Homocysteine lowering – future trials
Johan Lökk
johan.lokk@telia.com

A previous editorial (Rondel 2000;5) suggested that on-going trials on homocystein lowering will not be conclusive concerning reduction of vascular events. The remaining question is how a conclusive trial should be designed and performed.

There is a growing body of cross-sectional studies investigating the correlation between homocysteine and further events in patients with established coronary heart disease (1-5). Therefore, I suggest as a working hypothesis that next generation large-size trial is restricted to patients with coronary heart disease, age 70-75 years, sample size 5,000 – 10,000 patients, observation time 4 years. Only centers in countries without folate fortification of cereals should be permitted to participate. For analogous reasons – many elderly citizens on oral high-dose cyanocobalamin, folic acid and vitamin combinations – Sweden should be excluded.

The vitamin combinations should be restricted to oral high-dose cyanocobalamin and oral high-dose folic acid, in this context defined as 1 mg cyanocobalamin daily and 5 mg folic acid daily (cf. 6). The manufacturer of the leading brands (Behepan, Folacin) should be approached for negotiations concerning supply of tablets and placebo to each participating center prior to start of the trial. Many trials have succumbed due to supply failure.

By and large, the best evidence so far for benefits of homocysteine lowering have emerged from studies on patients with established coronary artery disease (1-5). If effects of oral high-dose cyanocobalamin and oral high-dose folic acid cannot be proven, an effect of lower doses and weaker combinations seems unlikely.

I imagine that a design analogous to that of modern documentation of antihypertensive agents and lipid-lowering agents – prospective, placebo-controlled – may prove feasible even for homocysteine-lowering regimens.

In case a beneficial effect of homocysteine lowering in coronary patients by high-dose oral cyanocobalamin and high-dose oral folic acid cannot be documented, the indications for treating manifest deficiency states still remain.

1. Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and in patients with coronary artery disease. N Engl J Med 1997; 337:230-6.
2. Aronow WS, Ahn C. Increased plasma homocysteine is an independent predictor of new coronary events in older persons. Am J Cardiol 2000; 86:346-7.
3. Omland T, Samuelsson A, Hartford M, Herlitz J, Karlsson T, Christensen B. Caidahl K. Serum homocysteine concentration as an indicator of survival in patients with acute coronary syndromes. Arch Intern Med 2000; 160:1834-40.
4. Stubbs PJ, Al-Obaidi MK, Conroy RM, Collinson PO, Graham IM, Noble MTM. Effect of plasma homocysteine concentration on early and late events in patients with acute coronary syndromes. Circulation 2000; 102:605-10.
5. Anderson et al. Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease. Circulation 2000; 102. 1227-1232.
6. Kuzminski AM, DelGiacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin defiency with oral cobalamin. Blood. 1998;92(4):1191-98.

Published January 28, 2001