Homocysteine Level, Serum

Title XVIII of the Social Security Act §1862(a)(1)(A) excludes expenses incurred for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member

42 CFR §410.32 indicates that diagnostic tests may only be ordered by the treating physician (or other treating practitioner acting within the scope of his or her license and Medicare requirements)

42 CFR §411.15(k)(11) excludes routine physical examinations

42 CFR §482.24 Conditions of participation: Medical record services

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 6, §20.4.1 Diagnostic Services Defined

Indications:

Elevated serum levels of the amino acid homocysteine have been associated with increased risk of cardiovascular (CV)^3,16 and cerebrovascular¹⁶ disease events as well as an increased risk of osteoporosis.^13,15,19 Elevated serum levels of homocysteine may reflect a deficiency of folate, vitamin B6, or vitamin B12.^7,16 The majority of hyperhomocysteinemia is caused by low levels of folate and vitamin B12 associated with anemia. Both vitamins are required for the metabolism of homocysteine to methionine. In the absence of either vitamin, this process cannot occur normally, and homocysteine accumulates. When initial testing results for vitamin B12 and/or folate levels are inconclusive, or if clinical findings are inconsistent with initial testing values, an elevated homocysteine level confirms the vitamin deficiency as the source of anemia.^10,18

Correcting nutritional inadequacy of folic acid and vitamin B12 will lower homocysteine levels in most patients.^4,5,7 However, the published evidence is insufficient to justify that such vitamin supplementation, while lowering the serum homocysteine levels, also reduces the risks for CV^{1,2,8,11,12,14} or cerebrovascular^1,6,9,14 events or osteoporosis.¹⁷

• Medicare will cover homocysteine levels to confirm vitamin B12 or folate deficiency.

• In the absence of evidence that treatment of hyperhomocysteinemia reduces CV or cerebrovascular events, this test can only be covered in patients with known vascular disease or risk thereof (based upon abnormal lipid metabolism, high blood pressure (BP) or diabetes mellitus (DM)) for the purpose of risk stratification. In this circumstance it will be covered only once per lifetime.

Limitations:

• When used to determine the risk of developing atherosclerotic CV disease or cerebrovascular disease, measurement of serum homocysteine levels in the absence of known vascular disease, hyperlipidemia, or DM will be denied as screening.
• Serum homocysteine levels for the evaluation of treatment of hyperhomocysteinemia in patients with CV or cerebrovascular risk factors will be denied as not medically necessary.
• Serum homocysteine levels for the evaluation of treatment of hyperhomocysteinemia in patients with osteoporosis or primary prevention of fracture will be denied as not medically necessary.

In their 2004 report, Lange H, et al. reported that folate and B vitamin supplementation to lower homocysteine levels, after coronary stenting, may increase the risk of in-stent restenosis and the need for target vessel revascularization even though it significantly lowered plasma homocysteine levels.⁸ The authors conducted a double-blind, multicenter trial with a total of 636 patients who had successful coronary stenting. The patients were randomly assigned to receive 1mg of folic acid, 5mg of vitamin B6, and 1mg of vitamin B12 intravenously, followed by daily oral doses of 1.2mg of folic acid, 48mg of vitamin B6, and 60µg of vitamin B12 for 6 months, or to receive placebo. Quantitative coronary angiography assessed the end points (minimal luminal diameter, late loss, and restenosis rate) at 6 months. Results showed the mean minimal luminal diameter was significantly smaller in the folate group when compared to placebo (1.59±0.62mm vs. 1.74±0.64mm, p=0.008). The extent of late luminal loss was greater in the folate group when compared to placebo (34.5% vs. 26.5%, p=0.05). Additionally, more patients in the folate group required repeated target-vessel revascularization (15.8% vs. 10.6%, p=0.05).

