Coverage Policy Manual
Policy #: 2006028
Category: Laboratory
Initiated: August 2006
Last Review: February 2019
  Homocysteine Measurement

Description:
Homocysteine is an amino acid found in the blood; levels are inversely correlated with folate levels. Homocysteine has been evaluated as a potential marker of cardiovascular disease (CVD) in the general population and as a potential risk marker among people with CVD. The association between homocysteine-lowering interventions and risk of CVD has also been examined.
 
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. The laboratory test is referred to as either homocysteine or homocyst(e)ine.
 
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 cardiovascular disease. Subsequently, prospective epidemiologic studies were conducted to determine if an elevated plasma level of homocysteine was an independent risk factor for cardiovascular disease and could be used to improve current risk prediction models.
 
Interest in homocysteine as a potentially modifiable risk factor has been stimulated by the epidemiologic finding that levels of homocysteine are inversely correlated 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 cardiovascular disease. Therefore, homocysteine has 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.
 
Regulatory Status
Administration (FDA) through the 510(k) process. These include the liquid-stable 2-part homocysteine reagent test by Catch Inc. (Maple Valley, WA) in 2006. Catch Inc. was purchased by Axis-Shield (Scotland) in 2010 and the Catch-branded products were phased out in 2011. The test is indicated for the in vitro quantitative determination of total homocysteine in serum and plasma to assist in diagnosing and treating patients with suspicion of homocystinuria and hyperhomocysteinemia. Other homocysteine test systems cleared for marketing by FDA include the Homocysteine Enzymatic Assay (Roche Diagnostics, Indianapolis, IN) in 2012, the Diazyme Enzymatic Homocysteine Assay (Diazyme Laboratories, Poway, CA) in 2012, the A/C Automatic Enzymatic Hcy [Homocysteine] Assay (AntiCancer Inc., San Diego, CA) in 2008, and the Teco Enzymatic Homocysteine Assay (Teco Diagnostics, Anaheim, CA) in 2007. FDA product code: LPS.
 

Policy/
Coverage:
Screening tests are exclusions in most member benefit certificates of coverage except for coverage based on the Patient Protection and Affordable Care Act (PPACA) screening recommendations for non-grandfathered plans and those contracts with wellness benefits (which like PPACA, covers specific screening procedures).
  
Plasma or serum measurement of homocysteine meets primary coverage criteria for effectiveness and is covered for patients with hereditary homocystinuria and undiagnosed megaloblastic anemia in childhood.  
  
Homocysteine measurement does not meet member benefit certificate Primary Coverage Criteria for routine testing of patients to determine risk for developing atherosclerotic vascular disease or to determine need for treatment of  hyperhomocysteinemia as studies have shown that plasma levels of homocysteine do not predict the future development of atherosclerotic vascular disease, and treatment of elevated levels of serum homocysteine are not effective in reducing risk of cardiovascular disease.
 
For contracts without primary coverage criteria, Homocysteine measurement for routine testing of patients to determine risk for developing atherosclerotic vascular disease or to determine need for treatment of hyperhomocysteinemia is considered investigational.  Investigational services are contract exclusions.
 
 

Rationale:
This policy was initiated in 2006 following publication of the results of The Heart Outcomes Prevention Evaluation Trial (Lonn 2006) and the Norwegian Vitamin Trial Bonaa 2006).
 
In 2003, the Medical Letter reviewed the effect of prevention of coronary artery disease by lowering plasma homocysteine levels and concluded that, “Trying to lower plasma homocysteine concentrations to prevent coronary disease seems premature.  There is no convincing evidence to date that such a practice is beneficial, and it may not necessarily be harmless.”
 
In 2006, The Hope Trial, (Lonn et al, 2006) concluded the following: “Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease.  The NORVIT Trial, (Bonaa et al, 2006), found that “treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction.  A harmful effect from combined B vitamin treatment was suggested.  Such treatment should therefore not be recommended.”
 
