Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.39000.486701.68 (Published 23 November 2006) Cite this as: BMJ 2006;333:1114All rapid responses
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Dear Sir,
We read with interest the commentary by Wald et al, on folic acid,
homocysteine and cardiovascular disease.[1] The authors describe elegantly
the neutrality of long-term (mean 20; range 6-60 months) randomised
placebo-controlled studies in which more than 15,000 post-infarction,
stroke or vascular disease patients have now taken part. They do not
however mention the trend to worse outcomes with combined B-vitamin
supplementation in both the post-infarct study with 3749 patients,[2] and
the largest post angioplasty study with 636 patients.[3] Mechanistic in
vivo studies shed some light; there is, for example, no change in
biomarkers thought to be associated with increased risk of stroke and
ischaemic heart disease with multiple B-vitamin supplementation.[4]
The authors state that in their view “…the evidence is now sufficient
to justify action on lowering homocysteine concentrations …”, which is
surprising in light of the evidence they present. Including the recently
presented Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS)
which enrolled 5442 middle aged women at high risk for vascular events,[5]
there have now been more patients enrolled in research into the effects of
B-vitamins than were required to gain approval for use of HMGCoA reductase
inhibitors (statins) for coronary heart disease and angiotensin converting
enzyme inhibitors and beta blockers for heart failure, and the
intervention trials are uniformly negative, or suggest harm. Although
there is a clear epidemiological association between homocysteine and
vascular events, the routine, widespread use of folic acid and other B-
vitamins to lower homocysteine levels,[6] is, as yet, entirely without
proven benefit and may be harmful. It would surely be rash to start
widespread treatment in the absence of a single trial to suggest that the
treatment might be associated with benefit.
Sincerely
Klaus K Witte, (Specialist Registrar in Cardiology, Leeds)
Andrew L Clark, (Reader and Consultant in Cardiology, University of
Hull, Hull)
Alyn H Morice (Professor of Medicine, University of Hull, Hull)
John GF Cleland (Professor of Cardiology, University of Hull, Hull)
1.Wald DS, Wald NJ, Morris JK, Law M. Folic acid, homocysteine, and
cardiovascular disease: judging causality in the face of inconclusive
trial evidence. BMJ 2006;333:1114-7
2.Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T,
Wang H, Nordrehaug JE, Arnesen E, Rasmussen K; NORVIT Trial Investigators.
Homocysteine lowering and cardiovascular events after acute myocardial
infarction. N Engl J Med 2006;354:1578-88
3.Lange H, Suryapranata H, De Luca G, Borner C, Dille J, Kallmayer K,
Pasalary MN, Scherer E, Dambrink JH. Folate therapy and in-stent
restenosis after coronary stenting. N Engl J Med 2004;350:2673-81
4.Dusitanond P, Eikelboom JW, Hankey GJ, Thom J, Gilmore G, Loh K, Yi
Q, Klijn CJ, Langton P, van Bockxmeer FM, Baker R, Jamrozik K.
Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine
does not reduce blood markers of inflammation, endothelial dysfunction, or
hypercoagulability in patients with previous transient ischemic attack or
stroke: a randomized substudy of the VITATOPS trial. Stroke 2005;36:144-6
5.Albert C. A randomized trial of folic acid and B-vitamins in the
secondary prevention of cardiovascular events in women: Results from the
Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS). American
Heart Association 2006 Scientific Sessions; November 13, 2006; Chicago,
IL. PS.03.Late-Breaking Clinical Trials I
6.Wald NJ, Law MR. A strategy to reduce cardiovascular disease by
more than 80%. BMJ 2003;326:1419
Competing interests:
None declared
Competing interests: No competing interests
It takes about 9 months of increased folic acid, and thus lowered homocysteine, to prevent neural tube defects or a neonate
cancer, neuroblastoma (1) but folic acid is no cure after the fact.