The Heart Outcomes Prevention Evaluation (HOPE) 2 investigators (Lonn, et al., 2006) reported that the combined daily administration of vitamin supplementation for 5 years to lower homocysteine had no beneficial effect on major vascular events in a high-risk population with vascular disease.¹¹ 5522 patients ≥55 years old with vascular disease or diabetes were randomly assigned to daily treatment with the combination of 2.5mg folic acid, 50mg vitamin B6, and 1mg of vitamin B12 or with placebo. The study’s primary outcome was a composite of death from CV causes, myocardial infarction, and stroke. Results showed the mean plasma homocysteine levels decreased by 2.4µmol/liter in the treatment group and increased by 0.8µmol/liter in the placebo group. Primary outcome events occurred in 18.8% of the patients within the treatment group compared to 19.8% of patients assigned to the placebo group (relative risk, 0.95; 95% confidence interval (CI), 0.84 to 1.07; p=0.41). When compared with placebo, active treatment reportedly did not significantly decrease the risk of death from CV causes (relative risk, 0.96; 95% CI, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95% CI, 0.85 to 1.14), or any of the secondary outcomes (total ischemic events, death from any cause, hospitalization for unstable angina, hospitalization for congestive heart failure, and revascularization). The authors did observe an absolute reduction of 1.3% and a relative reduction of 24% with risk of stroke with patients in the treatment group. However, the authors do caution that the apparent beneficial effect of B vitamin supplements on stroke in this trial may represent either an overestimate of the real effect or a spurious result due to the play of chance. The number of strokes was much lower than the number of coronary events, the CIs around the estimated risk reduction were wide, and the results were not adjusted for the multiplicity of outcomes compared. Also, the authors found no effect of treatment on transient ischemic attacks (TIAs). The authors concluded that the study results do not support the use of folic acid and B vitamin supplementation as a preventative treatment for major CV events in patients with vascular disease.

The Norwegian Vitamin Trial (NORVIT) investigators (Bonaa, et al., 2006) found that treatment with folic acid, with or without high doses of vitamin B6, did not lower the risk of recurrent CV disease or death after acute myocardial infarction.² The trial included 3749 patients who had an acute myocardial infarction within 7 days before being randomly assigned to either receive 0.8mg of folic acid, 0.4mg of vitamin B12, and 40mg of vitamin B6, or 0.8mg of folic acid and 0.4mg of vitamin B12, or 40mg of vitamin B6, or placebo. Median follow-up was 40 months, and the study’s primary outcome was a composite of recurrent myocardial infarction, stroke, and sudden death secondary to coronary artery disease. Results showed the mean total homocysteine level was lowered by 27% for those patients given folic acid with vitamin B12. However, the same treatment had no significant effect on the primary outcome when compared to placebo (risk ratio (RR), 1.08; 95% CI, 0.93 to 1.25; p=0.31). No significant benefit was seen by the investigators for the primary outcome when compared to placebo with treatment with vitamin B6 (relative risk of the primary outcome, 1.14; 95% CI, 0.98 to 1.32; p=0.09). For patients given folic acid, vitamin B12, and vitamin B6, the investigators reported a trend toward increased risk (relative risk, 1.22; 95% CI, 1.00 to 1.50; p=0.05). The authors concluded that the trial showed that not only did treatment with B vitamins not lower the risk of recurrent CV disease after acute myocardial infarction, but also that such treatment may be harmful after acute myocardial infarction or coronary stenting and should be avoided.

Bazzano, et al. (2006) performed a meta-analysis of 12 randomized controlled trials that compared folic acid supplementation with either placebo or usual care for at least 6 months with clinical CV disease as the end point.¹ The objective was to evaluate the effects of folic acid supplementation on CV diseases and all-cause mortality for patients with preexisting CV or renal disease. Results showed that all trials reported a reduction in homocysteine levels; however, no trial showed a statistically significant relationship between net change in homocysteine level and relative risk for any of the clinical outcomes. The overall relative risks (95% CI) of patients treated with folic acid supplementation vs. controls were 0.95 (0.88 to 1.03) for CV diseases, 1.04 (0.92 to 1.17) for coronary heart disease, 0.86 (0.71 to 1.04) for stroke, and 0.96 (0.88 to 1.04) for all-cause mortality. The findings of this meta-analysis suggested that folic acid supplementation is ineffective in the secondary prevention of CV disease among patients with vascular diseases.