Also, in 2006, an editorial in the Annals of Internal Medicine addressed the question of homocysteine measurement. “Several observational studies involving healthy populations in the 1990s showed positive associations between elevated homocysteine level and increased risk for ischemic heart disease and stroke.  Several small trials conducted in western populations in the early and mid-1990s suggested that ‘daily supplementation with both 0.5 - 5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 μmol/l to 8-9μmol)’.  In 1998, the U.S. Food and Drug Administration mandated fortification of enriched cereal grain flour products with 140 μg of folic acid per 100 g of flour.  The prevalence of folate deficiency and hyperhomocysteinemia fell sharply.  A population cohort study that assessed the impact of folic acid fortification found a decrease in stroke deaths in the year after fortification.  Several large secondary prevention trials in the Vitamin Intervention for Stroke Prevention trial, found that a moderate reduction of total homocysteine level after nondisabling cerebral infarction had no statisticall significant effect on vascular outcomes during 2 years of follow-up.  The trial was designed with the expectation of lowering homocysteine levels by 5 μmol/L, but a lower than expected average baseline homocysteine level permitted only a 2-μmol decrease in plasma homocysteine.  Two larger, double-blind, placebo-controlled trials with longer follow-up followed: the Heart Outcomes Prevention Evaluation 2 and the Norwegian Vitamin Trial.”
 
The findings of these 2 studies showed no benefit from the addition of folic acid and vitamin B-12.  The unexpected finding of increased rates of cardiovascular events among patients receiving combined vitamin B treatment in the NORVIT Trial suggested that hyperhomocysteinemia might cause cardiovascular  disease, but therapy aimed at lowering homocysteine levels might have independent and deleterious effects that offset potential benefits.  It was suggested that folic acid might adversely affect either atherosclerotic plaque formation or homocysteine metabolism, or the hyperhomocysteinemia may mark increased risk for cardiovascular disease but may not cause it.”
 
“Many physicians already follow the recommendations set out by the American Heart Association in 1999, in which population-wide screening for blood homocysteine is not recommended until (or unless) controlled clinical trials show that modifying homocysteine levels reduces cardiovascular disease risk.  Although several major trials are still ongoing, current best evidence shows that supplements  combining folic acid and vitamin B do not reduce overall cardiovascular disease risk by large amounts in patients with vascular disease and homocysteine levels of about 12 μmol/L to 13 μmol/L.  In 2006, we find that folate deficiency and hyperhomocysteinemia decreased markedly after mandated folic acid fortification of food products, and we have no proven beneficial therapy that targets homocysteine levels that are prevalent in the U.S. population.  Ergo, clinicians need not routinely measure homocysteine levels nor routinely treat mild hyperhomocysteine levels with folic acid or vitamin B supplementation.”
 
 Research has evaluated the clinical utility of homocysteine as a predictor of CAD risk in the general population and as a modifiable risk factor for patients with CAD. Several prospective studies have evaluated the relationship between homocysteine  and cardiovascular disease in asymptomatic patients, but the data derived from these studies are inconclusive. For example, Folsom and colleagues identified all patients who developed coronary heart disease among an initial cohort of 15,792 patients who participated in the Atherosclerosis Risk in Communities (ARIC) trial.  The median follow-up time was 3.3 years. Plasma homocysteine was evaluated from the stored blood samples of the 232 patients plus a random sample of the rest of the cohort. While homocysteine was a significant univariate predictor of CAD, this association was not significant after adjusting for other cardiac risk factors in multivariate analysis. Similarly, Evans and colleagues identified 240 cases of  nonfatal myocardial infarction or coronary death among a cohort of 12,866 men participating in the Multiple Risk Factor Intervention Trial (MRFIT).  Plasma homocysteine from stored blood samples from these patients plus 472 control patients were evaluated. With a follow-up ranging from 11 to 17 years, homocysteine levels did not appear to be an independent risk factor for coronary heart disease. In contrast, in a prospective study using similar methodology as the above studies, Wald and colleagues reported that the initial stored plasma level of homocysteine was significantly higher among 229 men who ultimately died of ischemic heart disease compared to a control group of 1,126 men, drawn from the original study of 21,520 men.  Also, Arnesen and colleagues found homocysteine was a risk factor for coronary heart disease based on their study of 122 patients who developed coronary heart disease from a sample of 21,826 men and women.
 
For patients with known CAD, prospective data are more consistent in supporting the utility of homocysteine as a risk factor for future events. For example, Nygard and colleagues prospectively studied the plasma homocysteine levels in 587 patients with angiographically confirmed coronary artery disease.  After a median follow-up of 4.6 years, the authors compared the initial homocysteine levels of the 64 patients (10.9%) who had died to those of the remaining 523 survivors. The authors reported a strong graded dose-response relation between plasma homocysteine and mortality. Stubbs and colleagues evaluated the relationship between plasma homocysteine levels and cardiac events in 440 patients with acute coronary syndromes admitted to the hospital.  Admission plasma homocysteine levels were not related to short-term outcomes at 28 days; however, in long-term follow-up, patients with homocysteine levels in the 2 highest quintiles had a 2.6-fold increase in the subsequent risk of a cardiac event.
 
