Folate and cardiovascular disease

[Guest guest]

Hi All,

See the below that indicates disappointment in findings reported recently of

folate

not being related to cardiovascular disease.

Comment

Folate supplementation and cardiovascular disease

Davey and Shah Ebrahim

Lancet. 2005 Nov 12;366(9498):1679-1681

Many observational studies have suggested that folate and homocysteine—the

intermediate phenotype lowered by folate supplementation—are causally related to

coronary heart disease (CHD) and stroke.1 Indeed, the evidence was deemed strong

enough to recommend inclusion of folate in the “polypill”—the combination tablet

championed as a one-stop solution for cardiovascular disease2—and to recommend

folate supplements as part of a healthy lifestyle.3 Thus the recent finding of

no

benefit with folate supplementation in NORVIT—the largest trial to date to test

the

hypothesis that folate supplementation reduces risk of cardiovascular disease—is

a

clear disappointment.4

To aficionados of observational epidemiology, the story has both a familiar

ring,

and a familiar cast. Observational studies suggesting that & #946;-carotene,5

vitamin

E and C supplements,6 and 7 and hormone replacement therapy8 would protect

against

CHD were followed by large intervention trials showing no such protection. In

each

case there was special pleading to try to explain the discrepancy. However,

rather

than such accounts being correct (with the happy result that both the

observational

studies and the trials had the right answers, but to different questions), it is

likely that a general problem of confounding—by lifestyle and socioeconomic

factors,

or by baseline health status, and prescription policies—was responsible.

Observational studies specifically examined the use of folate supplements and

found

them to be protective,1 and were therefore testing precisely the same hypothesis

as

the randomised trials. Studies examining the association between homocysteine

and

CHD, together with the trial evidence of homocysteine-lowering effects of folate

supplementation, increased enthusiasm for widespread use of folate

supplementation.

One approach to such problems in observational epidemiology, which was used in

the

folate-homocysteine case,9 and 10 is Mendelian randomisation. The essentially

random

allocation of alleles of MTHFR (the gene for methylene tetrahydrofolate

reductase)

that are related to circulating homocysteine levels, and the association between

MTHFR genotype and CHD risk, are used to provide an unbiased estimate of the

strength of association between homocysteine and CHD.11 This approach supports

the

observational epidemiology which shows that a 3 mmol/L decrease in homocysteine

(achievable by supplementation with 0·8 mg folic acid daily) produced a 16%

reduction in CHD risk.10 This finding presupposes that the published evidence is

complete, but publication bias, leading to a loss of negative studies, is

possible.12 Furthermore, there is no strong evidence of effect in European,

north

American or Australian studies, with effects seen only in middle-eastern and

Asian

studies.12 A recent meta-analysis of the MTHFR C677T polymorphism and stroke

also

found a stronger effect in Japanese and Asian studies.13 It is not possible in

this

meta-analysis to determine if there really are different effects in different

countries or if publication bias has generated these discrepancies. However,

these

findings certainly cast doubt on the usefulness of folate supplementation to

prevent

CHD in western countries.

At least nine trials randomising over 1000 participants are underway and have

yet to

report.14 The figure shows the findings from five trials4, 15, 16, 17 and 18

that

have reported clinical CHD events to date. The pooled effect is disappointing

with a

relative risk associated with folate supplementation (in some trials combined

with B

vitamins) of 1·05 (95% CI 0·96–1·15). The pooled effects of folate alone and

folate

plus B vitamins were similar. However, the ongoing trials with over 40 000

participants are expected to generate about 6000 events, whereas our analysis

includes 10 540 participants and 1256 events. Moreover, all the current and

awaited

trials are of secondary prevention, and it is possible that folate

supplementation

is effective for primary but not secondary prevention. It is also possible that

folic acid has beneficial effects in Asian, but not western, populations. For

these

reasons, it would be premature to discard the role of folic acid in CHD

prevention.

