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Trials That Matter: Should We Routinely Measure Homocysteine Levels and “Treat” Mild Hyperhomocysteinemia?

Irwin H. Rosenberg, MD; and Cynthia D. Mulrow, MD, MSc, Deputy Editor
[+] Article, Author, and Disclosure Information

From U.S. Department of Agriculture Jean Mayer Human Nutrition Research Center on Aging, Boston, MA 02111, and American College of Physicians, Philadelphia, PA 19106.

Potential Financial Conflicts of Interest: Grants received: I.H. Rosenberg (National Institutes of Health).

Corresponding Author: Cynthia D. Mulrow, MD, MSc, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.

Current Author Addresses: Dr. Rosenberg: U.S. Department of Agriculture Jean Mayer Human Nutrition Research Center on Aging, 711 Washington Street, Boston, MA 02111.

Dr. Mulrow: American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.

Ann Intern Med. 2006;145(3):226-227. doi:10.7326/0003-4819-145-3-200608010-00011
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Several observational studies involving healthy populations in the 1990s showed positive associations between elevated homocysteine level and increased risk for ischemic heart disease and stroke (1). Several small trials conducted in western populations in the early and mid-1990s suggested that “daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 µmol/l to 8-9 µmol/l)” (2). In 1998, the U.S. Food and Drug Administration mandated fortification of enriched cereal grain flour products with 140 µg of folic acid per 100 g of flour (3). The prevalence of folate deficiency and hyperhomocysteinemia fell sharply (4). A population cohort study that assessed the impact of folic acid fortification found a decrease in stroke deaths in the year after fortification (5). Several large secondary prevention trials in patients with vascular disease began. One of the first trials, the Vitamin Intervention for Stroke Prevention (VISP) trial, found that a moderate reduction of total homocysteine level after nondisabling cerebral infarction had no statistically significant effect on vascular outcomes during 2 years of follow-up (6). The trial was designed with the expectation of lowering homocysteine levels by 5 µmol/L, but a lower than expected average baseline homocysteine level permitted only a 2-µmol decrease in plasma homocysteine. Two larger, double-blind, placebo-controlled trials with longer follow-up followed: the Heart Outcomes Prevention Evaluation (HOPE) 2 (7) and the Norwegian Vitamin (NORVIT) Trial (8).

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Submit a Comment/Letter
Homocysteine Lowering Vitmains - Don't write them off!
Posted on August 30, 2006
Aziz A. Keshvani
Medical Director, Indoco Remedies Ltd.
Conflict of Interest: None Declared

This is in reply to the editorial by Rosenberg and Mulrow on HOPE 2 & NORVIT Trials. We agree with the authors that the baseline homocysteine levels in the HOPE 2 study populations were low, homocysteine lowering vitamins reduced homocysteine levels by only 15-20% and that more marked homocysteine lowering in patients with higher homocysteine levels might be beneficial. Studies conducted in India have shown that baseline homocysteine levels of the normal population vary from 19.7 to 23.2 micromols/L(1,2). One also sees much greater homocysteine reduction following treatment(3). Hence, benefits of homocysteine reduction are likely to be significant in the Indian population. We feel that the authors conclusion about measuring homocysteine and treating the same may not apply to countries like India.

Moreover, in the HOPE 2 study, baseline homocysteine levels were measured in only 60% of patients and at the end of 5 years, homocysteine levels were measured in only 19%. As the intention of the study was to examine the benefits of homocysteine lowering on the primary events, and when homocysteine levels were not examined in 81% of patients during final evaluation, it is surprising that a conclusion was drawn on the absence of benefits of homocysteine lowering on primary events. Also, no mention of the statistical significance for homocysteine lowering is noticed in this study. In the absence of the same, it is possible that homocysteine lowering was not statistically significant, in which case one cannot expect the reduction in primary events to be statistically significant.

In the NORVIT study, beneficial effects of homocysteine lowering on cardiovascular events after acute myocardial infarction were examined. More number of myocardial infarctions were noticed in the group receiving combination of folic acid, vitamin B12 & pyridoxine as compared to placebo. However, in table 3 of this study, one notices that 447 (47.4%) patients in placebo group underwent a protective coronary intervention (CABG or PCI) as against 395 (42.3%) in the active treatment group (p=0.02). After acute myocardial infarction, these interventions usually done to improve survival and protect against subsequent myocardial infarctions. Hence, rather than more number of myocardial infarctions in the active treatment group, it is likely that there were less number of myocardial infarctions in the placebo group due to significantly higher number of protective coronary interventions undertaken. Blaming the vitamins for the increased incidence of myocardial infarction does not seem justified.


1. Anoop Misra et al , Hyperhomocysteinemia and low intakes of folic acid and vitamin B12 in urban North India, European Journal of Nutrition 2002;41:68-77

2. Helga Refsum et al, Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians, American Journal of Clinical Nutrition 2001;74:233-41

3. Aziz Keshvani & Pradeep Talwalkar, Homocysteine levels in patients with type II diabetes mellitus and vascular complications, Paper presented on 15th March 2005 at RSSDI Mahacon, Mumbai, India.

Conflict of Interest:

None declared

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