Knekt and colleagues reported the outcomes at 13 years’ follow-up of 3,471 middle-aged Finnish males, 884 of whom had known cardiovascular disease at baseline. Using the homocysteine values from stored blood samples, they found no association between serum homocysteine concentration and the incidence of major coronary events (death from coronary heart disease or nonfatal myocardial infarction) among men originally free of heart disease. However, a strong positive correlation was noted between homocysteine concentration and subsequent major coronary events in men with known cardiovascular disease at baseline.
 
A  meta-analysis of 30 observational studies concluded that homocysteine was, in general, a modest independent risk factor for the occurrence of cardiovascular events and strokes. The association between homocysteine levels and CAD was much stronger in retrospective studies involving subjects diagnosed with vascular disease than in prospective studies of healthy individuals.   
 
2009 Update
The Vitamin Intervention for Stroke Prevention trial (VISP) (Toole et al, 2004) enrolled 3,680 patients with a prior history of ischemic stroke and randomized to either a high dose or a low dose of folate, vitamin B6 and vitamin B12. There was no significant difference reported for the primary outcome, risk of recurrent stroke, which was 9.2% in the high-dose group compared with 8.8% in the low-dose group. Similarly, there were no significant differences reported in the rate of cardiac outcomes between groups.
 
Another recently published large randomized, controlled trial was the Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) (Albert et al, 2008).  This trial randomized 5,442 women with a history of cardiovascular disease or at least three cardiovascular disease risk factors to a combination of folate, vitamin B6, and vitamin B12, with a mean follow-up of 7.3 years. The primary outcome was a composite of cardiovascular mortality, myocardial infarction, stroke, and myocardial revascularization. There was no significant reduction in the primary outcome for the treatment group (RR 1.03; 95% CI: 0.90–1.13, p=0.65). There were also no significant reductions in risk for the individual endpoints, including stroke.
 
Viswanathan and colleagues published results of a double-blind randomized controlled trial of Vitamin therapy for stroke prevention.  The study demonstrated, “strong correlation between serum tHcy and plasma Abeta40 concentrations in subjects with ischemic stroke.  Treatment with high dose vitamins does not, however, influence plasma levels of Abeta, despite their effect on lowering tHcy.  Our results suggest that although tHcy is associated with plasma Abeta40, they may be regulated by independent mechanisms”.
 
The American Heart Association does not recommend population-wide screening for homocysteine levels, nor do they recommend routine supplementation with folate and/or B vitamins to reduce homocysteine levels (Malinow et al, 1999).  This statement suggests that measurement of plasma homocysteine may have some role in patients with a personal or family history consistent with premature cardiovascular disease, with the suggestion that those with levels above10.0 micromol/L be advised to increase their intake of folic acid. The outcomes of this treatment strategy have not been addressed in controlled trials.
 
The U.S. Preventive Services Task Force published guidelines for the use of emerging risk factors for coronary heart disease (Hefland, 2009).  According to the results of the systematic review, the scientific evidence does not support the routine use of homocysteine level measurement for further risk stratification of persons with intermediate risk for coronary heart disease.
 
2010 Update
A large (n=12,064) double-blind, randomized controlled trial of patients with a history of myocardial infarction was conducted to assess the effects of reducing homocysteine levels with folic acid and vitamin B12 on vascular and nonvascular outcomes (SEARCH TRIAL, 2010).  The primary outcome measured was first major vascular event defined as major coronary event (coronary death, myocardial infarction, or coronary revascularization), fatal or nonfatal stroke, or noncoronary revascularization.  Patients were randomized to receive 2 mg folic acid plus 1 mg vitamin B12 or placebo.  Follow-up visits were conducted at 2, 4, 8, and 12 months and then every 6 months thereafter for a total follow-up of 6.7years.
 
Patients in the folic acid plus vitamin B12 group had an average decreased blood level of homocysteine of 3.8 µmol/L.  Despite this lowered blood homocysteine level, no beneficial effects were seen on major vascular, stroke or coronary events.
 
