Post on 30-May-2018
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892019 Arbor B Vitamins and Stroke Prevention
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Re Saposnik G et al Homocysteine-lowering therapy and stroke risk severity anddisability additional ndings rom the HOPE 2 trial Stroke 2009 Apr40(4)1365-72
Study 3 B vitamins and carotid arterial function
A recent Australian trial tested the impact o B vitamin
supplements on carotid arteries and combined this
with a meta-analysis o previous similar RCTs
Subjects and method 162 patients with previous
stroke (rom the VITATOPS trial) randomised to receive
either placebo or a B vitamin supplement (olic acid 2
mg vitamin B6 25 mg vitamin B12 500 microg) or a meano 39 yrs Carotid intima-medial thickness (CIMT) and
brachial ow-mediated dilation (FMD) were measured
In addition a meta-analysis was conducted on this
trial combined with a urther 6 previous RCTs on CIMT
NUTRITION RESEARCH REVIEW
Study 1 B vitamins and stroke severity
A new study rom Turkey looked at vitamin B12
and
olate levels in relation to outcome o acute stroke
Subjects and method Longitudinal observational
study o 109 patients with acute stroke (frac34 were
ischaemic frac14 haemorrhagic Baseline vitamin levels
were compared with initial clinical stroke severity
(Glasgow coma scale) and hospital mortality at 7 days
Results The mean initial vitamin levels were each
signifcantly lower in those who subsequently died
within 7 days than in those who survived both or
vitamin B12
(186 vs 278 pmolL p=0001) and olate
(176 vs 211 pmolL p=0003) A similar relationship
was seen between the baseline levels o the two
vitamins and worse initial Glasgow coma scale
Re Bayir A et al Acute-phase vitamin B12 and olic acid levels in patients with ischemic and hemorrhagic stroke is there a relationship with prognosis NeurolRes 2010 Mar32(2)115-118
Study 2 Is there any HOPE for stroke
A new analysis o the HOPE-2 trial ocused on the
stroke outcomes including severity
Subjects and method Multi-national RCT on 5522
patients with known CVD randomised to receive either
placebo or supplements (olic acid 25 mg vitamin
B650 mg vitamin B
121000 microg) designed to lower
homocysteine (Hcy) levels daily or 5 years
Results Compared with placebo the vitamin-
supplemented group had 25 ewer strokes non-atalones in particular Amongst those who had strokes
the severity (as judged by neurological defcit at 24 hrs
or unctional dependence at 7 days) was not improved
by supplementation See Graph
In a nutshellThe association between
elevated Hcy the B vitamins
linked to it and stroke incidence
and severity appears strong
So ar a dozen RCTs (almost
all in patients with signiicant
atherosclerosis) have tried to
prevent stroke by reducing Hcy
through various combinations
o olate B12
and B6 In only one
trial did this clearly succeed
Issue 318 Stroke amp prevention - B vitamins Arbor Clinical Nutrition Updates 2010 (Mar)3181-5 ISSN 1446-5450
Graph 1 Hazard ratio for stroke active vs placebo(Study 2)
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This issue is or the personal use o Premium subscribers only(except where being used within the terms o an institutional subscription)
Previous issues
Premium subscribers may obtain all past issues o the Updates by logging
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08
10
04
0
02
06
HR
12
Anystroke
14
075
Non-fatal
072 091
Fatal Functldepend
095057
gt138 le 138
(micromolL)
with initialHcy
066
892019 Arbor B Vitamins and Stroke Prevention
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COMMENTARY
The connection between homocysteine (Hcy) and
stroke is one aspect of the broader and controversial
`Hcy hypothesisrsquo - that elevated Hcy is an independent
and treatable cause of atherosclerosis including
heart disease It also concerns the vitamins closely
connected to Hcy through their role in methionine
metabolism regeneration and Hcy breakdown - see
Figure opposite Those Hcy-vitaminsrsquo are folate
vitamin B12
and to a lesser extent vitamin B6
and vitamin B2 1-3
We easily found over two dozen studies on Hcy as
a risk factor for stroke of which the large majority
reported a positive association In some recent
examples Hcy levels in stroke cases were a third
higher than in controls in one 4 and double in the other
(odds ratio for elevated Hcy a remarkable 157) 5 A
recent British study found the association strongest in
relation to small vessel strokes 6 whilst one from China
reported that elevated Hcy predicted for brain atrophy
post-stroke (OR=98) 7
Three meta-analyses (curiously each published in
2002) confirmed this association One included 30observational studies involving 1113 stroke events
and concluded that Hcy is an independent though
moderate risk factor for stroke and that in the
prospective studies stroke risk was reduced by 11
for every 25 reduction in Hcy 8 The second meta-
analysis collated 20 sets of prospective data to derive
OR=159 that a future stroke patient would have had
a 5 elevation in their baseline Hcy level 9 In the
third meta-analysis the pooled OR for subjects with
elevated Hcy having an ischaemic stroke (from 14studies involving 1769 stroke cases) was 179 10
Other epidemiological research has focused
specifically on the Hcy-vitamins and stroke Although
not entirely consistent there have been many
reports of stroke being associated with lower folate
levels (eg 7 11-14 ) somewhat fewer reports of lower
vitamin B12
(eg 13 15 16 ) and much fewer of lower
vitamin B6(eg 17 18 ) A single study found lower
vitamin B2
level in stroke patients than controls 19
but another did not 20 New Study 1 showed a link
between two of these nutrients and stroke severity
There is a genetic factor at play in this association as
well due to the extensively documented impact onHcy metabolism of polymorphism in the gene for the
MTHFR enzyme (whose role is shown in the Figure
above) A good many studies have looked at the
risk for stroke associated with the particular MTHFR
genotype (TT) in which Hcy recycling is impaired
(n=768 no other trials on stroke patients) and 20 other
RCTs on FMD (n=1282 only one other trial on stroke
patients)
Results There was no signifcant change in CIMT or
FMD in their own trial The meta-analysis showed a
decrease in CIMT (010 mm 95 CI 001-020 mm)
and increase in FMD (by 14 07-21) mainly seen
in trials o less than 9 weeks duration
Re Potter K et al The eect o long-term homocysteine-lowering on carotid intima-media thickness and fow-mediated vasodilation in stroke patients a randomized controlled trial and meta-analysis BMC Cardiovasc Disord 2008 Sep 20824
A meta-analysis in 2002 of 19 studies reported the ORfor (ischaemic) stroke in the TT genotype to be 123 10
Research since then has confirmed the link 21-24
What is not so clear is how much independent risk
this genetic variation has beyond the Hcy levels and
whether it affects the impact of Hcy lowering vitamin
supplementation with the general consensus being thatsuch effects are modest at best 10 25-27
Given that there clearly is an association three
questions spring to mind Firstly is it causal or merely
an indicator of some other process Secondly if