Equally, recent reports of possible breast and prostate cancer hazards

associated

with folate supplementation or higher circulating folate make the adage that

vitamin

supplements “at least do no harm” less viable.19 and 20 While the findings with

respect to adverse events may well be spurious, further evidence is clearly

required

on this issue.

Figure: Randomised trials of folate and vitamin B supplementation

=====================================

Trial Ref Risk ratio (95%CI)

=====================================

Overall – 1·05 (0·96–1·15)

VISP 15 0·97 (0·84–1·12)

NORVIT 4 1·09 (0·96–1·24)

Liem 16 1·10 (0·70–1·70)

Lange 17 1·53 (1·03–2·28)

Baker 18 0·94 (0·64–1·38)

There are lessons to be learned from this story. Both Mendelian randomisation

approaches and meta-analyses of randomised trial evidence require very large

sample

sizes, and both are prone to publication bias. In observational epidemiology,

publication bias can of course also distort the literature. For & #946;-carotene

and

CHD, a report appeared in 1991 as a conference abstract showing the familiar

apparent “protection” of higher intake against CHD,5 but these results were

never

deemed worthy of full publication (unlike folate1 or vitamin E6), possibly as a

result of the publication of the findings from the first negative large-scale

randomised controlled trial of & #946;-carotene and CHD.

Is it acceptable that so little effort has been made to understand why these

observational studies reached the wrong conclusions? The observational studies

of

vitamin E supplements and CHD produced evidence of apparently robust 40%

reductions

in risk6 that were clearly spurious.21 The same team produced observational data

suggesting a similar reduction in CHD risk in those taking folate supplements.

The

data were robust enough to conclude: “Our results suggest that any widespread

increase in folate intake will have a favourable impact on CHD rates.”1 As

Potter has pointed out, in related areas the findings have been changing and are

sometimes contradictory.22 Surely more effort should be taken to understand why

the

wrong answers were obtained in the past, instead of applying precisely the same

methods to the same datasets to produce a continuing stream of “40% reductions

in

risk” for exposures that either have not been, or cannot be, investigated in

randomised trials.

4 KH Bønaa, NORVIT: randomised trial of homocysteine-lowering with B-vitamins

for

secondary prevention of cardiovascular disease after acute myocardial

infarction,

European Society of Cardiology, Stockholm (Sept 5, 2005)

(http://www.escardio.org/knowledge/onlinelearning/slides/ESC_Congress_2005/Bonaa\

FP1334.htm)

(accessed Oct 20, 2005).

15 JF Toole, MR Malinow and LE Chambless et al., Lowering homocysteine in

patients

with ischemic stroke to prevent recurrent stroke, myocardial infarction, and

death:

the vitamin intervention for stroke prevention (VISP) randomized controlled

trial,

JAMA 294 (2004), pp. 565–575. Abstract-EMBASE | Abstract-Elsevier BIOBASE |

Abstract-MEDLINE | $Order Document | Full Text via CrossRef

16 A Liem, GH Reynierse-Buitenwerf, AH Zwinderman, JW Jukema and DJ van

Veldhuisen,

Secondary prevention with folic acid: effects on clinical outcomes, J Am Coll

Cardiol 41 (2003), pp. 2105–2113. SummaryPlus | Full Text + Links | PDF (136 K)

17 H Lange, H Suryapranata and G de Luca et al., Folate therapy and in-stent

restenosis after coronary stenting, N Engl J Med 350 (2004), pp. 2673–2681.

Abstract-Elsevier BIOBASE | Abstract-EMBASE | Abstract-MEDLINE | $Order

Document |

Full Text via CrossRef

18 F Baker, D Picton and S Blackwood et al., Blinded comparison of folic acid

and

placebo in patients with ischemic heart disease: an outcome trial, Circulation

106

(2002) (suppl II), p. 741S.

Al Pater, PhD; email: old542000@...

__________________________________

FareChase: Search multiple travel sites in one click.

http://farechase.