HOMOCYSTEINE AND RISK OF ISCHEMIC HEART DISEASE AND STROKE: 6,000 EVENTS AMONG 17,000 ADULTS IN 30 OBSERVATIONAL STUDIES

Authors: JACQUES, PAUL - HNRCA; CLARKE, ROBERT - OXFORD U, UK

Submitted to: Journal of the American Medical Association
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/1/2002
Publication Date: 10/1/2002
Citation: JACQUES, P.F., CLARKE, R. HOMOCYSTEINE AND RISK OF ISCHEMIC HEART DISEASE AND STROKE: 6,000 EVENTS AMONG 17,000 ADULTS IN 30 OBSERVATIONAL STUDIES. JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION. 288(16):2015-23,2002.

Interpretive Summary: The hypothesis that elevated blood concentrations of the sulfur-containing amino acid homocysteine was a risk factor for ischemic heart disease (IHD) and stroke was supported by the initial retrospective epidemiological studies that consistently demonstrated that patients with IHD had higher circulating levels of homocysteine than normal controls. More recent prospective epidemiological studies have provided markedly different results, with some showing a higher risk of developing IHD and stroke among persons with elevated homocysteine while other showed no increase risk. The extent to which these discrepant results were due to chance or problems in the design or analysis of these studies is unclear. To address these issues, a collaborative meta-analysis of individual participant data from all the relevant epidemiological studies was established to help provide more reliable estimates of the strength of the association between homocysteine and stroke risk. Information was obtained from 16,786 separate individuals for a meta-analysis involving 5,073 IHD events and 1,113 stroke events from 30 studies. The risks of IHD associated with differences in homocysteine concentrations in prospective studies were only half as strong as in retrospective studies (p<0.0001), and were attenuated with increasing time to event (p<0.001 for trend). After making allowance for mean time to event and differences in known cardiovascular risk factors in prospective studies of healthy people, 25% lower usual homocysteine was associated with 9% lower IHD risk and 20% lower stroke risk. These data provide some support for homocysteine being an independent, albeit modest, predictor of IHD and stroke risk in healthy populations.

Technical Abstract: The Homocysteine Studies Collaboration has brought together and re-analyzed the world-wide epidemiological evidence on the relation of ischemic heart disease (IHD) and stroke risk with blood total homocysteine concentrations. The objective of this study was to assess the importance of elevated homocysteine concentrations for risk of IHD and stroke, after making allowance for differences between studies and for confounding by known cardiovascular risk factors. Information was obtained from 16,786 separate individuals for a meta-analysis involving 5,073 IHD events and 1,113 stroke events from 30 studies. The odds ratios for IHD and stroke associated with 25% lower homocysteine concentration were obtained by conditional logistic regression. The risks of IHD associated with differences in homocysteine concentrations in prospective studies were only half as strong as in retrospective studies (p<0.0001), and were attenuated with increasing time to event (p<0.001 for trend). After making allowance for mean time to event and differences in known cardiovascular risk factors in prospective studies of healthy people, 25% lower usual homocysteine (about 3 [micromole/L) was associated with 9% (95% Cl: 1-16%) lower IHD risk and 20% (95%Cl: 6-33%) lower stroke risk. These data provide some support for homocysteine being an independent, albeit modest, predictor of IHD and stroke risk in healthy populations. The strength of the associations observed in prospective studies was weaker than had been previously suggested. The results of ongoing large-scale trials of vitamin supplementation to lower homocysteine levels may help to demonstrate whether these associations are causal.