causal what is the mechanism and is it the Hcy or thevitamins that are the most important element Thirdly
can the damage be corrected by supplementation
In relation to causality the majority of experts have
expressed the view that the weight of evidence
suggests this is true (eg 1 28-31 ) An interesting
perspective on this comes from one of the meta-
analyses we have already cited which calculated odds
ratios from genetic and prospective studies separately
The authors concluded that since each analysis had
similar highly significant outcomes but were unlikely
to share confounders the evidence for causality was
strong 9 Others have not been so sure and havepreferred to await the results of quality RCTs 32-35
When it comes to mechanisms there is no shortage
of evidence that elevated Hcy could predispose
to stroke through contribution to inflammation
SAM
(S-Adenosyl-
methionine)
Homocysteine
Methionine
Excreted or converted
to other aa
Methionine
cycle
VitB2
NADPH
NADP+
Methioninesynthase
VitB6
VitB12
cycleFolate
MTHFR
Nucleotide
synthesis(DNA RBC etc)
Methyl
donation(nerves
DNA etc)
Cysteine
THF
5-methyl
THF
Super simplified Hcy biochemistry lesson
Methyl donation and nucleotide synthesis are both vitalfunctions served by the conversion of methionine to andregeneration from Hcy involving the folate cycle Vitamindeficiency can lead to Hcy accumulation
892019 Arbor B Vitamins and Stroke Prevention
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Some potential limitations of these trial data have been
raised One is that these supplements in the doses
used would be ineffective or the effect too weak to be
detected with the sample sizes tested in people with
the kind of advanced atherosclerotic disease that was
true of the subjects in all these trials except one 77
Let alone in patients who recently had a stroke which
was the basis of the VISP trial (included in all three
meta-analyses) - that is secondary prevention hardlycomparable with the other RCTs Moreover VISP
compared high dose Hcy-vitamins not with placebo
but with low dose And control subjects in WAFACS
were allowed to take multivitamin supplements up to
RDA level 61
atherosclerosis thrombogenesis hypertension and
impaired cerebro-arterial function a good deal of
which is contributed to by oxidative stress 29 30 36-39
For example a solid body of work shows the
relationship between Hcy and carotid intima-media
thickness (CIMT) 40-42 a measure of atherosclerosis
generally but also specifically related to stroke
risk 43-45 Whilst not all observational data has founda strong connection 46 47 a number of RCTs have
demonstrated improved CIMT after elevated Hcy was
lowered through vitamin supplements 48-53 though not
all have done so 54 New Study 3 did not demonstrate
this but when its data was added to other trial results
in meta-analysis this conclusion was supported
Another interesting light on mechanism comes from a
new Canadian study which showed that excess Hcy
can inhibit the expected migration of progenitor cells
from bone marrow to repair vascular endothelium
damaged in stroke patients
55
Mechanisms involving the Hcy-vitamins which do
not involve Hcy are less clear although some animal
evidence suggests folate may have some such
role 56 57 including in endothelial function 58 and
perhaps riboflavin in traumatic brain injury 59
This brings us to the third and most important
question can any damage caused by excess Hcy
be corrected by supplementation New Study 2 is a
fresh analysis of the HOPE-2 trial showing that the
25 protection against stroke incidence had a non-
significant trend to being for non-fatal strokes andparticularly in those subjects with higher baseline Hcy
HOPE-2 is best seen in the context of other RCTs that
have looked at this question Eleven have published
their results so far 60-71 Various combinations and
permutations of these eleven form the basis of no less
than three separate meta-analyses 72-74 That these
meta-analyses did not reach complete consensus is
perhaps not surprising bearing in mind that they did
not include all the same data - see Graph 2
Looking at that Graph it is hard to find strong support
for the idea that giving vitamins to reduce Hcy
prevents stroke Although 711 RCTs showed a risk
reduction in only one was this clearly significant That
was the HOPE-2 trial the largest on patients with past
history of diabetes or vascular disease 63 On the other
hand results from the even more recently completed
SEARCH trial of 12064 heart attack survivors 75 (as yet
unpublished) failed to show any stroke prevention 76
Some might take comfort from the sub-grouping
data in the Wang meta-analysis 74 which showed a
protective effect in patients without a stroke history
(ie primary prevention which was true of all trials barone) in those whose treatment lasted more than 3 yearsand which successfully reduced their Hcy levels
On the other hand Wangrsquos analysis was too early to
include the 2 RCT results published in 2008 (n=8532)
both lasting over 3 years but with negative results 60 61
20
07500 15
Bazzano 73
Cochrane 72
Wang 74
10 125050025
089
086
075
WENBIT60
088
WAFACS 61114
NORVIT 62
085
HOPE-2 63076
ASFAST 64045
Haemo-
dialysis 65
055
VISP 66 67104
GOES
68065
FOLARDA 69
End stage
renal 70
117
LINXIAN 71063
Overall
Durationgt 3612
Hcy reducgt 20
No strokehistory
306
3090
5442
3749
5522
315
88
3680
593
283
510
3318
077
082
071
RCTs
Meta-analyses
18086
13806
16841
9748
9018
12165
N =
N =
meta-analyses trial
incl in x1 x3x2
Graph 2 RR for stroke RCTs o Hcy lowering
vitamin supplements vs control
892019 Arbor B Vitamins and Stroke Prevention
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Reerences1 Saacutenchez-Moreno C et al Stroke roles o B vitamins homocysteine and antioxidants Nutr Res Rev 2009 Jun22(1)49-67 2 McNulty H et al Homocysteine B-vitamins and CVD Proc Nutr Soc 2008May67(2)232-73 McNulty H et al Ribolavin lowers homocysteine in individuals homozygous or the MTHFR 677C-gtT polymorphism Circulation 2006 Jan 3113(1)74-80 4 Narang AP et al Homocysteine--risk actor or ischemic stroke Indian JPh ysiol Pharmacol 2009 Jan-Mar53(1)34-85 Dhamija RK et al Homocysteine and lipoprotein (a) correlation in ischemic stroke patients J Neurol Sci 2009 Jun 15281(1-2)64-8
6 Khan U et al Homocysteine and its relationship to stroke subtypes in a UK black population the south London ethnicity and stroke study Stroke 2008Nov39(11)2943-97 Yang LK et al Correlations between olate B12 homocysteine levels and radiological markers o neuropathology in elderly post-stroke patients J Am CollNutr 2007 Jun26(3)272-88 Homocysteine Studies Collaboration Homocysteine and risk o ischemic heartdi sease and stroke a meta-analysis JAMA 2002 Oct 23-30288(16)2015- 229 Wald DS et al Homocysteine and cardiovascular disease evidence oncausality rom a meta-analysis BMJ 2002 Nov 23325(7374)120210 Kelly PJ et al Homocysteine MTHFR 677C--gtT polymorphism and risk o ischemic stroke results o a meta-analysis Neurology 2002 Aug 2759(4)529-3611 Weng LC et al Is ischemic stroke risk related to olate status or other nutr ients correlated with olate intake Stroke 2008 Dec39(12)3152-812 Larsson SC et al Folate vitamin B6 vitamin B12 and methionine intakes and risk o stroke subtypes in male smokers Am J Epidemiol 2008 Apr 15167(8)954-61
