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(Stroke. 2006;37:282.)
© 2006 American Heart Association, Inc.

Editorials

Homocysteine

Call Off the Funeral

J. David Spence, MD, FRCPC, FAHA

From the Stroke Prevention and Atherosclerosis Research Centre, London, ON, Canada.

Correspondence to Dr David Spence, Stroke Prevention and Atherosclerosis Research Centre, 1400 Western Rd, London, ON, Canada N6G 2V2. E-mail dspence{at}robarts.ca

Key Words: hyperhomocysteinemia

The authors of the much publicized though not yet published Norwegian Vitamin Study (NORVIT)¹ of vitamin therapy in coronary artery disease, are widely quoted as saying that vitamin therapy for lowering plasma total homocysteine (tHcy) was harmful, and that "homocysteine is dead." However, the slides of their presentation¹ do not show the B₁₂ status of the participants, nor do they indicate whether B₁₂ injections were given to participants with low levels of B₁₂. Commentators² have called NORVIT "the largest trial to date to test the hypothesis that folate supplementation reduces risk of cardiovascular disease," but because there were 4 treatment arms in NORVIT, each with 900 participants, the number of patients randomized to folate/B₁₂ or folate/B₁₂/B₆ was essentially the same as that in the Vitamin Intervention for Stroke Prevention (VISP) trial³ (1800). They used a much higher dose of B₆ than other studies and cannot exclude the possibility that their results were driven by that choice. As did VISP, they also used a dose of B₁₂ that, as has recently become apparent, was too low for adequate absorption of B₁₂ in elderly subjects (discussed below).

In this issue of Stroke, a substudy of the Vitamins to Prevent Stroke (VITATOPS) trial⁴ reports that in Singapore, treatment with 2.5 mg folic acid, 0.5 mg vitamin B₁₂, and 25 mg B₆ reduced levels of tHcy by 3.8 µmol/L compared with placebo.⁵ The authors also studied 2 polymorphism of methylene tetrahydrofolate reductase (MTHFR) and found that the MTHFR C677T genotype was an independent determinant of tHcy levels at baseline (P=0.005), but A1298C was not (P=0.08). The reduction of tHcy was similar among patients with the wild-type alleles as in those with the 2 polymorphisms and was similar to that observed in VITATOPS patients in Perth, Australia.⁶ These findings indicate that VITATOPS should have sufficient power to adequately test the hypothesis that lowering of tHcy reduces cardiovascular risk.

The authors suggested that the null effect of the VISP trial,³ in which the separation of tHcy between high-dose and low-dose vitamin groups was only 2 µmol/L, was attributable to folate fortification of grain cereal products in North America. However, there was more to the issue.

Reflection on the result of the intention-to-treat analysis of VISP, in light of evidence that became available after VISP was initiated, suggested that in the era of folate fortification, which coincided with the initiation of VISP, vitamin B₁₂ became the key determinant of response to vitamin therapy. In VISP, we did not use a placebo control; we gave to both arms of the study a multiple vitamin containing the usual recommended daily intake (RDI) of many vitamins, with either a low dose or a high dose of folate, B₆, and B₁₂.⁷ Unfortunately, it appears we gave too high a dose of B₁₂ in the low-dose vitamin arm of the study (6 mcg daily; at least the RDI, or by some lights, 3x the RDI), and too low a dose of B₁₂ (400mcg daily) for elderly patients in the high-dose arm. A dose-response study⁸ published 5 years after the initiation of VISP showed that elderly patients with B₁₂ levels <221 pmol/L require 1000 µg daily for adequate absorption. In part, that high-dose requirement may be related to administration of vitamin tablets at times other than mealtimes, when intrinsic factor is released from gastric mucosa. Then, we inadvertently negated the effect of B₁₂ in our randomized treatment by giving injections of vitamin B₁₂, for safety and ethical reasons, to patients in both arms of the study who had low levels of serum B₁₂. Thus, we ensured that the very patients most likely to respond to B₁₂ were not receiving their randomized therapy. Therefore, in VISP, what we showed was essentially that 25 mg daily of vitamin B₆ was ineffective.

We therefore analyzed⁹ the results of VISP for patients who were capable of showing a response by excluding patients with B₁₂ levels <250 pmol/L (meaning they would have received B₁₂ injections or had reduced capacity to absorb B₁₂, those with B₁₂ levels >637 pmol/L (indicating they were probably taking supplements) and excluding patients with renal failure (because they are less responsive to vitamin therapy¹⁰). In the 2155 patients remaining, there was a significant 21% reduction of stroke/death/coronary events. When we stratified this subgroup at the median serum B₁₂ level at entry (322 pmol/L), it became apparent that the principal determinant of response to vitamin therapy was the ability to absorb adequate levels of B₁₂. The participants who fared the best were those with higher baseline B₁₂ levels who received high-dose vitamins; the ones who fared the worst were those who came into the trial with lower levels of B₁₂ and received low-dose vitamins (P=0.03 for stroke/coronary events; P=0.02 for stroke/death/coronary events). Thus, B₁₂ status was a key determinant of response to vitamin therapy.