2011 Update
The National Academy of Clinical Biochemistry released guidelines for the use of biomarkers for the prevention of cardiovascular disease and stroke (Myers, 2009).   The guidelines included the following recommendations for the measurement of homocysteine levels as a predictor of risk of development of cardiovascular disease:
 
    • Homocysteine concentrations (μmol/L) derived from standardized assays categorize patients as follows:
        • Desirable ≤10
        • Intermediate (low to high) >10 to <15
        • High ≥15 to <30
        • Very high ≥30
       (Classification of recommendation: IIa, Level of evidence C)
 
    • The analytical performance goal for clinical usefulness for measurement of homocysteine level should be <10% for bias, <5% for precision, and <18% for total error. Manufacturers of diagnostic assays for homocysteine should follow approved value transfer protocols to assure that standardized assays are used for vascular risk assessment. (Classification of recommendation: IIa, Level of evidence, C)
 
These recommendations do not prompt a change in the coverage statement.
 
2012 Update
A search of the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement.
 
A 2010 statement issued by the American Heart Association (AHA) states that the organization does not consider high homocysteine levels in the blood to be a major risk factor for cardiovascular disease (AHA, 2010). It further states that a causal link between homocysteine levels and atherosclerosis has not been established.
 
A 2010 guideline from the American College of Cardiology Foundation and the American Heart Association on assessment of cardiovascular risk in asymptomatic adults did not address measurement of homocysteine levels (Greenland, 2010).
 
2013 Update
A search of the MEDLINE database through August 2013 did not reveal any new information that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
In 2013, a Cochrane systematic review on the effectiveness of homocysteine-lowering interventions for preventing cardiovascular events was updated (Marti-Carvajal, 2013). The review included trials that recruited adults with established CVD and had at least 1 year of follow-up and excluded trials with end-stage renal disease patients. Twelve trials with a total of 47,429 participants met eligibility criteria. Nine of the studies included more than 1,000 participants. Nine studies used placebo controls, 2 used usual care controls and 1 compared high and low doses of homocysteine-lowering therapy. In a pooled analysis of 11 trials, there was no statistically significant difference in non-fatal or fatal MI between intervention and control groups [relative risk (RR): 1.02, 95% CI: 0.95 to 1.10]. In a pooled analysis of 9 studies, there was no significant difference between groups in the rate of non-fatal or fatal stroke (RR: 0.91; 95% CI: 0.82 to 1.00). There was also no significant mortality benefit in groups assigned to homocysteine-lowering therapy. For mortality of any cause, the relative risk was 1.01 (95% CI: 0.96 to 1.07) in a meta-analysis of data from 10 trials.
 
In 2012, Huang and colleagues published a meta-analysis  which included RCTs evaluating B vitamin supplementation in patients with pre-existing vascular disease (Huang, 2012).  This review had more lenient inclusion criteria, as there was no limitation on study size or intervention duration. A total of 19 trials with 47,921 patients were included in the meta-analysis. Unlike the other meta-analyses discussed above, in a pooled analysis of study data, the authors found a statistically significant benefit of vitamin B supplementation on stroke (RR: 0.88, 95% CI: 0.82 to 0.95). Similar to the other meta-analyses, vitamin B supplementation was not found to have a statistically significant impact on other outcomes, including CHD, myocardial infarction and all-cause mortality. Given the more relaxed entry criteria, the meta-analysis may have included some lower-quality studies; the authors did not present a formal analysis of trial quality.
     
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Since publication of the Homocysteine Studies Collaboration meta-analysis, a number of studies have reported on the association between homocysteine and various types of CVD. Representative studies are described below:
 
Park and colleagues (2010; population 6371 individuals aged 40-79 without history if MI, stroke, or PAD; 3860 (61%) with homocysteine level available; outcome (s) evaluated 1-year CVD risk based on Framingham score: (low risk [n=2527], intermediate risk [n=3336], high risk [n=508]; major findings included homocysteine levels at the 85 % or above were associated with high Framingham risk score: or 2.1, 95% confidence inerval1.48 to 3.01 and Homocysteine levels at the 85% or above were not significantly associated with intermediate Framingham risk score: or 1.11, 95% CO 0.89 to 1.38.
 