13 Weikert C et al B vitamin plasma levels and the risk o ischemic stroke andtransient ischemic attack in a German cohort Stroke 2007 Nov38(11)2912-814 Van Guelpen B et al Folate vitamin B12 and risk o ischemic and hemorrhagic stroke a prospective nested case-reerent study o plasmaconcentrations and dietary intake Stroke 2005 Jul36(7)1426-3115 Pieters B et al Periventricular white matter lucencies relate to low vitaminB12 levels in patients with small vessel stroke Stroke 2009 May40(5)1623-616 He K et al Folate vitamin B6 and B12 intakes in relation to risk o stroke among men Stroke 2004 Jan35(1)169-7417 Kelly PJ et al Inlammation homocysteine and vitamin B6 status ater ischemic stroke Stroke 2004 Jan35(1)12-518 Robinson K et al Low circulating olate and vitamin B6 concentrations risk actors or stroke peripheral vascular disease and coronary artery diseaseEur opean COMAC Group Circulation 1998 Feb 1097(5)437-4319 Gariballa S et al Ribolavin status in acute ischaemic stroke Eur J Clin Nutr 2007 Oct61(10)1237-40 20 Ross RK et al Prospective evaluation o dietary and other predictors o atal
stro ke in Shanghai China Circulation 1997 Jul 196(1)50-5 21 Biswas A et al Homocystine levels polymorphisms and the risk o ischemic stroke in young Asian Indians J Stroke Cerebrovasc Dis 2009 Mar- Apr18(2)103-10 22 Saacutenchez-Mariacuten B et al [Prevalence o methylenetetrahydroolate reductaseC677T mutation among patients with acute ischemic cerebrovascular disease in Ara gon] An Med Interna 2006 Apr23(4)153-5 23 Panigrahi I et al Role o MTHFR C677T polymorphism in ischemic strokeNeu rol India 2006 Mar54(1)48-50 24 Cantu C et al Hyperhomocysteinemia low olate and vitamin B12concentrations and methylene tetrahydroolate reductase mutation in cerebralvenous thrombosis Stroke 2004 Aug35(8)1790-4 25 Lim PS et al Polymorphism in methylenetetrahydroolate reductase gene its impact on plasma homocysteine levels and carotid atherosclerosis in ESRD patients receiving hemodialysis Nephron 2001 Mar87(3)249-56 26 Demuth K et al Opposite eects o plasma homocysteine and the methylenetetrahydroolate reductase C677T mutation on carotid artery geometry in a symptomatic adults Arterioscler Thromb Vasc Biol 1998 Dec18(12)1838-43 27 Ho GY et al Methylenetetrahydroolate reductase polymorphisms and homocysteine-lowering eect o vitamin therapy in Singaporean stroke patientsStroke 2006 Feb37(2)456-60 28 Terwecoren A et al Ischemic stroke and hyperhomocysteinemia truth or myt h Acta Neurol Belg 2009 Sep109(3)181-8 29 Pezzini A et al Homocysteine and cerebral ischemia pathogenic andther apeutical implications Curr Med Chem 200714(3)249-6330 Hankey GJ et al Clinical useulness o plasma homocysteine in vascular dise ase Med J Aust 2004 Sep 20181(6)314-831 Stanger O et al DACH-LIGA homocystein (german austrian and swiss homocysteine society) consensus paper on the rational clinical use o homocysteine olic acid and B-vitamins in cardiovascular and thromboticdiseases guidelines and recommendations Clin Chem Lab Med 2003Nov 41(11)1392-40332 Herrmann W et al Hyperhomocysteinaemia a critical review o old and new
aspects Curr Drug Metab 2007 Jan8(1)17-3133 Ntaios GC et al Vitamins and stroke the homocysteine hypothesis still indou bt Neurologist 2008 Jan14(1)2-434 Lonn E Homocysteine in the prevention o ischemic heart disease stroke andvenous thromboembolism therapeutic target or just another distraction Curr Opin Hematol 2007 Sep14(5)481-735 Wierzbicki AS Homocysteine and cardiovascular disease a review o theevidence Diab Vasc Dis Res 2007 Jun4(2)143-50
Other potential limitations of the existing trial data
include any masking effect of concurrent treatment
(eg statins) or the Hcy metabolic situation beingdifferent in the RCTs on renal failure patients 77-79 Another possible issue is the baseline status of the
Hcy-vitamins and ability to absorb them For example
people living in areas with folate-fortified flour (higher
baseline status) or with B12
malabsorption may show
less protective effect from those supplements
74 79 80
What all of this might mean is that we have not as yet
narrowed down the population group in whom Hcy
lowering prevents stroke For example we lack trials
on patients with high Hcy who have not yet displayed
clinical atherosclerosis Others have argued (both
for stroke and heart disease) that the benefits of Hcy
lowering may take years to be seen and that we do
not have enough of that kind of long term data Or
that the effect of genetic polymorphism has not been
adequately taken into account or that benefit may
be confined to even higher risk patients (such as
atherosclerotic smokers) 81 82
In short given all these consideration and at least
one substantial trial having positive results there are
certainly those who do not believe we should rule
these treatments out just yet (eg 78-82 )
At the same time it would be fair to say that the
majority view is that despite the very strong
epidemiological data such a frankly disappointing
set of trial results means that current evidence simply
does not justify using these vitamins for stroke
prevention certainly not in a routine way (eg1 33 83 )
Whilst considering these different viewpoints
and maybe even whether it might be worth giving
supplements to prevent stroke on a lsquono harm in tryingrsquo
basis we should also think about their safety On the
whole the supplement regimes used in these trials havebeen considered safe (and cheap) interventions 28
There were two exceptions NORVIT reported a
rise of borderline statistical significance in non-
fatal myocardial infarction (but not in stroke) in the
vitamin group (OR=130 95 CI 100ndash168) 62
HOPE-2 found that more of the vitamin subjects werehospitalised for unstable angina (RR=124 95 CI
104-149) compared with placebo 63 In the absence
of confirmation of such increased risk from other
trials it is hard to know what significance to place
on this (There is also the question of whether folate
might sometimes promote cancer growth - a complex
subject that will be the topic of a later issue)
Two further large RCTs involving Hcy-vitamins and
stroke prevention are due to report in the next several
years the SUFOLOM3 study on some 2500 patients
who had CHD or stroke within the previous year 83 and
VITATOPS with a target of 8000 patients who had
recent transient ischaemic attack 84 The FAVORIT and
HOST trials may a lso offer some less direct information 77
This is definitely a `watch this spacersquo topic
892019 Arbor B Vitamins and Stroke Prevention
httpslidepdfcomreaderfullarbor-b-vitamins-and-stroke-prevention 55
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36 Osanai T et al Novel pro-atherogenic molecule coupling actor 6 iselevated in patients with stroke a possible linkage to homocysteine Ann Med 201042(1)79-8637 Kumar M et al Homocysteine decreases blood low to the brain due tovascular resistance in carotid artery Neurochem Int 2008 Dec53(6-8)214-938 Stanger O et al Clinical use and rational management o homocysteine olic acid and B vitamins in cardiovascular and thrombotic diseases Z Kardiol 2004 Jun 93(6)439-5339 Guilland JC et al [Hyperhomocysteinemia an independent risk actor or a simple marker o vascular disease 1 Basic data] Pathol Biol (Paris) 2003
