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.  

 

 

 

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.   

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.

 

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.

 

 

 

 

 

 

 

 

 

 

     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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.