Elevated plasma homocysteine level is associated with ischemic stroke in Chinese hypertensive patients (Wang, 2014); population 5935 individuals with hypertension enrolled in a population-based prospective cohort study; outcome (s) evaluated incident of ischemia stroke and CHD; major findings Homocysteine levels ≥30 μmol/L (vs <15 μmol/L) w ere associated with higher ischemic stroke rates after adjusting for ischemic stroke risk factors: odds ratio 2.86, 95% confidence interval 1.72 to 4.75. and Homocysteine levels ≥30 μmol/L (vs <15 μmol/L) w ere not associated with CHD.
 
Homocysteine, Ischemic Stroke, and Coronary Heart Disease in Hypertensive Patients: A Population-Based, Prospective Cohort Study (Han, 2015). Population 5488 individuals with follow -up available from population-based prospective cohort study of 5935 hypertensive individuals; outcome (s) evaluated incident ishemic stroke; major findings homocysteine levels ≥15 μmol/L were associated with higher ischemic stroke rates: hazard ratio.18 (95% confidence interval 1.65 to 2.89) and among 501 subjects who took folic acid supplementation, plasma homocysteine levels declined an average 6.7 μmol/L (clinical outcomes not reported separately).
 
Association between homocysteine and incidence of ischemic stroke in subjects with essential hypertension: A matched case-control study (Wang, 2015); population 200 cases with hypertension and
ischemic stroke, compared with 400 age-matched controls with hypertension and without ischemic stroke; outcome (s) evaluated incident stroke; major findings after adjusting for ischemic stroke risk factors, total homocysteine was associated with ischemic stroke among w omen but not men: [Women: odds ratio for stroke (comparing highest with lowest total homocysteine quartile) 4.51 (95% confidence interval 1.29 to 15.7)], [Men: OR for stroke 0.83 (95% confidence interval 0.36 to1.90)]
 
Elevated Homocysteine Levels Are Associated with the Metabolic Syndrome and Cardiovascular Events in Hypertensive Patients (Catena, 2015); population 562 consecutive patients with hypertension evaluated at a single center; outcome (s) evaluated prevalence of metabolic syndrome; CHD, Cerebrovascular disease; major findings After adjustment for confounding variables, homocysteine was significantly associated with: [the presence of metabolic syndrome: odds ratio 1.01 (95% confidence interval 1.00 to 1.02, P=0.02)], [the presence of cerebro/cardiovascular disease: odds ratio 1.011 (95% confidence interval 1.00 to 1.02, P=0.01)].
 
 
Plasma homocysteine levels are independently associated with alterations of large artery stiffness in men but not in women (Sheng, 2015). Population 1680 subjects with arterial stiffness measurements enrolled in a community-based corss-sectional study; outcome (s) evaluated vascular function measurements: (CF-PVV; ; heart rate-correlated AI); major findings Homocysteine levels w ere positively correlated with (CAROTID-FEMORAL PULSE WAVE VELOCITY: r=0.211, P<0.0001) (: r=0.148, P<0.0001) Levels w ere negatively correlated with AI: r=- 0.052, P=0.016
 
Elevated Total Homocysteine Levels in Acute Ischemic Stroke Are Associated With Long-Term Mortality (Shi, 2015). Population 3799 adults with ischemic stroke enrolled a single hospital in China; outcome (s) evaluated post-stroke mortality; major findings among 223 patients w ho died during follow up, those with highest 3rd and 4th quartiles of homocysteine had higher risk of stroke death, after adjusting for confounding variables: (3th vs 1st quartile: adjusted hazard ratio 2.27, 95% confidence interval 1.06 to 4.86, P=0.029), (4th vs 1st quartile: adjusted hazard ratio.15, 95% CI 1.01 to 4.63, P=0.049)
 
Overall, the available evidence suggests that homocysteine levels are associated with increased risk of a variety of cardiovascular disorders and outcomes among patients with existing CVD.
 