Mar51(2)101-10 40 Baptista AP et al Inlammation homocysteine and carotid intima-mediathickness Rev Port Cardiol 2008 Jan27(1)39-48 41 Sabaliauskene Z et al [Hyperhomocysteinemia in patients with atherosclerotic extracranial disease o the carotid artery] Klin Lab Diagn 2006 Jun (6)20-2 35 42 Wang H et al Serum level o homocysteine is correlated to carotid artery athe rosclerosis in Chinese with ischemic stroke Neurol Res 2006 Jan28(1)25-30 43 Silvestrini M et al Carotid wall thickness and stroke risk in patients with asymptomatic internal carotid stenosis Atherosclerosis 2010 Jan 4 Epub 44 Cobble M et al Carotid intima-media thickness knowledge and applicationto everyday practice Postgrad Med 2010 Jan122(1)10-8 45 Sahoo R et al Common carotid intima-media thickness in acute ischemic stro ke A case control study Neurol India 2009 Sep-Oct57(5)627-30 46 Ntaios G et al Homocysteine and carotid intima-media thickness in ischemic stro ke patients are not correlated Neuropsychiatr Dis Treat 2008 Apr4( 2)477-9 47 Held C et al Correlations between plasma homocysteine and olate
concentrations and carotid atherosclerosis in high-risk individuals baseline datarom the Homocysteine and Atherosclerosis Reduction Trial (HART) Vasc Med 2008 Nov13(4)245-53 48 Nanayakkara PW et al Eect o a treatment strategy consisting o pravastatinvitamin E and homocysteine lowering on carotid intima-media thicknessendothelial unction and renal unction in patients with mild to moderatechronic kidney disease results rom the Anti-Oxidant Therapy in Chronic RenalInsuiciency (ATIC) Study Arch Intern Med 2007 Jun 25167(12)1262-70 49 Fernaacutendez-Miranda C et al Eect o olic acid treatment on carotid intima- media thickness o patients with coronary disease Int J Cardiol 2007 Jun12118(3)345-950 Hodis HN et al High-dose B vitamin supplementation and progressiono subclinical atherosclerosis a randomized controlled trial Stroke 2009Mar 40(3)730-651 Vianna AC et al Uremic hyperhomocysteinemia a randomized trial o olate treatment or the prevention o cardiovascular events Hemodial Int 2007 Apr 11(2)210-6
52 Tungkasereerak P et al Eect o short-term olate and vitamin B supplementation on blood homocysteine level and carotid artery wall thickness inchronic hemodialysis patients J Med Assoc Thai 2006 Aug89(8)1187-9353 Till U et al Decrease o carotid intima-media thickness in patients at risk tocerebral ischemia ater supplementation with olic acid Vitamins B6 and B12 Atherosclerosis 2005 Jul181(1)131-554 van Dijk RA et al Long-term homocysteine-lowering treatment with olic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiness a 2-year randomized placebo-controlled trial Arterioscler Thromb VascBiol 2001 Dec21(12)2072-955 Alam MM et al Homocysteine reduces endothelial progenitor cells in stroke patients through apoptosis J Cereb Blood Flow Metab 2009 Jan29(1)157-6556 Hwang IK et al Folic acid deiciency increases delayed neuronal death DNAdamage platelet endothelial cell adhesion molecule-1 immunoreactivity and gliosis in the hippocampus ater transient cerebral ischemia J Neurosci Res 2008 Jul86(9)2003-1557 Huang GW et al [Eects o olic acid vitamin B(6) and vitamin B(12) on learning and memory unction in cerebral ischemia rats] Zhonghua Yu Fang Yi Xue Za Zhi 2007 May41(3)212-458 Doshi SN et al Folic acid improves endothelial unction in coronary artery disease via mechanisms largely independent o homocysteine loweringCirculation 2002 Jan 1105(1)22-659 Hoane MR et al Administration o ribolavin improves behavioral outcome and reduces edema ormation and glial ibrillary acidic protein expression ater trau matic brain injury J Neurotrauma 2005 Oct22(10)1112-2260 Ebbing M et al Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins ater coronary angiography a randomizedcontrolled trial JAMA 2008 Aug 20300(7)795-804
61 Albert CM et al Eect o olic acid and B vitamins on risk o cardiovascular events and total mortality among women at high risk or cardiovascular disease a randomized trial JAMA 2008 May 7299(17)2027-3662 Boslashnaa KH et al Homocysteine lowering and cardiovascular events ater acute myocardial inarction N Engl J Med 2006 Apr 13354(15)1578-8863 Lonn E et al Homocysteine lowering with olic acid and B vitamins invascular disease N Engl J Med 2006 Apr 13354(15)1567-7764 Zoungas S et al Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renalailure a multicenter randomized controlled trial J Am Coll Cardiol 2006 Mar
2147(6)1108-1665 Righetti M et al Homocysteine-lowering vitamin B treatment decreasescardiovascular events in hemodialysis patients Blood Puri 200624(4)379-8666 Spence JD et al Vitamin Intervention For Stroke Prevention trial an eicacy ana lysis Stroke 2005 Nov36(11)2404-967 Toole JF et al Lowering homocysteine in patients with ischemic stroketo prevent recurrent stroke myocardial inarction and death the VitaminIntervention or Stroke Prevention (VISP) randomized controlled trial JAMA 2004Feb 4291(5)565-7568 Liem A et al Secondary prevention with olic acid results o the Goesextension study Heart 2005 Sep91(9)1213-469 Liem AH et al Eicacy o olic acid when added to statin therapy in patientswith hypercholesterolemia ollowing acute myocardial inarction a randomised pilot trial Int J Cardiol 2004 Feb93(2-3)175-970 Wrone EM et al Randomized trial o olic acid or prevention o cardiovascular events in end-stage renal disease J Am Soc Nephrol 2004Feb 15(2)420-6
71 Mark SD et al Lowered risks o hypertension and cerebrovascular disease ater vitaminmineral supplementation the Linxian Nutrition Intervention Trial Am J Epidemiol 1996 Apr 1143(7)658-6472 Martiacute-Carvajal AJ et al Homocysteine lowering interventions or preventingcardiovascular events Cochrane Database Syst Rev 2009 Oct 7(4)CD00661273 Bazzano LA et al Eect o olic acid supplementation on risk o cardiovascular diseases a meta-analysis o randomized controlled trials JAMA 2006 Dec 13296(22)2720-674 Wang X et al Eicacy o olic acid supplementation in stroke prevention a met a-analysis Lancet 2007 Jun 2369(9576)1876-8275 SEARCH Study Collaborative Group et al Study o the eectiveness o additional reductions in cholesterol and homocysteine (SEARCH) characteristicso a randomized trial among 12064 myocardial inarction survivors Am Heart J 2007 Nov154(5)815-23 82376 Amritage J et al SEARCH Study Collaborative Group SEARCH (Study o the Eectiveness o Additional Reductions in Cholesterol and Homocysteine) randomized comparison o olic acid 2 mg plus vitamin b12 1 mg daily versus