The seminal analysis be Wald et al(2) draws parallels with in-utero heterozygous 'exposure'
to homocysteine raising genetics and stroke and heart disease, and a homozygosity
(causing homocystinuria) and very early vascular disease. They present
data that, at least in vascular disease, such mutation-related illness
is delayed by homocysteine lowering B vitamins.
In a similar vein, the cumulative effect of protein glycation in diabetes
is obviously time-and-dose related and degrades lysine and arginine residues.
Life-long thiolation (by homocysteine and its lactone) affects these same
residues but also the thiol group of cysteine, the cross-linking amino
acid maintaining folding in virtually all proteins and key functional component
in enzymes.
It may be time to consider serum homocysteine <_6 m="m" a="a" treatment="treatment" target="target" just="just" like="like" glycated="glycated" hemoglobin="hemoglobin" since="since" the="the" protein="protein" damage="damage" is="is" similar="similar" and="and" complementary.="complementary." homocysteines="homocysteines" corrosive="corrosive" process="process" however="however" starts="starts" near="near" conception="conception" arguably="arguably" more="more" destructive="destructive" irreversible.3="irreversible.3" b-vitamins="b-vitamins" reducing="reducing" homocysteine="homocysteine" b-2="b-2" b-6="b-6" b12="b12" folic="folic" acid="acid" are="are" cheap="cheap" effective="effective" universally="universally" considered="considered" non-toxic="non-toxic" in="in" prevention="prevention" settings.4="settings.4" cardiovascular="cardiovascular" disease="disease" exceptionally="exceptionally" rare="rare" at="at" levels="levels" _6="_6" level="level" common="common" infants.="infants." interestingly="interestingly" british="british" women="women" have="have" life-time="life-time" exposure="exposure" to="to" about="about" _11-14="_11-14" below="below" men="men" href="http://www.food.gov.uk/multimedia/pdfs/ndnsfour.pdf"/>NDNS
Vol. 4 2004 Table 4.21], possibly explaining the decade of delay to
first infarct, relative to men.
Short-duration secondary prevention studies have, not surprisingly,
failed to reduce mortality but the significant
stroke reduction in HOPE-2 indicates that some repair is possible
even when elder (ref. 20 in (2) and (5)). Primary prevention, however,
obviously must start early in life. The current analysis (2) proposes action and should help the paradigm shift about homocysteine, its effects and treatment. vos{at}health-heart.org
1. French AE, Grant R, Weitzman S, Ray JG, Vermeulen MJ, Sung
L, et al. Folic acid food fortification is associated with a decline
in neuroblastoma. Clin Pharmacol Ther. 2003 Sep;74(3):288-94. Medline 12966372
2. Wald DS, Wald NJ, Morris JK, Law M. Folic acid, homocysteine,
and cardiovascular disease: judging causality in the face of inconclusive
trial evidence BMJ, Nov 2006; 333: 1114-7. Medline 17124224
3. McCully K. Chemical pathology of homocysteine. I. Atherogenesis.
Ann Clin Lab Sci. 1993 Nov-Dec;23(6):477-93. Medline 8291902
4. Vos, E. Multivitamin supplements are effective and inexpensive
agents to lower homocysteine levels. Arch Intern Med. 2001 Mar 12;161(5):774-5.
Medline 11231722
5. Refsum D, Smith AD. Homocysteine, B Vitamins, and Cardiovascular
Disease. NEJM 2006 V355:205-211 Figure 1 http://content.nejm.org/cgi/content/full/355/2/205/F1
Medline 16848014
Competing interests:
None declared
Competing interests: No competing interests
The article might have been an attempt to substantiate cardiovascular
morbidity links with raised serum homocysteine and contribution of folic
acid in a probable alleviation of this burden. Cardiovascular disease
remains the most burgeoning health risk facing humanity and also the most
researched. Everyday one comes across news in the print and tele media
about something new or something old that may have an impact on one's
heart.