Since the publication of the systematic reviews and meta-analyses described above, van Dijk and colleagues reported results of the B-PROOF trial, an RCT comparing B-vitamins (500 mg vitamin B12 and 400 mg folic acid) with placebo for improving cardiovascular outcomes among elderly patients with hyperhomocysteinemia (van Dijk, 2015). The study included 2929 subjects over age 65 with an elevated homocysteine level (12-50 μmol/L) who were randomized to 2 years of B-vitamin therapy (n=1458) or placebo (n=1461). A random sample of participants (n=569) underwent baseline vascular measurements. Within the vascular subgroup, the aortic pulse pressure after 2 years of intervention was significantly higher in the B - vitamin treatment group than the placebo group (49.6 vs 47.2 mmHg, P=0.02). However, aortic-femoral pulse-wave velocity and carotid intima-media thickness did not differ significantly between groups. In the vascular subgroup, serum homocysteine increased by 0.6 μmol/L in the placebo group but decreased by 3.6 μmol/L in the B-vitamin therapy group. In the entire study population, the treatment groups did not differ significantly in terms of blood pressure or hypertension incidence, cerebrovascular event incidence, or myocardial infarction incidence. In subgroup analyses, among women, treatment group subjects had lower incidence of cerebrovascular events than placebo group subjects (odds ratio 0.33, 95% confidence interval 0.15 to 0.71).
 
2017 Update
A literature search conducted through January 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2016 meta-analysis of RCTs evaluated homocysteine-lowering therapy with B vitamins for reducing risk of subsequent stroke among high CVD risk individuals who were not taking antiplatelet medications (Park, 2019). The review included 3 trials from 1966 to April 2015 that had at least 1 year of follow-up with stroke as the primary outcome: The Vitamin Intervention for Stroke Prevention (VISP) trial, the VITAmins TO Prevent Stroke (VITATOPS) trial and the Heart Outcomes Prevention Evaluation (HOPE) 2 trial. The meta-analysis included 4643 participants (1773 in VISP, 1463 in VITATOPS, 1407 in HOPE-2) who were not taking antiplatelet agents at baseline. There was no evidence of heterogeneity for the stroke outcome.
Those taking vitamin B supplementation had a lower risk of recurrent stroke (HR=0.71; 95% CI, 0.58 to 0.88) compared to controls (low dose supplementation or placebo). In VITATOPS, participants not on antiplatelet therapy were more likely to be East Asian. In HOPE-2, the effect of supplementation on stroke was highest in those with hyperhomocysteinemia or residing in a country without food fortification. Therefore it is not clear if the effect of homocysteine-lowering therapy on stroke risk in those not on antiplatelets would apply to a U.S. population.
 
Clinical Validity of Homocysteine and Venous Thromboembolism
den Heijer and colleagues published a meta-analysis of observational studies on the relation between homocysteine and risk of venous thrombosis (Den Heijer, 2005). Twenty-four retrospective studies (3289 patients) and 3 prospective studies (476 patients) published before July 2003 were included. A 5 μmol/L higher measured total plasma homocysteine level was associated with a 27% (95% CI, 1% to 59%) higher risk of venous thrombosis in prospective studies and a 60% (95% CI, 10% to 134%) higher risk in retrospective studies. The included studies had varying cutoffs for high homocysteine and a mix of first-time and recurrent venous thromboembolism (VTE). Two earlier systematic reviews reached similar conclusions on the association between homocysteine and risk of VTE (Den Heijer, 1998; Ray, 1998).
 
Several studies examined the risk of VTE in patients who have both homocysteinemia and an inherited thrombophilia (eg, factor V Leiden) with mixed results. Keijzer and colleagues performed a meta-analysis of the interaction between factor V Leiden and hyperhomocysteinemia (Keijer, 2007). In 5 observational studies (825 patients with venous thrombosis, 2109 controls), there was no evidence for additive or multiplicative interaction between factor V Leiden and hyperhomocysteinemia. The relative excess risk due to additive interaction was -1.77 (95% CI, -8.61 to 5.08) and multiplicative interaction term was 0.86 (95% CI, 0.35 to
2.14).
 
Following the systematic reviews, a case cohort study from the large Norwegian Health Study of Nord-Trøndelag (HUNT2) prospectively investigated whether elevated plasma homocysteine levels before the event were associated with subsequent first VTE in a general population (Naess, 2008). VTE was identified in 505 patients and 1458 age- and sex-matched controls were selected for the case cohort study from the original cohort of 66,140 HUNT2 participants. Serum total homocysteine blood was collected between August 1995 and June 1997, a median of 33 months before the events. The odds ratio for VTE for homocysteine levels above versus below the 95th percentile was 1.50 (95% CI, 0.97 to 2.30). Results were similar after control for age, predisposing risk factors, or time to event. The association was limited to men (OR=2.17; 95% CI, 1.20 to 3.91); no association was found in women (OR=1.00; 95% CI, 0.52 to 1.92). There was not a dose-response relationship between VTE and homocysteine.
 