placebo or 7 years in 12064 myocardial inarction survivors Circulation 2008Nov 118(22)2309-231777 Marcus J et al Homocysteine lowering and cardiovascular disease risk lost in translation Can J Cardiol 2007 Jul23(9)707-1078 Pietrzik K Opinion on the COCHRANE Review lsquorsquoHomocysteine-lowering interventions or preventing cardiovascular events European Nutraceutical As sociation website at httpwwwenaonlineorg79 Spence JD Perspective on the eicacy analysis o the Vitamin Intervention or Stro ke Prevention trial Clin Chem Lab Med 200745(12)1582-580 Ueland PM et al Homocysteine and olate status in an era o olic acidortiication balancing beneits risks and B-vitamins Clin Chem 2008May54(5)779-8181 Wald DS et al Folic acid homocysteine and cardiovascular disease judging causality in the ace o inconclusive trial evidence BMJ 2006 Nov 25333(7578)1114-782 Nainggolan L Folic acid modestly protects against cardiovascular eventsHea rtwire 2006 reproduced in Medscape web site wwwmedscapecom83 Bazzano LA Folic acid supplementation and cardiovascular disease the stateo t he art Am J Med Sci 2009 Jul338(1)48-984 Galan P et al The SUFOLOM3 Study a secondary prevention trial testingthe impact o supplementation with olate and B-vitamins andor Omega-3 PUFAon atal and non atal cardiovascular events design methods and participantscharacteristics Trials 2008 Jun 1093585 VITATOPS Trial Study Group et al VITATOPS the VITAmins TO prevent stroke trial rationale and design o a randomised trial o B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669)(ISRCTN74743444) Int J Stroke 2007 May2(2)144-50
892019 Arbor B Vitamins and Stroke Prevention
httpslidepdfcomreaderfullarbor-b-vitamins-and-stroke-prevention 25
COMMENTARY
The connection between homocysteine (Hcy) and
stroke is one aspect of the broader and controversial
`Hcy hypothesisrsquo - that elevated Hcy is an independent
and treatable cause of atherosclerosis including
heart disease It also concerns the vitamins closely
connected to Hcy through their role in methionine
metabolism regeneration and Hcy breakdown - see
Figure opposite Those Hcy-vitaminsrsquo are folate
vitamin B12
and to a lesser extent vitamin B6
and vitamin B2 1-3
We easily found over two dozen studies on Hcy as
a risk factor for stroke of which the large majority
reported a positive association In some recent
examples Hcy levels in stroke cases were a third
higher than in controls in one 4 and double in the other
(odds ratio for elevated Hcy a remarkable 157) 5 A
recent British study found the association strongest in
relation to small vessel strokes 6 whilst one from China
reported that elevated Hcy predicted for brain atrophy
post-stroke (OR=98) 7
Three meta-analyses (curiously each published in
2002) confirmed this association One included 30observational studies involving 1113 stroke events
and concluded that Hcy is an independent though
moderate risk factor for stroke and that in the
prospective studies stroke risk was reduced by 11
for every 25 reduction in Hcy 8 The second meta-
analysis collated 20 sets of prospective data to derive
OR=159 that a future stroke patient would have had
a 5 elevation in their baseline Hcy level 9 In the
third meta-analysis the pooled OR for subjects with
elevated Hcy having an ischaemic stroke (from 14studies involving 1769 stroke cases) was 179 10
Other epidemiological research has focused
specifically on the Hcy-vitamins and stroke Although
not entirely consistent there have been many
reports of stroke being associated with lower folate
levels (eg 7 11-14 ) somewhat fewer reports of lower
vitamin B12
(eg 13 15 16 ) and much fewer of lower
vitamin B6(eg 17 18 ) A single study found lower
vitamin B2
level in stroke patients than controls 19
but another did not 20 New Study 1 showed a link
between two of these nutrients and stroke severity
There is a genetic factor at play in this association as
well due to the extensively documented impact onHcy metabolism of polymorphism in the gene for the
MTHFR enzyme (whose role is shown in the Figure
above) A good many studies have looked at the
risk for stroke associated with the particular MTHFR
genotype (TT) in which Hcy recycling is impaired
(n=768 no other trials on stroke patients) and 20 other
RCTs on FMD (n=1282 only one other trial on stroke
patients)
Results There was no signifcant change in CIMT or
FMD in their own trial The meta-analysis showed a
decrease in CIMT (010 mm 95 CI 001-020 mm)
and increase in FMD (by 14 07-21) mainly seen
in trials o less than 9 weeks duration
Re Potter K et al The eect o long-term homocysteine-lowering on carotid intima-media thickness and fow-mediated vasodilation in stroke patients a randomized controlled trial and meta-analysis BMC Cardiovasc Disord 2008 Sep 20824
A meta-analysis in 2002 of 19 studies reported the ORfor (ischaemic) stroke in the TT genotype to be 123 10
Research since then has confirmed the link 21-24
What is not so clear is how much independent risk
this genetic variation has beyond the Hcy levels and
whether it affects the impact of Hcy lowering vitamin
supplementation with the general consensus being thatsuch effects are modest at best 10 25-27
Given that there clearly is an association three
questions spring to mind Firstly is it causal or merely
an indicator of some other process Secondly if
causal what is the mechanism and is it the Hcy or thevitamins that are the most important element Thirdly
can the damage be corrected by supplementation
In relation to causality the majority of experts have
expressed the view that the weight of evidence
suggests this is true (eg 1 28-31 ) An interesting
perspective on this comes from one of the meta-
analyses we have already cited which calculated odds
ratios from genetic and prospective studies separately
The authors concluded that since each analysis had
similar highly significant outcomes but were unlikely
to share confounders the evidence for causality was
strong 9 Others have not been so sure and havepreferred to await the results of quality RCTs 32-35
When it comes to mechanisms there is no shortage
of evidence that elevated Hcy could predispose
to stroke through contribution to inflammation
SAM
(S-Adenosyl-
methionine)
Homocysteine
Methionine
Excreted or converted
to other aa
Methionine
cycle
VitB2
NADPH
NADP+
Methioninesynthase
VitB6
VitB12
cycleFolate
MTHFR
Nucleotide
synthesis(DNA RBC etc)
Methyl
donation(nerves
DNA etc)
Cysteine
THF
5-methyl
THF
Super simplified Hcy biochemistry lesson
Methyl donation and nucleotide synthesis are both vitalfunctions served by the conversion of methionine to andregeneration from Hcy involving the folate cycle Vitamindeficiency can lead to Hcy accumulation
892019 Arbor B Vitamins and Stroke Prevention
httpslidepdfcomreaderfullarbor-b-vitamins-and-stroke-prevention 35
Some potential limitations of these trial data have been
raised One is that these supplements in the doses
used would be ineffective or the effect too weak to be
detected with the sample sizes tested in people with
the kind of advanced atherosclerotic disease that was
true of the subjects in all these trials except one 77
Let alone in patients who recently had a stroke which
was the basis of the VISP trial (included in all three
meta-analyses) - that is secondary prevention hardlycomparable with the other RCTs Moreover VISP
compared high dose Hcy-vitamins not with placebo
but with low dose And control subjects in WAFACS
were allowed to take multivitamin supplements up to
RDA level 61
atherosclerosis thrombogenesis hypertension and
impaired cerebro-arterial function a good deal of
which is contributed to by oxidative stress 29 30 36-39
For example a solid body of work shows the