Aren't we already aware of the antioxidant properties of folic acid
that benefit in Ischaemic Heart Disease (IHD), breast/pancreatic/colon
cancers and so on? Don't we all know that IHD is a consequence of long-
term oxidative damage to the myocardial and vascular tissue? These are no
longer claims... These are foregone conclusions since the facts remain
that IHD prevalence is the lowest in vegetarians (who consume the maximum
folate-rich diet) and that long-term antioxidant therapy is known to
reduce cardiovascular morbidity. Folate is essentially required in
cellular division. Cancer cells divide rapidly, and drugs that interfere
with folate metabolism are used to treat cancer. Methotrexate is a drug
often used to treat cancer because it inhibits the production of the
active form, tetrahydrofolate.
Linking raised serum homocysteine levels with cardiovascular disease
is a biochemical exercise in what one can call as a needle in a haystack.
There are myriad proposed causes for IHD, of which homocysteinemia is one
of the easiest ones to combat given the low-cost of folic acid therapy. In
developing nations like India, this remains the verdict underlining any
new research.
Competing interests:
None declared
Competing interests: No competing interests
SIR:
The authors claim that there is "inconclusive evidence". However,
this does not follow from the references and other data they present.
Thus, they present only a couple of dozen references (granted, some
minor meta-analyses included) and then go with talk about "inconclusive
evidence".
What troubles me as a bioinformatician is that if anybody who would
care to search PubMed (not to mention EMBASE), will find that there are
thousands of studies dealing with the MTHF reductase. Thousands(!), not
dozens...
For instance, there are over 600 genetic association studies (NOT
meta-analyses) that attempt to link folates, hyperhomocysteinemia, CHD
etc. There are over 20 meta-analyses related to MTHFR 677 C/T polymorphism
alone (not to mention meta-analyses dealing with other folate-related
factors). Moreover, your humble servant, among others, has conducted a
thorough analysis of this entire array of data [1]. So, how the statement
"inconclusive evidence" is, actually, conclusive and substantiated---
especially given the ACTUAL extent of the available evidence?
[1] Torshin IY. Bioinformatics in post-genomic era: medicine and
physiology. Nova Sci Pub, NY, in press (coming out fall 2007).
Competing interests:
None declared
Competing interests: No competing interests
Sir,
When, in future, Wald et al. turn their attention to marketing their
polypill, they will presumably rely heavily on the results of randomised
trials to support the inclusion of statins, beta-blockers, diuretics, ACE
inhibitors and aspirin. They might, however, reflect on how this will
square with their readiness to dismiss the clinical trials of folic acid
in the prevention of vascular events. [1]
In order to promote the folic acid component of their polypill, the
authors emphasize the data from observational studies which correlate
raised homocysteine levels with an increased risk of vascular disease.
Although a causal link has been disputed, [2] they argue that such a
conclusion is unwarranted. However, even if they were correct, it would
not follow that folic acid reduces vascular events. Thus, contrary to
their assertion, clinical trials were still required. Of seven randomised
trials, none showed any statistically significant difference in favour of
folic acid reducing ischaemic heart disease while only one reported
benefit in reducing stroke. Moreover, meta-analysis showed no efficacy in
either disease. Despite this evidence, Wald et al. maintain the contrary
view that folic acid reduces vascular events. But they do so only by
cherry picking, as well as twisting and distorting the data, to satisfy
their vested interests.
This is not to argue the case for the primacy of randomised trials or
meta-analyses over observational studies - indeed, there are sound reasons
for rejecting both methodologies as providing nothing but entertainment
for statisticians. Rather, it is to draw attention to the poverty of the
data emanating from both randomised trials and observational studies that
allows so much interpretation and manipulation. [3]
References
[1] Wald DS, Morris JK, Law M, Wald NJ. Folic acid, homocyteine, and
cardiovascular disease: judging causality in the face of inconclusive
trial evidence. BMJ 2006;333;1114-7.
[2] Lewis SJ, Ebrahim S, Davey-Smith G. Meta-analysis of the MTHFR C
to T polymorphism and coronary heart disease: does the totality of
evidence support a causal role for homocysteine and the preventive
potential of folate? BMJ 2005;331;1053-6.