Miller, et al. (2010) also conducted a meta-analysis of 14 randomized controlled trials that investigated potential interactions between folic acid supplementation and baseline homocysteine levels on CV disease events.¹⁴ Although all trials found a significant decrease in homocysteine levels with folic acid supplementation, overall, folic acid supplementation did not affect primary CV clinical outcomes (relative risk 1.02, 95% CI, 0.93 to 1.13, p=0.66) or stroke (relative risk 0.95, 95% CI, 0.84 to 1.08, p=0.43). The authors concluded that folic acid supplementation should not be recommended to prevent or treat CV disease or stroke.

A 2017 Cochrane Review (Martí-Carvajal, et al.) was conducted to determine whether homocysteine-lowering interventions were effective in preventing CV events, as well as reducing all-cause mortality, and to evaluate their safety for patients with and without pre-existing CV disease.¹² Fifteen randomized controlled trials involving 71,422 participants were identified by the authors. The identified trials assessed the effects of homocysteine-lowering interventions (different regimens of B vitamins (cyanocobalamin (B12), folic acid (B9) and pyridoxine (B6)) with a control or any other comparison group) for preventing CV events with a follow-up period of 1 year or longer. Myocardial infarction and stroke were the primary outcomes. Results showed no evidence that supplementation with vitamins B6, B12, or folic acid, given alone or in combination, at any dosage compared with placebo, or standard care, prevented heart attack or reduced death rates in patients at risk of, or living with CV disease. The authors found a small difference in effect in favor of homocysteine-lowering interventions regarding stroke. Homocysteine-lowering interventions, when compared to placebo, were associated with reduced stroke outcome (homocysteine-lowering=4.3% versus comparator=5.1%, RR 0.90, 95% CI, 0.82 to 0.99, I²=8%, 10 trials, N=44,224; high-quality evidence).

Lee, et al. (2010) performed a meta-analysis of randomized controlled trials to investigate the efficacy of folic acid supplementation in stroke prevention.⁹ Thirteen trials were identified by the authors. Results showed that folic acid supplementation was associated with a mild benefit in reducing the risk of stroke, but the result was not statistically significant (RR=0.93; 95% CI, 0.85 to 1.03; p=0.16). Folic acid supplementation did not demonstrate a major effect in averting stroke. However, the authors also concluded that potential mild benefits in primary stroke prevention, especially when folate is combined with B vitamins and in male patients, should be investigated further.

A 2021 systematic review (Kleindorfer, et al.) published by the American Heart Association (AHA) / American Stroke Association (ASA) presented guidelines for the secondary prevention of ischemic stroke or TIA.⁶ The authors concluded that in patients with ischemic stroke or TIA with hyperhomocysteinemia, supplementation with folate, vitamin B6, and vitamin B12 is not effective for preventing subsequent stroke. The class of recommendation given by the reviewers was “No Benefit (Moderate)” with the level of evidence determined to be of moderate-quality.

Sawka, et al. (2007) used the data from the HOPE 2 trial to evaluate the effect of combined treatment with folic acid, vitamin B6, and vitamin B12 on the risk of clinical fractures.¹⁷ Patients were randomly assigned to daily treatment with the combination of 2.5mg folic acid, 50mg vitamin B6, and 1mg of vitamin B12 or with placebo. After randomization, the patients were evaluated every 6 months with the mean duration of follow-up of 5 years. Data on clinical fractures were prospectively collected during the study. Clinical fractures at any skeletal site were included by the authors except for the sternum, skull, face, fingers, and toes. Presumed pathologic fractures secondary to metastatic malignant neoplasms were also excluded from the final analysis. 2758 participants received homocysteine level–lowering therapy with daily vitamin supplementation and 2764 received daily placebo. Results showed the mean plasma homocysteine levels decreased by 0.29mg/liter in the treatment group and increased by 0.11mg/liter in the placebo group. During the mean 5-year follow-up, there were a total of 350 incident clinical fractures (313 nonvertebral; 50 vertebral). 175 incident clinical fractures were reported in each group (treatment group vs. placebo), corresponding to a crude hazard ratio (HR) of 1.01 (95% CI, 0.82 to 1.24; p=0.97) and an adjusted HR of 1.06 (95% CI, 0.81 to 1.40; p=0.67). The respective number of nonvertebral fractures was 161 in the treatment group and 152 in the placebo group. The respective number of vertebral fractures was 24 and 26. Regarding incident of fractures, homocysteine level–lowering therapy did not appear to be significantly more efficacious than placebo. The authors concluded that their findings did not support the use of routine folic acid and B vitamin supplementation for the primary prevention of fractures among elderly community-dwelling adults.

