LCD L34419: Homocysteine Level, Serum

Indications:

Elevated serum levels of the amino acid homocysteine have been associated with increased risk of cardiovascular (CV) 3,16 and cerebrovascular 16 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.