Section Summary: Clinical Validity of Homocysteine and Venous Thromboembolism
A meta-analysis of observational studies found a statistically significant moderate association between homocysteine levels and risk of VTE. However, a subsequent large prospective study found the risk to only be increased in men. The available evidence suggests that homocysteine levels may be associated with increased risk of VTE in the general population.
 
Clinical Utility of Homocysteine and Venous Thromboembolism
Zhou and colleagues published a systematic review of observational studies on the association between B-group vitamins and VTE (Zhou, 2012). Five studies relating to the effects of B-group vitamins supplementation on VTE prevention were included. The studies included 1 uncontrolled interventional study in patients with homocystinuria, 1 observational study of pregnant women, a trial with measured homocysteine levels as the primary outcome, a secondary analysis of the HOPE-2 trial and a secondary prevention trial. Reviewers did not perform a meta-analysis due to varying study designs and different baseline homocysteine levels. The uncontrolled study in patients with homocystinuria and the study in pregnant women both found an association between supplementation and decreased risk of VTE. The trial with homocysteine levels as an outcome showed that supplementation with a multivitamin (folic acid 5 mg, vitamin B12 0.4 mg, vitamin B6 50 mg) reduced homocysteine levels in patients with recurrent VTE and in healthy volunteers. The 2 trials with VTE outcomes are described in more detail in the following section.
 
Randomized Controlled Trials
The Vitamins and Thrombosis (VITRO) RCT evaluated the effect of homocysteine lowering by daily supplementation with B vitamins on the risk reduction of deep vein thrombosis (DVT) and pulmonary embolism (PE) (den Heijer, 2007). Patients between 20 and 80 years old with a first DVT or PE in the absence of major risk factors and a homocysteine concentration above the 75th percentile of a reference group were eligible and called the hyperhomocysteinemic group. A second group of patients with a homocysteine below the 75th percentile of the reference group (called the normohomocysteinemic group) were also enrolled. Patients were randomized to daily multivitamin supplementation of folic acid 5 mg, pyridoxine 50 mg, and cyanocobalamin 0.4 mg, or to a placebo. Follow-up continued for 2.5 years. The primary outcome was objectively diagnosed recurrent DVT or PE. A total of 701 patients were enrolled (360 in the hyperhomocysteinemic group, 341 in the normohomocysteinemic group). Of the 353 assigned to the vitamin group, 43 events were observed (54/1000 person-years). In the 348 assigned to the placebo group, 50 events were observed (64/1000 person-years). The hazard ratio did not differ statistically significantly from 1 (HR=0.84; 95% CI, 0.56 to 1.26). There was not a statistically significant reduction in recurrent VTE in the 360 patients with baseline homocysteine levels above the 75th percentile (HR=1.14; 95% CI, 0.65 to 1.98), or in the 341 patients with normal homocysteine levels (HR=0.58; 95% CI, 0.31 to 1.07).
 
The Heart Outcomes Prevention Evaluation 2 (HOPE-2) was a trial designed to evaluate whether long-term supplementation with folic acid, vitamin B6, and vitamin B12 aimed at homocysteine reduction reduces the rates of major fatal and nonfatal cardiovascular events in patients with established cardiovascular disease and/or diabetes (Ray, 2007). HOPE-2 was conducted at 145 clinical centers in 13 countries and enrolled 5522 patients 55 years of age or older with known cardiovascular disease or diabetes and at least 1 other risk factor for vascular disease. Baseline information on previous VTE was not available. A secondary analysis from the HOPE-2 trial evaluated whether supplementation could reduce risk of symptomatic VTE. VTE occurred in 88 patients during a mean follow-up of 5 years. There was no effect of vitamin supplementation on rates of VTE in the total population (HR=1.01; 95% CI, 0.66 to 1.53) or in the 821 patients with a baseline homocysteine in the highest quartile (>13.8 μmol/L) in the study (HR=1.71; 95% CI, 0.48 to 6.06).
 
Section Summary: Clinical Utility of Homocysteine and Venous Thromboembolism
Two placebo-controlled RCTs have been published that evaluate the impact of folic acid and vitamin B supplementation on risk of VTE. Homocysteine-lowering interventions do not have a statistically significant effect on the rate of VTE in patients with previous VTE or in patients unselected for previous VTE but with cardiovascular disease. Based on these trials, there is insufficient evidence to conclude that supplementation to reduce homocysteine will reduce risk of VTE.
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
Cardiovascular Disease
National Institute for Health and Care Excellence
In 2016, the National Institute for Health and Care Excellence updated the guidance on risk assessment and reduction of cardiovascular disease, including lipid modification (NICE, 2016). The guidance asserts that full formal risk assessments should use a combination of risk assessment tools as well as informed clinical judgment. Homocysteine testing is not mentioned.
 
