Trials of trials - effects of homocystein-lowering regimes on atherothrombotic disease
Johan Hultdin

There are a number if questions to be answered. A scientific dilemma is the fact that homocystinuric patients experience a reduced frequency of events when homocysteine is reduced to around 70-80 µmol/L (1). This is approximately five times the upper reference limit. In the general population the increase in risk is continuous even within the reference interval (3).

One problem with homocysteine is standardization. It is crucial to be able to rely on the transferability of a homocysteine measurement when evaluating increased risk in a population or in an individual. Homocysteine measurements need to be standardized with international calibrators and external quality assurance programs. In the Nordic countries there is an external quality assurance program, which will decrease inter-laboratory variations in the laboratories participating (4).

A meta-analysis standardizing the effects of vitamin effects on standardized homocysteine levels has shown that folic acid reduces homocysteine 25% (5). There are similar effects of folic acid in the doses 0,5-5 mg. For a mean dose of 0,5 mg B12 daily an additional lowering effect of 7% is seen. Vitamin B6 does not seem to have an effect in the mean dose 16,5 mg.

There are a number of ongoing randomized clinical trials trying to establish if homocysteine is a causal risk factor (5). Most studies were planned some five years ago and we will have to wait another five years for the conclusions of all studies. The vitamin regimes differ between the studies (Table 1). The doses of folic acid generally vary from 0,2 to 5 mg, B12 from 0 to 1 mg and B6 from 0 to 50 mg. There are also different combinations of the vitamins in the studies. In one study a multivitamin regime is apparently chosen as placebo.

It is conceivable that a possible causal role of homocysteine in atherothrombotic vascular disease might not be clarified by the ongoing studies. The main reasons are the variations in vitamin dose regimens and difficulties in recruiting the planned number of patients (Table 1).

Another problem is that some countries are fortifying flour with folic acid. In the US fortification started in July 1997 and was mandatory in January 1998. Canada began its mandatory fortification in November 1998. In Victoria, Australia, fortification began in 1996. This fortification might blur the results of some intervention studies. The fortification in itself is a huge, non-randomized trial of the populations as a whole.

In conclusion, intervention trials are needed for the evaluation of homocysteine as a causal risk factor for atherothrombotic disease. The ongoing trials might not be able to give the answer but we are going to gain a lot of knowledge from them. Further intervention trials need to be started with this new information. Fortification of flour with folic acid might blur the results of some studies.

References:

1. Online Mendelian Inheritance of Man. http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?236200 2000-10-07.

2. Hankey GJ and Eikelboom JW. Homocysteine and vascular disease. Lancet 1999; 354:407-413.

3. Nygard O et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337:230-6.

4. Møller J, Rasmussen K, Christensen L. External quality assessment of methylmalonic acid and total homocysteine. Clin Chem 1999;45(9):1536-42.