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LETTER TO THE EDITOR |
Pathology and Laboratory Medicine Service
Veterans Affairs Boston Healthcare System
West Roxbury, MA 02132
E-mail: Kilmer.mccully{at}med.va.gov
Dear Sir:
In their letter concerning the negative results of the HOST trial of homocysteine reduction by high-dose B vitamins in renal failure patients (1) and the recent meta-analysis by Bazzano et al (2), Soliman and Shalash comment that "all of these negative results are making the evidence for a possible benefit of reducing CVD through reducing homocystein doubtful." They further suggest that possible primary prevention by this approach "needs revision" because blood homocysteine may be a marker of disease rather than a causal risk factor.
In their recent meta-analysis of 8 intervention trials with supplemental folic acid, which involved a total of almost 17 000 subjects, Wang et al (3) concluded that this approach "significantly reduced the risk of stroke by 18%." They further found that a greater beneficial effect was seen in those trials with a treatment duration of >36 mo (29% reduction), a decrease in the concentration of homocysteine of >20% (23% reduction), no fortification or partly fortified grain (24% reduction), and no history of stroke (25% reduction). They also commented that the meta-analysis by Bazzano et al (2) showed a significant reduction in stroke after removal of the VISP trial from the analysis, because the VISP trial was conducted in individuals with a history of stroke. In the VISP trial, exclusion of subjects with renal failure, subjects with malabsorption of vitamin B-12, and subjects with high levels of vitamin B-12 from non-study supplementation yielded significant reductions in stroke, coronary disease, and mortality from B vitamin intervention in 2155 subjects over a 2-y period (4).
In their commentary on "judging causality in the face of inconclusive trial evidence," Wald et al (5) examined evidence from the meta-analysis of cohort studies, the genetic polymorphism studies, and the randomized intervention trials. They concluded that "the summary estimate from the trials is consistent with a short term protective effect [of homocysteine lowering] of 12% on ischemic heart disease events and 22% on stroke, or a larger long term effect."
It is worth pointing out that the larger trials (VISP, HOPE2, VORVIT, and HOST) were conducted in subjects with advanced vascular disease. In these trials the subjects were also given a variety of drugs and other treatments that may have obscured the potential beneficial effects of the B vitamin intervention. Advanced vascular disease is in theory accompanied by depletion of thioretinaco ozonide from cellular membranes (6). Intervention with B vitamins could not be expected effectively to counteract depletion of this substance, which is implicated in oxidative metabolism (7). Future human trials with this substance in subjects with advanced vascular disease would be expected to be more effective than intervention with folic acid, vitamin B-6, and vitamin B-12 because thioretinaco ozonide requires synthesis from homocysteine thiolactone, retinoic acid, cobalamin, and ozone. If future studies confirm this prediction, homocysteine that is bound to plasma proteins, as determined by current assay methods, is correctly considered to be a marker of disease caused by the underlying cellular deficiency of thioretinaco ozonide.
ACKNOWLEDGMENTS
No conflicts of interest were reported.
REFERENCES
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