[3] Penston J. An enlightening analogy. Rapid response letter. BMJ
22nd November 2006.
Competing interests:
None declared
Competing interests: No competing interests
We should use caution
To the editor
I read with interest the comments by Wald et al (1) in the November
issue of the eBMJ regarding folic acid and cardiovascular prevention.
Although many studies showed that folic acid reduces homocysteine levels
in all populations (2), can improve artery stiffness (3), endothelial
function (4) and even reduce atherosclerosis (5), no randomized placebo
controlled study ever proved that folic acid reduces hard endpoint
occurrence such as cardiovascular events (6,7). Interestingly, this non-
significant effect was observed despite a significant reduction of
homocysteine levels. In view of this data, and despite the association
between homocysteine and cardiovascular risk, I think that regarding
homocysteine a cardiovascular “risk factor”, somewhat premature. The term
“risk factor” (instead of “risk marker” for instance) denotes that
intervention aimed at reducing the levels of homocysteine (i.e. folic
acid) reduces cardiovascular risk, a speculation still to be proven. It is
indeed highly likely that this relationship between homocysteine and
cardiovascular risk is not random. However, the beneficial effects of
folic acid treatments are still to be proven.
I also find the beginning of the section somewhat misleading, since the
Meta-analyses of cohort studies did not show that a 3-µmol/l decrease in
serum homocysteine reduces the incidence of myocardial infarction and
stroke, but rather the opposite. I would prefer interpreting the data as:
increased risk of myocardial infarction by 15% and stroke by 24%, with an
increase of 3 µmol/l increase in serum homocysteine levels.
The authors failed to provide unequivocal evidence to show that reducing
homocysteine levels reduce cardiovascular risk. The authors tend to rely
on genetic and population based surveys that suggest the possibility that
this treatment might work. To my knowledge, no data is available even
among “high-risk” patients that have a better chance of risk reduction
with folic acid, such as individuals with high homocysteine levels and/or
MTHFR gene mutations.
From a clinical standpoint, patients’ compliance is lacking, even with
medications proven repeatedly to have a marked beneficial effect on
cardiovascular disease incidence, such as statins and blood pressure
reducing medications. I think that adding a debatable treatment,
especially one with a moderate effect at best, such as folic acid to the
regime will not help, and might even hinder the patients’ compliance.
Given the once presumed beneficial hormonal replacement therapy
“experience”, I consider recommending folic acid to all cardiovascular
patients premature. It is therefore my opinion that caution should be used
when recommending the addition of a new drug to the preventive drug
regime.
Sincerely
Dr. Eyal Leibovitz
1.Wald DS, et al. Folic acid, homocysteine, and cardiovascular
disease: judging causality in the face of inconclusive trial evidence. BMJ
2006;333:1114-1117
2. Ho GY, et al. Methylenetetrahydrofolate reductase polymorphisms
and homocysteine-lowering effect of vitamin therapy in Singaporean stroke
patients. Stroke. 2006;37:456-60
3. Williams C, et al. Folic acid supplementation for 3 wk reduces
pulse pressure and large artery stiffness independent of MTHFR genotype.
Am J Clin Nutr. 2005;82:26-31.
4. Assanelli D, et al. Folic acid and vitamin E supplementation
effects on homocysteinemia, endothelial function and plasma antioxidant
capacity in young myocardial-infarction patients. Pharmacol Res.
2004;49:79-84
5. Marcucci R, et al. Vitamin supplementation reduces the progression
of atherosclerosis in hyperhomocysteinemic renal-transplant recipients.
Transplantation. 2003;75:1551-5
6. Bonaa KH, et al; NORVIT Trial Investigators. Homocysteine lowering
and cardiovascular events after acute myocardial infarction. N Engl J Med.
2006;354(15):1578-88
7. Lonn E, et al (HOPE) 2 Investigators. Homocysteine lowering with
folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr
13;354
Competing interests:
None declared
Competing interests: No competing interests