relationship between Hcy and carotid intima-media
thickness (CIMT) 40-42 a measure of atherosclerosis
generally but also specifically related to stroke
risk 43-45 Whilst not all observational data has founda strong connection 46 47 a number of RCTs have
demonstrated improved CIMT after elevated Hcy was
lowered through vitamin supplements 48-53 though not
all have done so 54 New Study 3 did not demonstrate
this but when its data was added to other trial results
in meta-analysis this conclusion was supported
Another interesting light on mechanism comes from a
new Canadian study which showed that excess Hcy
can inhibit the expected migration of progenitor cells
from bone marrow to repair vascular endothelium
damaged in stroke patients
55
Mechanisms involving the Hcy-vitamins which do
not involve Hcy are less clear although some animal
evidence suggests folate may have some such
role 56 57 including in endothelial function 58 and
perhaps riboflavin in traumatic brain injury 59
This brings us to the third and most important
question can any damage caused by excess Hcy
be corrected by supplementation New Study 2 is a
fresh analysis of the HOPE-2 trial showing that the
25 protection against stroke incidence had a non-
significant trend to being for non-fatal strokes andparticularly in those subjects with higher baseline Hcy
HOPE-2 is best seen in the context of other RCTs that
have looked at this question Eleven have published
their results so far 60-71 Various combinations and
permutations of these eleven form the basis of no less
than three separate meta-analyses 72-74 That these
meta-analyses did not reach complete consensus is
perhaps not surprising bearing in mind that they did
not include all the same data - see Graph 2
Looking at that Graph it is hard to find strong support
for the idea that giving vitamins to reduce Hcy
prevents stroke Although 711 RCTs showed a risk
reduction in only one was this clearly significant That
was the HOPE-2 trial the largest on patients with past
history of diabetes or vascular disease 63 On the other
hand results from the even more recently completed
SEARCH trial of 12064 heart attack survivors 75 (as yet
unpublished) failed to show any stroke prevention 76
Some might take comfort from the sub-grouping
data in the Wang meta-analysis 74 which showed a
protective effect in patients without a stroke history
(ie primary prevention which was true of all trials barone) in those whose treatment lasted more than 3 yearsand which successfully reduced their Hcy levels
On the other hand Wangrsquos analysis was too early to
include the 2 RCT results published in 2008 (n=8532)
both lasting over 3 years but with negative results 60 61
20
07500 15
Bazzano 73
Cochrane 72
Wang 74
10 125050025
089
086
075
WENBIT60
088
WAFACS 61114
NORVIT 62
085
HOPE-2 63076
ASFAST 64045
Haemo-
dialysis 65
055
VISP 66 67104
GOES
68065
FOLARDA 69
End stage
renal 70
117
LINXIAN 71063
Overall
Durationgt 3612
Hcy reducgt 20
No strokehistory
306
3090
5442
3749
5522
315
88
3680
593
283
510
3318
077
082
071
RCTs
Meta-analyses
18086
13806
16841
9748
9018
12165
N =
N =
meta-analyses trial
incl in x1 x3x2
Graph 2 RR for stroke RCTs o Hcy lowering
vitamin supplements vs control
892019 Arbor B Vitamins and Stroke Prevention
httpslidepdfcomreaderfullarbor-b-vitamins-and-stroke-prevention 45
Reerences1 Saacutenchez-Moreno C et al Stroke roles o B vitamins homocysteine and antioxidants Nutr Res Rev 2009 Jun22(1)49-67 2 McNulty H et al Homocysteine B-vitamins and CVD Proc Nutr Soc 2008May67(2)232-73 McNulty H et al Ribolavin lowers homocysteine in individuals homozygous or the MTHFR 677C-gtT polymorphism Circulation 2006 Jan 3113(1)74-80 4 Narang AP et al Homocysteine--risk actor or ischemic stroke Indian JPh ysiol Pharmacol 2009 Jan-Mar53(1)34-85 Dhamija RK et al Homocysteine and lipoprotein (a) correlation in ischemic stroke patients J Neurol Sci 2009 Jun 15281(1-2)64-8
6 Khan U et al Homocysteine and its relationship to stroke subtypes in a UK black population the south London ethnicity and stroke study Stroke 2008Nov39(11)2943-97 Yang LK et al Correlations between olate B12 homocysteine levels and radiological markers o neuropathology in elderly post-stroke patients J Am CollNutr 2007 Jun26(3)272-88 Homocysteine Studies Collaboration Homocysteine and risk o ischemic heartdi sease and stroke a meta-analysis JAMA 2002 Oct 23-30288(16)2015- 229 Wald DS et al Homocysteine and cardiovascular disease evidence oncausality rom a meta-analysis BMJ 2002 Nov 23325(7374)120210 Kelly PJ et al Homocysteine MTHFR 677C--gtT polymorphism and risk o ischemic stroke results o a meta-analysis Neurology 2002 Aug 2759(4)529-3611 Weng LC et al Is ischemic stroke risk related to olate status or other nutr ients correlated with olate intake Stroke 2008 Dec39(12)3152-812 Larsson SC et al Folate vitamin B6 vitamin B12 and methionine intakes and risk o stroke subtypes in male smokers Am J Epidemiol 2008 Apr 15167(8)954-61
13 Weikert C et al B vitamin plasma levels and the risk o ischemic stroke andtransient ischemic attack in a German cohort Stroke 2007 Nov38(11)2912-814 Van Guelpen B et al Folate vitamin B12 and risk o ischemic and hemorrhagic stroke a prospective nested case-reerent study o plasmaconcentrations and dietary intake Stroke 2005 Jul36(7)1426-3115 Pieters B et al Periventricular white matter lucencies relate to low vitaminB12 levels in patients with small vessel stroke Stroke 2009 May40(5)1623-616 He K et al Folate vitamin B6 and B12 intakes in relation to risk o stroke among men Stroke 2004 Jan35(1)169-7417 Kelly PJ et al Inlammation homocysteine and vitamin B6 status ater ischemic stroke Stroke 2004 Jan35(1)12-518 Robinson K et al Low circulating olate and vitamin B6 concentrations risk actors or stroke peripheral vascular disease and coronary artery diseaseEur opean COMAC Group Circulation 1998 Feb 1097(5)437-4319 Gariballa S et al Ribolavin status in acute ischaemic stroke Eur J Clin Nutr 2007 Oct61(10)1237-40 20 Ross RK et al Prospective evaluation o dietary and other predictors o atal
stro ke in Shanghai China Circulation 1997 Jul 196(1)50-5 21 Biswas A et al Homocystine levels polymorphisms and the risk o ischemic stroke in young Asian Indians J Stroke Cerebrovasc Dis 2009 Mar- Apr18(2)103-10 22 Saacutenchez-Mariacuten B et al [Prevalence o methylenetetrahydroolate reductaseC677T mutation among patients with acute ischemic cerebrovascular disease in Ara gon] An Med Interna 2006 Apr23(4)153-5 23 Panigrahi I et al Role o MTHFR C677T polymorphism in ischemic strokeNeu rol India 2006 Mar54(1)48-50 24 Cantu C et al Hyperhomocysteinemia low olate and vitamin B12concentrations and methylene tetrahydroolate reductase mutation in cerebralvenous thrombosis Stroke 2004 Aug35(8)1790-4 25 Lim PS et al Polymorphism in methylenetetrahydroolate reductase gene its impact on plasma homocysteine levels and carotid atherosclerosis in ESRD patients receiving hemodialysis Nephron 2001 Mar87(3)249-56 26 Demuth K et al Opposite eects o plasma homocysteine and the methylenetetrahydroolate reductase C677T mutation on carotid artery geometry in a symptomatic adults Arterioscler Thromb Vasc Biol 1998 Dec18(12)1838-43 27 Ho GY et al Methylenetetrahydroolate reductase polymorphisms and homocysteine-lowering eect o vitamin therapy in Singaporean stroke patientsStroke 2006 Feb37(2)456-60 28 Terwecoren A et al Ischemic stroke and hyperhomocysteinemia truth or myt h Acta Neurol Belg 2009 Sep109(3)181-8 29 Pezzini A et al Homocysteine and cerebral ischemia pathogenic andther apeutical implications Curr Med Chem 200714(3)249-6330 Hankey GJ et al Clinical useulness o plasma homocysteine in vascular dise ase Med J Aust 2004 Sep 20181(6)314-831 Stanger O et al DACH-LIGA homocystein (german austrian and swiss homocysteine society) consensus paper on the rational clinical use o homocysteine olic acid and B-vitamins in cardiovascular and thromboticdiseases guidelines and recommendations Clin Chem Lab Med 2003Nov 41(11)1392-40332 Herrmann W et al Hyperhomocysteinaemia a critical review o old and new
