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DISCUSSANT: Hall, R., Norwich, UK
The Hope 2 trial involved randomising patients with established cardiovascular disease or diabetes to a combination of Folate, vit B6 and vit B12 or placebo. This design was based on the previous observation that there is a correlation between the homocysteine level and cardiovascular risk and strokes, and that this regime lowers the homocysteine level.
The trialists have already reported in the New England Journal of Medicine earlier this year a negative result over a five year period of follow-up with no change in a composite primary end point of the incidence of death from CV causes, MI and stroke.
During the course of the trial dietary supplementation with folate was introduced for the whole population in some countries and this applied to 70% of the patients in the study. This may have been a confounding factor.
Further subgroup analysis revealed a possible small benefit in reduction of all stroke (but not TIA) and a possible increase in unstable angina without a change in CV mortality. In addition, in a subgroup with low GFR, there was also a possible increase in heart failure. As pointed out by the trialists, these further results need to be treated with extreme caution for various reasons including small numbers, multiple comparisons and possible ambiguity in the definition of the end points studied in this further analysis.
It seems to me that at present the most rational position is to say that in the population studied there was neither a definite positive nor a negative cardiovascular effect from folate, B6 and B12 treatment and, as such, this treatment cannot be recommended as being desirable in such patients based on present knowledge. This lack of benefit may be because a raised homocysteine is an epiphenomenon associated with other risk factors for CVD or with the atheromatous process itself or that the benefit gained from lowering homocysteine levels will be seen only in more tightly defined and possibly higher risk patients with CVD. This can only be resolved by further studies of specific groups but, in view of the present results, such further studies may well also prove negative.