Validation of Homocyst(e)ine-Lowering Treatment in the Era of Folic Acid Fortification of Cereal Grains
To the Editor:
Bostom et al1 assert that fortification of grain products with folic acid in the United States will negate ongoing clinical trials on US populations. However, by dismissing the general population, he overlooks the fact that it is still beneficial to focus on those with elevated homocyst(e)ine [H(e)] levels. [Plasma or serum H(e), or total homocysteine, refers to the sum of the concentrations of the sulfhydryl amino acid homocysteine and the homocysteinyl moieties of the disulfides homocystine and homocysteine-cysteine, whether free or bound to plasma proteins.] Lowering response of H(e) to folic acid supplementation is related to basal concentrations of H(e).2
Extrapolating from study by Bostom et al1, to indicate that studies such as the Vitamin Intervention for Stroke Prevention (VISP) Study3 would not remain adequately powered to test the H(e) lowering hypothesis, is incorrect because the study population in the article by Bostom et al differed substantially from that of VISP. VISP does not use the “general population,” yet rather those with a previous stroke and who were above a fixed level of H(e) at baseline3 above the 25th percentile. Thus, a shift in the general population values for H(e) would be more likely to reduce the prevalence of eligible subjects (ie, increase the difficulty of recruitment), yet would have a smaller effect on the average level of H(e) at admission, because all individuals were above a fixed threshold at admission.3 This selection would generate a population where it could reasonably be expected to observe a significant decrease in plasma H(e). To date, data in the study are still blinded. However, the unblinded data from the entire cohort are reviewed extensively by the Patient Safety Monitoring Board (PSMB) convened by the National Institutes of Health semi-annually, which interprets the data that may have impact on the safety of the participants, the ethics of the study, and the potential accomplishment of the initial hypothesis. The approval of the PSMB of the continuation of the trial means data to date are adequately powered to assess whether lowering the concentration of plasma H(e) will be able to assess the risk of repeated cerebral or cardiac infarction, which was the underlying hypothesis of the VISP trial.
We wish to thank Dr. George Howard for his critical review of the manuscript.
- ↵Bostom AG, Jacques PF, Liaugaudas G, Rogers G, Rosenberg IH, Selhub J. Total homocysteine lowering treatment among coronary artery disease patients in the era of folic acid–fortified cereal grain flour.Arterioscler Thromb Vasc Biol. 2002; 22: 488–491.
- ↵Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomized trials: Homocysteine Lowering Trialists’ Collaboration.BMJ. 1998; 316: 894–898.
Malinow and Toole do not state our design accurately1 and do not refer to an important confirmatory report which we cited.2 We studied a clinical population,1 ie, patients with established coronary heart disease (CHD), not a “general population.” It is true we did not exclude CHD patients with fasting total homocysteine (tHcy) levels in the lowest quartile distribution, as in VISP.3 However, as we reported quite clearly,1 the VISP recruitment strategy was in fact executed by Title and colleagues2 in their study of tHcy-lowering treatment among Canadian CHD patients similarly exposed to the background effect of cereal grain flour products fortified with folic acid. These investigators2 excluded all patients with a screening tHcy level less than 9 μmol/L, a cutpoint virtually identical to the VISP sex-specific exclusion criteria (Reference 3, ie, <8.5 μmol/L for women, <9.5 μmol/L for men). Despite using this exclusion criterion, which resulted in mean tHcy levels of 12.0 μmol/L at baseline, Title et al2 reported that a high-dose folic acid–based regimen reduced mean tHcy levels by only 1 μmol/L. Accordingly, it is quite reasonable to anticipate that the findings of Title et al2 are directly relevant to VISP. Thus the best available evidence suggests VISP will likely achieve only about 20% to 25% (ie, mean reductions of 1.0 to 1.5 vs 4.0 to 6.0 μmol/L) of its projected mean tHcy-lowering treatment effect. As a consequence, VISP3 would not remain adequately powered to test its specific tHcy-lowering hypothesis identified a priori (ie, a 4.0 to 6.0 μmol/L reduction in mean tHcy levels, with each 1.0 μmol/L reduction associated with a 4% to 5% reduction in the incidence of hard events).
- ↵Bostom AG, Jacques PF, Liaugaudas G, Rogers G, Rosenberg IH, Selhub J. Total homocysteine lowering treatment among coronary artery disease patients in the era of folic acid-fortified cereal grain flour.Arterioscler Thromb Vasc Biol. 2002; 22: 488–491.
- ↵Spence JD, Howard VJ, Chambless LE, Malinow MR, Pettigrew LC, Stampfer M, Toole JF. Vitamin Intervention for Stroke Prevention (VISP) trial: rationale and design.Neuroepidemiology. 2001; 20: 16–25.