aspects Curr Drug Metab 2007 Jan8(1)17-3133 Ntaios GC et al Vitamins and stroke the homocysteine hypothesis still indou bt Neurologist 2008 Jan14(1)2-434 Lonn E Homocysteine in the prevention o ischemic heart disease stroke andvenous thromboembolism therapeutic target or just another distraction Curr Opin Hematol 2007 Sep14(5)481-735 Wierzbicki AS Homocysteine and cardiovascular disease a review o theevidence Diab Vasc Dis Res 2007 Jun4(2)143-50
Other potential limitations of the existing trial data
include any masking effect of concurrent treatment
(eg statins) or the Hcy metabolic situation beingdifferent in the RCTs on renal failure patients 77-79 Another possible issue is the baseline status of the
Hcy-vitamins and ability to absorb them For example
people living in areas with folate-fortified flour (higher
baseline status) or with B12
malabsorption may show
less protective effect from those supplements
74 79 80
What all of this might mean is that we have not as yet
narrowed down the population group in whom Hcy
lowering prevents stroke For example we lack trials
on patients with high Hcy who have not yet displayed
clinical atherosclerosis Others have argued (both
for stroke and heart disease) that the benefits of Hcy
lowering may take years to be seen and that we do
not have enough of that kind of long term data Or
that the effect of genetic polymorphism has not been
adequately taken into account or that benefit may
be confined to even higher risk patients (such as
atherosclerotic smokers) 81 82
In short given all these consideration and at least
one substantial trial having positive results there are
certainly those who do not believe we should rule
these treatments out just yet (eg 78-82 )
At the same time it would be fair to say that the
majority view is that despite the very strong
epidemiological data such a frankly disappointing
set of trial results means that current evidence simply
does not justify using these vitamins for stroke
prevention certainly not in a routine way (eg1 33 83 )
Whilst considering these different viewpoints
and maybe even whether it might be worth giving
supplements to prevent stroke on a lsquono harm in tryingrsquo
basis we should also think about their safety On the
whole the supplement regimes used in these trials havebeen considered safe (and cheap) interventions 28
There were two exceptions NORVIT reported a
rise of borderline statistical significance in non-
fatal myocardial infarction (but not in stroke) in the
vitamin group (OR=130 95 CI 100ndash168) 62
HOPE-2 found that more of the vitamin subjects werehospitalised for unstable angina (RR=124 95 CI
104-149) compared with placebo 63 In the absence
of confirmation of such increased risk from other
trials it is hard to know what significance to place
on this (There is also the question of whether folate
might sometimes promote cancer growth - a complex
subject that will be the topic of a later issue)
Two further large RCTs involving Hcy-vitamins and
stroke prevention are due to report in the next several
years the SUFOLOM3 study on some 2500 patients
who had CHD or stroke within the previous year 83 and
VITATOPS with a target of 8000 patients who had
recent transient ischaemic attack 84 The FAVORIT and
HOST trials may a lso offer some less direct information 77
This is definitely a `watch this spacersquo topic
892019 Arbor B Vitamins and Stroke Prevention
httpslidepdfcomreaderfullarbor-b-vitamins-and-stroke-prevention 55
Disclaimer copyright terms of use and subscribing
Your use o these Updates in any orm or ormat constitutes your agreement to our disclaimer and terms o use which can be ound on our web site atwwwnutritionupdatesorgsubterms_premphp You can also obtain the disclaimer and terms o use by emailing us at upTarborcomcom
copy Copyright Arbor Communications PTL 2010 All rights reserved This document may NOT be orwarded onto others without our written permission
I you want to receive the Clinical Nutrition Updates on an ongoing basis please register at wwwnutritionupdatesorgsub Or send a request email to
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36 Osanai T et al Novel pro-atherogenic molecule coupling actor 6 iselevated in patients with stroke a possible linkage to homocysteine Ann Med 201042(1)79-8637 Kumar M et al Homocysteine decreases blood low to the brain due tovascular resistance in carotid artery Neurochem Int 2008 Dec53(6-8)214-938 Stanger O et al Clinical use and rational management o homocysteine olic acid and B vitamins in cardiovascular and thrombotic diseases Z Kardiol 2004 Jun 93(6)439-5339 Guilland JC et al [Hyperhomocysteinemia an independent risk actor or a simple marker o vascular disease 1 Basic data] Pathol Biol (Paris) 2003
Mar51(2)101-10 40 Baptista AP et al Inlammation homocysteine and carotid intima-mediathickness Rev Port Cardiol 2008 Jan27(1)39-48 41 Sabaliauskene Z et al [Hyperhomocysteinemia in patients with atherosclerotic extracranial disease o the carotid artery] Klin Lab Diagn 2006 Jun (6)20-2 35 42 Wang H et al Serum level o homocysteine is correlated to carotid artery athe rosclerosis in Chinese with ischemic stroke Neurol Res 2006 Jan28(1)25-30 43 Silvestrini M et al Carotid wall thickness and stroke risk in patients with asymptomatic internal carotid stenosis Atherosclerosis 2010 Jan 4 Epub 44 Cobble M et al Carotid intima-media thickness knowledge and applicationto everyday practice Postgrad Med 2010 Jan122(1)10-8 45 Sahoo R et al Common carotid intima-media thickness in acute ischemic stro ke A case control study Neurol India 2009 Sep-Oct57(5)627-30 46 Ntaios G et al Homocysteine and carotid intima-media thickness in ischemic stro ke patients are not correlated Neuropsychiatr Dis Treat 2008 Apr4( 2)477-9 47 Held C et al Correlations between plasma homocysteine and olate
