Please note: In 2003, the CTF updated its Grades of Recommendations to include an "I Recommendation" for situations where insufficient evidence exists to allow a recommendation to be made. (Formerly, these situations were captured under a "C Recommendation".) This change is not retroactive, and all "C Recommendations" made prior to 2003 have not been reevaluated in light of the new "I" recommendation grade. For a discussion of these recommendation grades, please link to the 2003 article in the Canadian Medical Association Journal here.
Objective
To evaluate the quality of evidence pertaining
to homocysteine and coronary artery disease (CAD) and make recommendations
regarding screening and treatment of hyperhomocysteinemia.
Burden of Suffering
Cardiovascular disease is the leading cause of
death in Canada, accounting for almost 40% of all deaths. While mortality
rates for ischemic heart disease are declining, the costs to society remain
high. Since a number of cardiovascular deaths may be preventable, the search
for novel risk factors continues. Homocysteine is an intermediate that
is generated in the metabolism of methionine. Therefore, altered homocysteine
metabolism has become the focus of increasing attention based on its potential
role in the pathogenesis of atherosclerosis and other conditions, such
as venous thrombosis and neural tube defects.
The prevalence of hyperhomocysteinemia in the general population is between 5 and 10%, based on a threshold set at the 90th or 95th percentile (approximately 15 mmol/L). However, rates may be as high as 30 to 40% in the elderly. If population-based studies are correct, then up to 10% of coronary events may be attributable to plasma homocysteine. Thus, homocysteine may represent an important and potentially modifiable risk factor for cardiovascular disease.
Options
Screening of serum homocysteine in patients who
have either no symptoms of CAD at baseline (primary prevention) or those
with known CAD (secondary prevention); treatment of patients with high
homocysteine levels to prevent CAD
Outcomes
Cardiovascular death and overall mortality in patients with established
coronary artery disease.
Evidence
MEDLINE was searched from 1966 to June 1999 using
the MeSH headings homocysteine; hyperhomocysteinemia; methionine; coronary
disease; arteriosclerosis; myocardial ischemia; folic acid; vitamin B12;
vitamin B6; and pyridoxine. Relevant articles were also identified
through a manual review of references.
Values
The 10-member Task Force of experts in family medicine, geriatric medicine,
pediatrics, psychiatry and epidemiology used an evidence-based method for
evaluating the effectiveness of preventive health care interventions. Recommendations
were not based on cost-effectiveness of options. Patient preferences were
not discussed.
Background papers providing critical appraisal of the evidence and tentative recommendations prepared by the chapter author were pre-circulated to the members. Evidence for this topic was presented and deliberated upon in a 2-day meeting in May 1998. Consensus was reached on final recommendations.
Benefits, Harms, and Costs
High-pressure liquid chromatography (HPLC), the most common method
used to measure total homocysteine (tHcy), has a coefficient of variation
of 3 to 11%. tHcy levels may be falsely lowered in the acute phase
of illness, such as myocardial infarction, while factors that may elevate
tHcy include genetic predisposition, increasing age, male gender, serum
creatinine, as well as delays in placing samples on ice. Medications
such as anti-epileptic drugs, methotrexate, nitrous oxide, and certain
disease states, such as psoriasis, acute lymphoblastic leukemia, breast
cancer, and hypothyroidism also increase levels, likely through effects
on vitamin status. Homocysteine is inversely correlated with serum
vitamin B6, B12, and folate. Thus, in populations with a higher prevalence
of B12 deficiency (such as the elderly), the specificity of plasma tHcy
as a cardiac risk factor may be reduced.
Current costs range between $30 and $50. However, newer, less costly techniques for measuring tHcy have been developed and should become more readily available.
Recommendations
Recommendation grade [A, B, C, D, E] and level of evidence
[I, II-1, II-2, II-3, III] are indicated after each recommendation. Citations
in support of individual recommendations are identified in the guideline
text.
Sponsors
The Canadian Task Force on Preventive Health
Care developed this guideline with funding from
the Provincial and Territorial Ministries of Health and Health Canada.