Don't Give up on Folic Acid--It Might Work in Primary Prevention

[Guest guest]

A possible explanation for why lowering homocysteine with folic acid has not

shown benefit in reducing ischemic events, when genetic studies appear to

have identified homocysteine as a causal risk factor for heart disease, may

be related to the use of aspirin or other antiplatelet agents, according to

the authors of a new analysis [1].

The analysis was published online in *PLoS One* on February 2, 2011.

The authors explain that homocysteine increases platelet aggregation, but

the vast majority of studies testing folic acid as a possible treatment have

been conducted in patients with heart disease, so most were also taking

aspirin, which could have masked the effect of lowering homocysteine.

The researchers therefore graded the studies into those in which there was

high and not so high usage of aspirin, and they found that in those studies

with the lower use of aspirin, folic acid was indeed associated with a

reduction in ischemic heart disease events. But in the studies with high use

of aspirin, the same reduction in homocysteine with folic acid was not

associated with a reduction in ischemic events.

*Others Skeptical *

But *Dr Jane Armitage*(Oxford University, UK), who led one of the

meta-analyses previously showing no benefit of folic acid on ischemic heart

disease, said " it would be prudent to be skeptical " about these latest

claims. She points out that the authors didn't cite the recent *B-Vitamin

Treatment Trialists’ Collaboration* meta-analysis [2], involving individual

data from 37 500 participants, which demonstrated no overall beneficial

effect of folic acid on risk of heart disease or stroke, with no difference

between patients taking aspirin and those not taking aspirin.

* " Keeping the Door Open " *

Lead author *Dr Wald* (Wolfson Institute of Preventive Medicine,

London, UK) commented to *heartwire *: " Our results indicate that patients

who are already taking aspirin may not benefit from lowering homocysteine

with folic acid, since aspirin blocks platelets, so lowering homocysteine,

which does this too, may give no additional benefit. Trials in which fewer

patients took aspirin showed a protective effect of folic acid compared with

trials in which most patients took aspirin. If the hypothesis is true, folic

acid would have a role in primary prevention, when aspirin is not generally

used, but not in secondary prevention, when it is. The research keeps the

door open for folic acid as a means of preventing ischemic heart disease. "

He added that the current results are supported by the meta-analysis of Wang

et al, which suggested that folic acid prevents stroke [3], since fewer

patients in those studies would have been taking aspirin.

Wald believes that the new analysis strengthens the case for taking

folic-acid supplements. " There is no evidence of harm, and if you are not on

aspirin, it could reduce your risk of developing heart disease and stroke. "

*The Genetic Evidence *

Wald notes that the recent trials showing no benefit of folic acid in

heart-disease patients have led to a wave of opinion that homocysteine does

not have a causal role in heart disease, but this does not tally with the

genetic epidemiological studies. He explained that these have focused on the

methylenetetrahydrofolate reductase (*MTHFR*) gene, coding for an enzyme

involved in the disposal of homocysteine. Studies have shown that

individuals with the TT variant of this gene, who have a dysfunctional MTHFR

enzyme so homocysteine levels build up, have a significantly higher risk of

ischemic heart disease compared with those with CC homozygotes (the variant

associated with lower homocysteine).

He says: " These genetic epidemiological studies provide stronger evidence

for causality than cohort studies, since they are not susceptible to the

sort of confounding that can affect cohort studies. The genetic

epidemiological studies and the trials need to be reconciled; one should not

trump the other. The hypothesis we have presented is a possible explanation

for the paradox. "

He added: " We found a 6% reduction in risk of ischemic events with folic

acid in the studies with only moderate aspirin use compared with those with

high aspirin use. This would equate to a 15% risk reduction if no patients

had been taking aspirin, which would be consistent with the genetic

epidemiological studies. "

In the paper, Wald et al performed updated meta-analyses of both the genetic

studies and the randomized folic-acid trials. For the genetic meta-analysis,

they identified 75 studies comparing the prevalence of TT with CC

homozygotes in 22 068 cases with ischemic heart disease and 23 618 controls

without heart disease. They found that individuals with the TT genotype were

16% more likely to develop ischemic heart disease than those with the CC

genotype.

*Odds Ratio of Ischemic Heart Disease With TT vs CC MTHFR Genotypes*

*Odds ratio *

*95% CI *

*p*

1.16

1.04–1.29

0.006

The researchers also found that the studies with similar homocysteine

concentrations in the TT and CC groups showed no increased risk of ischemic

heart disease, whereas those with higher homocysteine in the TT group tended

to have an increased risk. The odds ratio increased by 1.13 for a 1-µmol/L

increase in serum homocysteine.

They also examined 53 studies (36 167 participants) that reported serum

homocysteine according to *MTHFR* genotype in people without a history of

cardiovascular disease and found that the average serum homocysteine level

was 1.9 µmol/L higher for the TT genotype than for the CC genotype. They

note that this figure was lower than their previous published estimate of

2.7 µmol/L, but that previous estimate was drawn from studies that included

people with cardiovascular disease.

For the second meta-analysis, Wald et al identified 14 randomized trials of

serum homocysteine reduction with B vitamins, including 39 597 participants

recording 3233 ischemic heart disease events, and used the data to test the

hypothesis that aspirin use may influence the protective effect of folic

acid.

Results showed that taking B vitamins was associated with a mean serum

homocysteine reduction of 3.3 µmol/L, but no reduction in ischemic heart

disease. However, on further analysis it was found that folic acid was

associated with a reduction in ischemic events in the five trials with the

lowest prevalence of antiplatelet therapy (60% on average, usually aspirin),

but not in the five studies reporting high aspirin use (91% on average).

*Effect of Folic Acid on Risk of Ischemic Heart Disease Events According to

Aspirin Use*

*Aspirin use *

*Odds ratio for ischemic heart disease events with folic acid *

*95% CI *

*Lower aspirin use *

0.94

0.84–1.05

*Higher aspirin use *

1.09

1.00–1.19

p for the difference between the two estimates=0.037

But in her critique of the new data for *heartwire *, Armitage pointed out

that there has been a debate about the interpretation of the genetic studies

of *MTHFR* and coronary disease risk, with some evidence that these results

may be an artifact of publication bias.

And noting that one of the authors of the report holds a patent on a

polypill containing folic acid, she added: " It is in their interest to keep

the possibility open that homocysteine lowering is worthwhile for reducing

vascular disease, despite now-overwhelming evidence that it does not. "

*Two of the authors of the current paper have an interest in a patent for a

combination pill for the prevention of cardiovascular disease in which folic

acid is an optional component.*

References

www.medscape.com

--

Ortiz, MS, RD

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