**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 CV1,2,8,11,12,14 or
cerebrovascular1,6,9,14 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 60g 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 (1.590.62mm vs. 1.740.64mm, 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
2.4mol/liter in the treatment group and increased by 0.8mol/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 (Marti-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 CV3,16 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).