The disparate results of 2 trials of vitamin therapy for homocysteine in coronary angioplasty also suggest that B₁₂ is a key component of such treatment. Whereas Schnyder et al, who showed a reduction of restenosis¹¹ and events¹² with vitamin therapy, used 400 mcg daily of B₁₂, Lange et al,¹³ who showed no effect of vitamin therapy, used only 40 mcg daily.

It is increasingly clear that in the elderly (who represent a large proportion of vascular patients), the key nutritional determinant of plasma homocysteine is vitamin B₁₂, and the real problem is malabsorption of B₁₂. Furthermore, it is inappropriate to define adequate levels of serum B₁₂ by the "normal" range (mean±2SD or variants of that definition) because when defined metabolically (by levels of B₁₂ below which methylmalonic acid is elevated), 20% of the elderly are B₁₂ deficient.¹⁴ Thus, the "normal" range includes patients with B₁₂ deficiency. The threshold B₁₂ level below which methylmalonic acid levels begin to rise (thus defining physiologically inadequate B₁₂) is 258 pmol/L; in Framingham, 40.5% of the elderly (versus 17.9% of younger subjects) had levels below that threshold.¹⁵ It has therefore been suggested that instead of measuring serum B₁₂, measurement of holotranscobalamin would be a more sensitive way of defining adequacy of B₁₂.¹⁶ Robertson et al showed that in the era since folate fortification, serum B₁₂ is strongly related to plasma tHcy and to carotid plaque area,¹⁷ and Quinlivan et al¹⁸ also showed that in the setting of folate fortification, B₁₂ becomes a key determinant of tHcy.

In addition to the increasingly apparent importance of B₁₂ in lowering of tHcy, it should be recognized that some patients unresponsive to folate/B₆/B₁₂ may need the addition of betaine,¹⁹ and in renal failure, the addition of thiols,^10,20,21 to achieve adequate reductions of tHcy. It is therefore time to stop calling vitamin intervention for lowering of tHcy "folate therapy"; it should be called "vitamin therapy."

It appears very likely that to achieve adequate reductions of tHcy in elderly patients, we will need higher doses of B₁₂ than have been used in the past. We should also await the results of VITATOPS⁴ and other trials before scheduling the funeral for homocysteine.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

See related article, pages 456–460.

References

1. Bønaa KH. NORVIT: randomised trial of homocysteine-lowering with B vitamins for secondary prevention of cardiovascular disease after acute myocardial infarction. Stockholm. Sept 5, 2005. European Society of Cardiology. http://www.escardio.org/knowledge/onlinelearning/slides/ESC_Congress_2005/BonaaFP1334.htm. Accessed November 24, 2005.
2. Davey Smith G, Ebrahim S. Folate supplementation and cardiovascular disease. Lancet. 2005; 366: 1679–1681.[CrossRef][Medline] [Order article via Infotrieve]
3. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Stampfer M, Wang C-H. Lowering plasma total homocysteine to prevent recurrent stroke, myocardial infarction, and death in ischemic stroke patients: results of the Vitamin Intervention for Stroke Prevention (VISP) Randomized Trial. J Am Med Assoc. 2004; 291: 565–575.[Abstract/Free Full Text]
4. The VITATOPS Trial Study Group. The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischemic attack or stroke. Cerebrovasc Dis. 2004; 13: 120–126.
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Related Article:

Methylenetetrahydrofolate Reductase Polymorphisms and Homocysteine-Lowering Effect of Vitamin Therapy in Singaporean Stroke Patients

Grace Y.-H. Ho, John W. Eikelboom, Graeme J. Hankey, Chen-Ru Wong, Siew-Li Tan, Jesscia B.-C. Chan, and Christopher P.L.-H. Chen
Stroke 2006 37: 456-460. [Abstract] [Full Text] [PDF]

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This Article Extract Full Text (PDF) All Versions of this Article: 37/2/282    most recent 01.STR.0000199621.28234.e2v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Spence, J. D. Search for Related Content PubMed PubMed Citation Articles by Spence, J. D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Coronary Artery Disease Stroke Hazardous Substances DB CYANOCOBALAMIN Related Collections Secondary prevention Risk Factors Related Article