Lowering homocysteine levels does not reduce stroke risk

February 03, 2004

Chicago, IL - Although several studies have demonstrated an association between homocysteine levels and stroke, a high-dose vitamin therapy to lower homocysteine failed to reduce the risk of recurrent stroke, according to a study published in the February 4, 2004 issue of the Journal of the American Medical Association[1].

"Moderate reduction of total homocysteine level after ischemic stroke had no effect on vascular outcomes during the two years of follow-up," the authors write.

Moderate reduction of total homocysteine level after ischemic stroke had no effect on vascular outcomes.



Based on previous studies, which have shown that elevated homocysteine levels are associated with an increased stroke risk, the Vitamin Intervention for Stroke Prevention (VISP) study investigated the effect of a high-dose vitamin therapy to lower homocysteine levels on recurrent stroke, CHD, and mortality. Researchers in the US, Canada, and Scotland, led by Dr James Toole (Wake Forrest University School of Medicine, Winston-Salem, NC), recruited 3680 patients who had suffered nondisabling stroke, with homocysteine levels at or above the 25th percentile of the North American stroke population (8.5 mol/L for women and 9.5 mol/L for men). They were randomized to a once-daily regimen of either high-dose or low-dose vitamin therapy:

  • 25 mg of vitamin B6, 0.4 mg of vitamin B12, and 2.5 mg of folic acid (n=1827).

  • 200 g of vitamin B6, 6 g of vitamin B12, and 20 g of folic acid (n=1853).

Although homocysteine level reductions were 2 mol/L greater in patients in the high-dose group than those in the low-dose group, neither vitamin therapy had an effect on outcomes.

Effect of high-dose vs low-dose vitamin therapy on outcomes within two years


High-dose (%)

Low-dose (%)


Ischemic stroke, CHD or death 18.0 18.6 0.65
Ischemic stroke 9.2 8.8 0.68
CHD 7.0 7.4 0.62
Death 5.9 6.9 0.24

Despite this lack of treatment effect, the researchers point out that "there was a persistent and graded association between baseline total homocysteine level and outcomes," with a 3 mol/L homocysteine reduction translating into a 10% lower risk of stroke, a 26% reduction in CHD risk, and a 16% decrease in mortality risk. However, this risk reduction was statistically significant only in the low-dose group. Given this association of baseline levels of homocysteine with risk, longer trials in different populations need to further explore a possible benefit of homocysteine-lowering therapy, Toole et al argue.

Folate fortification possibly reduced effect

They point to several possible explanations for the lack of effect in the VISP trial but rule out noncompliance, due to consistently higher blood levels of vitamins and lower levels of homocysteine in the high-dose vs the low-dose group. "One possible reason our treatment was not effective may have been that patients enrolled in this study had levels of total homocysteine that were too low to show a large effect," the authors write. Other possibilities could be lack of power and/or duration of the study to detect an event rate reduction. "The difference in event rates was smaller than necessary to establish an effect of the high-dose vitamins," coauthor Dr Elizabeth Sides (Wake Forrest University School of Medicine) explained to heartwire . "This could be because there is no effect of our particular treatment in this particular population over a two-year follow-up period or that the effect is so small that a much larger study would be needed to detect it." In addition, her team expected larger differences of 3 mol/L between the two groups. Alternative trial designs might consider a different population, a different treatment, or longer follow-up, said Sides. "It may take longer than two years to show differences, but we do not have data to make that recommendation from our study. The VITATOPS study is still under way," she added.

The authors point out that the initiation of VISP in 1996 coincided with a folate fortification of the grain supply in the US. This, they assume, could account for the modest reductions in total homocysteine. "Fortification probably reduced the number of participants with high total homocysteine who might be most likely to benefit," they state. Another alternative could be that elevated homocysteine merely indicates but does not increase vascular disease risk.

Despite knowledge of benefit, clinicians apparently have not accepted the need to aggressively optimize the medical and behavioral factors that lead to risk reduction.

Dr Daniel Hanley (Johns Hopkins Medical Institutions, Baltimore, MD), in an accompanying editorial[2], says the VISP trial was "carefully conducted" but also suggests a different study design to achieve a favorable effect on outcomes. He recommends either a larger study with more power to assess beneficial trends or a smaller trial including patients with higher homocysteine levels. "Such a trial would address the interpretation that either the amount of the total homocysteine reduction was insufficient or the inclusion of stroke patients with total homocysteine levels too close to 'normal' limited the beneficial effects," Hanley writes. He urges physicians to generally pay more attention to risk reduction and to identify patients at high risk of recurrent stroke. "Despite knowledge of benefit, clinicians apparently have not accepted the need to aggressively optimize the medical and behavioral factors that lead to risk reduction," he says.


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