi X, Zhou Y, Jiang D, et al. Efficacy of folic acid supplementation on endothelial function and plasma homocysteineconcentration in coronary artery disease: A meta-analysis of randomized controlled trials. Exp Ther Med. May 2014; 7(5):1100-1110. PMID 24940394
  14. Liu Y, Tian T, Zhang H, et al. The effect of homocysteine-lowering therapy with folic acid on flow- mediated vasodilation inpatients with coronary artery disease: a meta-analysis of randomized controlled trials. Atherosclerosis. Jul 2014; 235(1):31-5. PMID 24814647
  15. Huang T, Chen Y, Yang B, et al. Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular andall-cause mortality. Clin Nutr. Aug 2012; 31(4): 448-54. PMID 22652362
  16. Zhou YH, Tang JY, Wu MJ, et al. Effect of folic acid supplementation on cardiovascular outcomes: a systematic review andmeta-analysis. PLoS One. 2011; 6(9): e25142. PMID 21980387

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 4 (401) 274-4848 WWW.BCBSRI.COM

  1. Clarke R, Halsey J, Bennett D, et al. Homocysteine and vascular disease: review of published results of thehomocysteine-lowering trials. J Inherit Metab Dis. Feb 2011; 34(1): 83-91. PMID 21069462
  2. van Dijk SC, Enneman AW, Swart KM, et al. Effects of 2-year vitamin B12 and folic acid supplementation inhyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial. J Hypertens.Sep 2015; 33(9): 1897-906; discussion 1906. PMID 26147383
  3. Armitage JM, Bowman L, Clarke RJ, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo onmortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. Jun 23 2010; 303(24): 2486-94.PMID 20571015
  4. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl JMed. Apr 13 2006; 354(15): 1567-77. PMID 16531613
  5. Bønaa KH, Njølstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardialinfarction. N Engl J Med. Apr 13 2006; 354(15): 1578-88. PMID 16531614
  6. Jacques PF, Selhub J, Bostom AG, et al. The effect of folic acid fortification on plasma folate and total homocysteineconcentrations. N Engl J Med. May 13 1999; 340(19): 1449-54. PMID 10320382
  7. Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta- analysis ofpublished epidemiological studies. J Thromb Haemost. Feb 2005; 3(2): 292-9. PMID 15670035
  8. Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med.Oct 26 1998; 158(19): 2101-6. PMID 9801176
  9. den Heijer M, Rosendaal FR, Blom HJ, et al. Hyperhomocysteinemia and venous thrombosis: a meta- analysis. ThrombHaemost. Dec 1998; 80(6): 874-7. PMID 9869152
  10. Naess IA, Christiansen SC, Romundstad PR, et al. Prospective study of homocysteine and MTHFR 677TT genotype andrisk for venous thrombosis in a general population--results from the HUNT 2 study. Br J Haematol. May 2008; 141(4): 529-35. PMID 18318759
  11. Zhou K, Zhao R, Geng Z, et al. Association between B-group vitamins and venous thrombosis: systematic review andmeta-analysis of epidemiological studies. J Thromb Thrombolysis. Nov 2012; 34(4): 459-67. PMID 22743781
  12. den Heijer M, Willems HP, Blom HJ, et al. Homocysteine lowering by B vitamins and the secondary prevention of deepvein thrombosis and pulmonary embolism: A randomized, placebo-controlled, double-blind trial. Blood. Jan 01 2007;109(1): 139-44. PMID 16960155
  13. Ray JG, Kearon C, Yi Q, et al. Homocysteine-lowering therapy and risk for venous thromboembolism: a randomized trial.Ann Intern Med. Jun 05 2007; 146(11): 761-7. PMID 17470822
  14. National Institute for Health and Care Excellence (NICE). Cardiovascular disease: risk assessment and reduction, including lipid modification [CG181]. Updated December 2023; https://www.nice.org.uk/guidance/ng238. Accessed October 21, 2024.
  15. Bushnell C, Kernan WN, Sharrief AZ, et al. 2024 Guideline for the Primary Prevention of Stroke: A Guideline From the American Heart Association/American Stroke Association. Stroke. Dec 2024; 55(12): e344-e424. PMID 39429201
  16. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke andTransient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. Jul2021; 52(7): e364-e467. PMID 34024117
  17. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of CardiovascularDisease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical PracticeGuidelines. Circulation. Sep 10 2019; 140(11): e596-e646. PMID 30879355
  18. Gornik HL, Aronow HD, Goodney PP, et al. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. Jun 11 2024; 149(24): e1313-e1410. PMID 38743805
  19. Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report ofthe American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Jul01 2014; 63(25 Pt B): 2935-2959. PMID 24239921

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 5 (401) 274-4848 WWW.BCBSRI.COM

  1. Myers GL, Christenson RH, Cushman M, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practiceguidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem. Feb 2009; 55(2): 378-84.PMID 19106185
  2. National Institute for Health and Care Excellence (NICE). Cardiovascular disease: risk assessment and reduction, including lipid modification [CG181]. Updated December 2023; https://www.nice.org.uk/guidance/ng238. Accessed October 27, 2025.
  3. Maynard G. Preventing hospital-associated venous thromboembolism: a guide for effective quality improvement. 2nd ed.Rockville, MD: Agency for Healthcare Research and Quality; 2016.
  4. National Institute for Health and Care Excellence (NICE). Venous thromboembolism in over 16s: reducing the risk of hospita-acquired deep vein thrombosis or pulmonary embolism. [NG89]. 2018; updated August 2019. https://www.nice.org.uk/guidance/ng89. Accessed October 28, 2025.

  5. U.S. Preventive Services Task Force. Cardiovascular Disease: Risk Assessment Using Nontraditional Risk Factors. 2018; https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/cardiovascular-disease- screening-using-nontraditional-risk-assessment. Accessed October 29, 2025. i

    This medical policy is made available to you for informational purposes only. It is not a guarantee of payment or a substitute for your medical judgment in the treatment of your patients. Benefits and eligibility are determined by the member's subscriber agreement or member certificate and/or the employer agreement, and those documents will supersede the provisions of this medical policy. For information on member-specific benefits, call the provider call center. If you provide services to a member which are determined to not be medically necessary (or in some cases medically necessary services which are non-covered benefits), you may not charge the member for the services unless you have informed the member and they have agreed in writing in advance to continue with the treatment at their own expense. Please refer to your participation agreement(s) for the applicable provisions. This policy is current at the time of publication; however, medical practices, technology, and knowledge are constantly changing. BCBSRI reserves the right to review and revise this policy for any reason and at any time, with or without notice. Blue Cross & Blue Shield of Rhode Island is an independent licensee of the Blue Cross and Blue Shield Association. CLICK THE ENVELOPE ICON BELOW TO SUBMIT COMMENTS

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