BlueCross BlueShield of Tennessee Medical Policy Manual

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


Homocysteine is a sulfur-containing amino acid that is rapidly oxidized in plasma into homocysteine and cysteine-homocysteine disulfide. Plasma levels of homocysteine have been actively researched as a potential marker of cardiovascular disease and as a potential risk marker for individuals with cardiovascular disease and thrombotic disorders. 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. Several homocysteine test systems are currently available.




Numerous large placebo-controlled RCTs have been published that evaluate the impact of folic acid/ vitamin B supplementation on risk of cardiovascular events, including MI and stroke. With few exceptions, meta-analyses of these RCTs have found that homocysteine-lowering interventions do not have a statistically significant effect on the rate of major cardiovascular events. Two placebo-controlled RCTs have been published that evaluate the impact of folic acid

and vitamin B supplementation on the risk of VTE. Homocysteine-lowering interventions do not have a statistically significant effect on the rate of VTE in patients with previous VTE. Based on these trials, there is insufficient evidence to conclude that supplementation to reduce homocysteine will reduce risk of VTE.


American Heart Association and American Stroke Association. (2014). Guidelines for the primary prevention of stroke. Retrieved February 16, 2018 from 

BlueCross BlueShield Association. Evidence Positioning System. (12:2017). Homocysteine testing in the screening, diagnosis, and management of cardiovascular disease and venous thromboembolic disease (2.04.23). Retrieved December 21, 2018 from (46 articles and/or guidelines reviewed) Centers for Medicare & Medicaid Services. Palmetto GBA. (2018, October) MolDX: Biomarkers in Cardiovascular Risk Assessment (LCD ID L36129). Retrieved December 21, 2018 from 

Li, Y., Huang, T., Zheng, Y., Muka, T., Troup, J., & Hu, F. (2016). Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. Journal of American Heart Association, 5 (8), pii: e003768. (Level 1 evidence)

Liu, Y., Tian, T., Zhang, H., Gao, L., & Zhou, X. (2014). The effect of homocysteine-lowering therapy with folic acid on flow-mediated vasodilation in patients with coronary artery disease: a meta-analysis of randomized controlled trials. Atherosclerosis, 235 (1), 31-35. Abstract retrieved February 19, 2018 from PubMed database.

Park, J. H., Saposnik, G., Ovbiagele, B., Markovic, D., & Towfighi, A. (2016). Effect of B-vitamins on stroke risk among individuals with vascular disease who are not on antiplatelets: A meta-analysis. International Journal of Stroke, 11 (2), 206-211. Abstract retrieved December 12, 2016 from PubMed database.

Peng, H.Y., Man, C.F., Xu, J., & Fan, Y. (2015). Elevated homocysteine levels and risk of cardiovascular and all-cause mortality: a meta-analysis of prospective studies. Journal of Zhejiang University – Science B, 16 (1), 78-86. (Level 1 evidence)

Shi, Z., Guan, Y., Huo, Y., Liu, S., Zhang, M., Lu, H., et al. (2015). Elevated total homocysteine levels in acute ischemic stroke are associated with long-term mortality. Stroke, 46, 2419-2425. (Level 3 evidence)

U. S. Food and Drug Administration. (2004, February). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K033706. Retrieved April 8, 2008 from

U. S. Food and Drug Administration. (2006, October). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K062808. Retrieved April 8, 2008 from 

Van Dijk, S.C., Enneman, A.W., Swart, K.M., van Wijngaarden, J.P., Ham, A.C., Brouwer-Brolsma, E.M., et al. (2015). Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial.  Journal of Hypertension, 33 (9), 1897-1906. Abstract retrieved February 19, 2018 from PubMed database.

Wang, W.W., Wang, X.S., Zhang, Z.R., He, J.C., & Xie, C.L. (2017). A meta-analysis of folic acid in combination with anti-hypertension drugs in patients with hypertension and hyperhomocysteinemia. Frontiers in Pharmacology, 8, 585.

Yi, X., Zhou, Y., Jiang, D, Li, X., Guo, Y., & Jiang, X. (2014). Efficacy of folic acid supplementation on endothelial function and plasma homocysteine concentration in coronary artery disease: A meta-analysis of randomized controlled trials. Experimental and Therapeutic Medicine, 7, 1100-1110. (Level 1 evidence)




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