American Heart Association and American Stroke Association
In 2014, the American Heart Association and the American Stroke Association issued guidelines on the primary prevention of stroke (Meschia, 2014). These guidelines were endorsed by the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, and the Preventive Cardiovascular Nurses Association. The guidelines stated that patients with hyperhomocysteinemia may be treated with B complex vitamins to prevent ischemic stroke, but that the effectiveness is not clearly established (Class IIb; level of evidence B).
 
American College of Cardiology Foundation and American Heart Association
In 2013, the American College of Cardiology Foundation and the American Heart Association issued guidelines on the assessment of arteriosclerotic cardiovascular risk (ASCVD) (Goff, 2014). These guidelines were endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, American Society for Preventive Cardiology, American Society of Hypertension, Association of Black Cardiologists, National Lipid Association, Preventive Cardiovascular Nurses Association, and Women Heart: The National Coalition for Women with Heart Disease. The guidelines developed multivariable equations to estimate age- and race-specific ASCVD risk. The equations included age, total and high-density cholesterol levels, systolic blood pressure, antihypertensive treatment use, diabetes history, and current smoking status. The use of homocysteine screening for assessing risk of ASCVD was not considered in these guidelines.
 
National Academy of Clinical Biochemistry
In 2009, the National Academy of Clinical Biochemistry (NACB) published guidelines entitled biomarkers for primary prevention of cardiovascular disease (Myers, 2009). NACB concluded that while homocysteine is a modest independent cardiovascular disease risk factor, homocysteine screening for primary prevention and assessment in healthy individuals is unwarranted.
 
Thromboembolism
Agency for Healthcare Research and Quality
In 2016, the Agency for Healthcare Research and Quality (AHRQ) issued guidelines for effective quality improvement on preventing hospital-associated venous thromboembolism (VTE) (Maynard, 2016). The VTE prevention protocol recommended involves a VTE risk assessment, a bleeding risk assessment, and a clinical decision support on prophylactic choices. Homocysteine testing was not mentioned in this guideline.
 
National Institute for Health and Care Excellence
In 2015, the National Institute for Health and Care Excellence updated its guidance on VTE in adults admitted to hospital (NICE, 2015). This guidance recommended that all patients should be evaluated for VTE risk on hospital admission. Homocysteine testing was not mentioned in this guidance.
 
2018 Update
 
Annual policy review completed with a literature search using the MEDLINE database through February 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2016 prospective study by Ma et al assessed 30-day outcomes in 805 patients who were admitted to a single center for treatment of acute MI; 348 patients had low homocysteine levels (<15 mmol/L), and 457 patients had homocysteine levels greater than 15 mmol/L (Ma, 2016). The groups were compared for incidence of 5 adverse cardiac events (angina pectoris, reinfarction, heart failure [Killip class II-IV], cardiac rupture, death); of these end points, three were more prevalent in the high homocysteine group than in the low homocysteine group. Heart failure occurred in 44 (9.6%) of the high homocysteine group, but only 8 (2.3%) of the low homocysteine group (p<0.001); cardiac rupture occurred in 16 (3.5%) of the patients with high homocysteine levels, compared with 4 (1.1%) of those with low levels (p=0.03). Differences were also found between the low- and high-Hcy groups for the end points of death (2.3% vs 7.9%; p<0.001) and total adverse outcomes (22.8% vs 11.8%; p<0.001); however, no significant difference was found for either angina pectoris or reinfarction (p=0.45 and p=0.65, respectively). As independent predictors of adverse events following acute MI, age and homocysteine levels were determined to have significant odds ratios (OR; OR=2.114; 95% CI, 1.416 to 3.156; p<0.001; OR=2.055; 95% CI, 1.376 to 3.068; p<0.001, respectively). The authors acknowledged a lack of data on potential “pathogenic mechanisms” in the association between homocysteine levels and adverse cardiac events, recommending that future studies include a larger study sample and longer follow-up.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2019. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
82615Cystine and homocystine, urine, qualitative
83090Homocysteine

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