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Homocysteine hypothesis of CV disease is 'dead': lowering plasma levels may be dangerous.

STOCKHOLM -- Lowering plasma homocysteine with B vitamin therapy does not prevent subsequent MIs and strokes in patients who have had an MI--to the contrary, it may even be harmful, according to the results of the first large randomized treatment trial to examine the issue.

"The homocysteine hypothesis is dead. Homocysteine is not a causal risk factor. It is an innocent bystander," Kaare Harald Bonaa, M.D., told this newspaper at the annual congress of the European Society of Cardiology.

Homocysteine's relationship to cardiovascular disease has been a topic of intense investigation in the past decade.

The homocysteine story would now appear to illustrate the hazards of extrapolating from epidemiologic association to clinical practice in the absence of favorable treatment outcome studies.

On the strength of considerable epidemiologic evidence linking high plasma homocysteine to increased MI and stroke rates, many American and European physicians have in recent years suggested B vitamin therapy to reduce homocysteine levels in their patients at high cardiovascular risk. The rationale was that since such therapy was inexpensive, was thought safe, and could have turned out to have a big payoff in reduced clinical events, it might have been a reasonable strategy to use while awaiting results of randomized treatment outcome studies.

But now the Norwegian Vitamin Trial (NORVIT) has shown that such therapy doesn't prevent cardiovascular events; indeed, it may even increase the risk. And there was also a disturbing trend, albeit not statistically significant, for an increase in cancer, said Dr. Bonaa, professor of cardiology at the University of Tromso (Norway).

Dr. Bonaa was the principal investigator in NORVIT, a randomized, double-blind, multicenter trial in which 3,749 Norwegian patients were followed for 3.5 years following assignment to 0.8 mg/day of folic acid; 40 mg/day of vitamin [B.sub.6]; both; or placebo during their hospitalization for an acute MI.

Participants also received all of the standard drugs given post MI.

Patients in the two folic acid arms of NORVIT experienced a rapid and sustained mean 28% decrease in homocysteine. The rationale for including the vitamin [B.sub.6] arms in the trial came from epidemiologic studies showing that people with low dietary intake of this nutrient also have increased risks of stroke and MI.

The primary end point in NORVIT was a composite of fatal and nonfatal MI and stroke.

It occurred in 18% of the placebo group and in a similar percentage of those who got folic acid or vitamin [B.sub.6] alone. However, the incidence in patients randomized to both folic acid and vitamin [B.sub.6] was 20% higher, a highly significant difference. (See box.)

In a multivariate analysis, combination therapy was associated with statistically significant 20% increased relative risks of three study end points--MI, MI and stroke, and death--compared with the other three study groups, along with a more than 30% increase in cancer, which was not statistically significant.

No patient subgroup benefited from B vitamin therapy.

Those with a high baseline homocysteine--that is, in excess of 13 mcg/L--fared worst, with a 27% increase in cardiovascular events regardless of whether or not they received B vitamins.

Studies are being planned to learn whether folic acid accelerates cancer cell growth.

Discussant Ian M. Graham, M.D., was unwilling to declare the homocysteine hypothesis dead and buried.

Because of NORVIT's complex two-by-two factorial design, the study was underpowered to firmly conclude that B vitamin therapy was without benefit or indeed harmful. But there is certainly no evidence from this or any other source that the relationship between homocysteine and vascular disease is causal, said Dr. Graham, professor of epidemiology and public health at the Royal College of Surgeons, and a cardiologist at Trinity College, Dublin.

He agreed that the NORVIT cancer findings warrant further study. While epidemiologic data suggest a diet rich in folate protects against cancer, there is also evidence from in vitro studies to support the argument that folate promotes cancer cell growth.

NORVIT was sponsored by the Norwegian Research Council, the Norwegian Council on Cardiovascular Research, and other nonprofit institutions, with no industry support.


Denver Bureau
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Author:Jancin, Bruce
Publication:Internal Medicine News
Geographic Code:4EUSW
Date:Oct 1, 2005
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