Homocysteine is an intermediary amino acid. Elevated serum levels of homocysteine have been associated with increased risk of CV^3,16 and cerebrovascular¹⁶ disease events as well as an increased risk of osteoporosis. ^13,15,19 Current published peer-reviewed literature does not support that reducing levels of homocysteine with B vitamin supplementation prevents CV disease or assists in the treatment of osteoporosis or primary prevention of fracture. Given the paucity of evidence for benefit from lowering elevated homocysteine levels in patients with established CV disease or osteoporosis, testing for homocysteine levels will only be considered to be medically reasonable and necessary when performed as outlined in this Local Coverage Determination (LCD).

Documentation Requirements

Documentation supporting medical necessity should be legible, maintained in the patient's medical record, and must be made available to the A/B MAC upon request.

The patient's medical record must contain documentation that fully supports the medical necessity for services included within this LCD (see Coverage Indications, Limitations and/or Medical Necessity). This documentation includes, but is not limited to, relevant medical history, physical examination, and results of pertinent diagnostic tests or procedures.

Utilization Guidelines

When used for atherosclerotic CV disease risk stratification, measurement of serum homocysteine is considered to be medically necessary only once in a lifetime.

1. Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: A meta-analysis of randomized controlled trials. JAMA. 2006;296(22):2720-2726.
2. Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006;354(15):1578-1588.
3. Gori AM, Corsi AM, Fedi S, et al. A proinflammatory state is associated with hyperhomocysteinemia in the elderly. Am J Clin Nutr. 2005;82(2):335-341.
4. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. 1999;340(19):1449-1454.
5. Kang SS. Treatment of hyperhomocyst(e)inemia: Physiological basis. J Nutr. 1996;126(4):1273S-1275S.
6. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the prevention of stroke in patients with stroke and transient ischemic attack: A guideline from the American Heart Association/American Stroke Association. Stroke. 2021;52(7):e364-e467.
7. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998;92(4):1191-1198.
8. Lange H, Suryapranata H, De Luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med. 2004;350(26):2673-2681.
9. Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention. Stroke. 2010;41(6):1205-1212.
10. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol. 1990;34(2):99-107.
11. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease: The heart outcomes prevention evaluation (HOPE) 2 investigators. N Engl J Med. 2006;354(15):1567-1577.
12. Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;8(8):CD006612.
13. McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med. 2004;350(20):2042-2049.
14. Miller ER III, Juraschek S, Pastor-Barriuso R, et al. Meta-analysis of folic acid supplementation trials on risk of cardiovascular disease and risk interaction with baseline homocysteine levels. Am J Cardiol. 2010;106(4):517-527.
15. Raisz LG. Homocysteine and osteoporotic fractures – Culprit or bystander? N Engl J Med. 2004;350(20):2089-2090.
16. Robinson K, Arheart K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations: Risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation. 1998;97(5):437-443.
17. Sawka AM, Ray JG, Yi Q, Josse RG, Lonn E. Randomized clinical trial of homocysteine level lowering therapy and fractures. Arch Intern Med. 2007;167(19):2136-2139.
18. Stabler SP, Allen RH, Savage DG, Lindenbaum J. Clinical spectrum and diagnosis of cobalamin deficiency. Blood. 1990;76(5):871-881.
19. van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med. 2004;350(20):2033-2041.

• Homocysteine