concentrations and carotid atherosclerosis in high-risk individuals baseline datarom the Homocysteine and Atherosclerosis Reduction Trial (HART) Vasc Med 2008 Nov13(4)245-53 48 Nanayakkara PW et al Eect o a treatment strategy consisting o pravastatinvitamin E and homocysteine lowering on carotid intima-media thicknessendothelial unction and renal unction in patients with mild to moderatechronic kidney disease results rom the Anti-Oxidant Therapy in Chronic RenalInsuiciency (ATIC) Study Arch Intern Med 2007 Jun 25167(12)1262-70 49 Fernaacutendez-Miranda C et al Eect o olic acid treatment on carotid intima- media thickness o patients with coronary disease Int J Cardiol 2007 Jun12118(3)345-950 Hodis HN et al High-dose B vitamin supplementation and progressiono subclinical atherosclerosis a randomized controlled trial Stroke 2009Mar 40(3)730-651 Vianna AC et al Uremic hyperhomocysteinemia a randomized trial o olate treatment or the prevention o cardiovascular events Hemodial Int 2007 Apr 11(2)210-6
52 Tungkasereerak P et al Eect o short-term olate and vitamin B supplementation on blood homocysteine level and carotid artery wall thickness inchronic hemodialysis patients J Med Assoc Thai 2006 Aug89(8)1187-9353 Till U et al Decrease o carotid intima-media thickness in patients at risk tocerebral ischemia ater supplementation with olic acid Vitamins B6 and B12 Atherosclerosis 2005 Jul181(1)131-554 van Dijk RA et al Long-term homocysteine-lowering treatment with olic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiness a 2-year randomized placebo-controlled trial Arterioscler Thromb VascBiol 2001 Dec21(12)2072-955 Alam MM et al Homocysteine reduces endothelial progenitor cells in stroke patients through apoptosis J Cereb Blood Flow Metab 2009 Jan29(1)157-6556 Hwang IK et al Folic acid deiciency increases delayed neuronal death DNAdamage platelet endothelial cell adhesion molecule-1 immunoreactivity and gliosis in the hippocampus ater transient cerebral ischemia J Neurosci Res 2008 Jul86(9)2003-1557 Huang GW et al [Eects o olic acid vitamin B(6) and vitamin B(12) on learning and memory unction in cerebral ischemia rats] Zhonghua Yu Fang Yi Xue Za Zhi 2007 May41(3)212-458 Doshi SN et al Folic acid improves endothelial unction in coronary artery disease via mechanisms largely independent o homocysteine loweringCirculation 2002 Jan 1105(1)22-659 Hoane MR et al Administration o ribolavin improves behavioral outcome and reduces edema ormation and glial ibrillary acidic protein expression ater trau matic brain injury J Neurotrauma 2005 Oct22(10)1112-2260 Ebbing M et al Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins ater coronary angiography a randomizedcontrolled trial JAMA 2008 Aug 20300(7)795-804
61 Albert CM et al Eect o olic acid and B vitamins on risk o cardiovascular events and total mortality among women at high risk or cardiovascular disease a randomized trial JAMA 2008 May 7299(17)2027-3662 Boslashnaa KH et al Homocysteine lowering and cardiovascular events ater acute myocardial inarction N Engl J Med 2006 Apr 13354(15)1578-8863 Lonn E et al Homocysteine lowering with olic acid and B vitamins invascular disease N Engl J Med 2006 Apr 13354(15)1567-7764 Zoungas S et al Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renalailure a multicenter randomized controlled trial J Am Coll Cardiol 2006 Mar
2147(6)1108-1665 Righetti M et al Homocysteine-lowering vitamin B treatment decreasescardiovascular events in hemodialysis patients Blood Puri 200624(4)379-8666 Spence JD et al Vitamin Intervention For Stroke Prevention trial an eicacy ana lysis Stroke 2005 Nov36(11)2404-967 Toole JF et al Lowering homocysteine in patients with ischemic stroketo prevent recurrent stroke myocardial inarction and death the VitaminIntervention or Stroke Prevention (VISP) randomized controlled trial JAMA 2004Feb 4291(5)565-7568 Liem A et al Secondary prevention with olic acid results o the Goesextension study Heart 2005 Sep91(9)1213-469 Liem AH et al Eicacy o olic acid when added to statin therapy in patientswith hypercholesterolemia ollowing acute myocardial inarction a randomised pilot trial Int J Cardiol 2004 Feb93(2-3)175-970 Wrone EM et al Randomized trial o olic acid or prevention o cardiovascular events in end-stage renal disease J Am Soc Nephrol 2004Feb 15(2)420-6
71 Mark SD et al Lowered risks o hypertension and cerebrovascular disease ater vitaminmineral supplementation the Linxian Nutrition Intervention Trial Am J Epidemiol 1996 Apr 1143(7)658-6472 Martiacute-Carvajal AJ et al Homocysteine lowering interventions or preventingcardiovascular events Cochrane Database Syst Rev 2009 Oct 7(4)CD00661273 Bazzano LA et al Eect o olic acid supplementation on risk o cardiovascular diseases a meta-analysis o randomized controlled trials JAMA 2006 Dec 13296(22)2720-674 Wang X et al Eicacy o olic acid supplementation in stroke prevention a met a-analysis Lancet 2007 Jun 2369(9576)1876-8275 SEARCH Study Collaborative Group et al Study o the eectiveness o additional reductions in cholesterol and homocysteine (SEARCH) characteristicso a randomized trial among 12064 myocardial inarction survivors Am Heart J 2007 Nov154(5)815-23 82376 Amritage J et al SEARCH Study Collaborative Group SEARCH (Study o the Eectiveness o Additional Reductions in Cholesterol and Homocysteine) randomized comparison o olic acid 2 mg plus vitamin b12 1 mg daily versus
placebo or 7 years in 12064 myocardial inarction survivors Circulation 2008Nov 118(22)2309-231777 Marcus J et al Homocysteine lowering and cardiovascular disease risk lost in translation Can J Cardiol 2007 Jul23(9)707-1078 Pietrzik K Opinion on the COCHRANE Review lsquorsquoHomocysteine-lowering interventions or preventing cardiovascular events European Nutraceutical As sociation website at httpwwwenaonlineorg79 Spence JD Perspective on the eicacy analysis o the Vitamin Intervention or Stro ke Prevention trial Clin Chem Lab Med 200745(12)1582-580 Ueland PM et al Homocysteine and olate status in an era o olic acidortiication balancing beneits risks and B-vitamins Clin Chem 2008May54(5)779-8181 Wald DS et al Folic acid homocysteine and cardiovascular disease judging causality in the ace o inconclusive trial evidence BMJ 2006 Nov 25333(7578)1114-782 Nainggolan L Folic acid modestly protects against cardiovascular eventsHea rtwire 2006 reproduced in Medscape web site wwwmedscapecom83 Bazzano LA Folic acid supplementation and cardiovascular disease the stateo t he art Am J Med Sci 2009 Jul338(1)48-984 Galan P et al The SUFOLOM3 Study a secondary prevention trial testingthe impact o supplementation with olate and B-vitamins andor Omega-3 PUFAon atal and non atal cardiovascular events design methods and participantscharacteristics Trials 2008 Jun 1093585 VITATOPS Trial Study Group et al VITATOPS the VITAmins TO prevent stroke trial rationale and design o a randomised trial o B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669)(ISRCTN74743444) Int J Stroke 2007 May2(2)144-50
892019 Arbor B Vitamins and Stroke Prevention
httpslidepdfcomreaderfullarbor-b-vitamins-and-stroke-prevention 35
Some potential limitations of these trial data have been
raised One is that these supplements in the doses
used would be ineffective or the effect too weak to be
detected with the sample sizes tested in people with
the kind of advanced atherosclerotic disease that was
true of the subjects in all these trials except one 77
Let alone in patients who recently had a stroke which
was the basis of the VISP trial (included in all three
meta-analyses) - that is secondary prevention hardlycomparable with the other RCTs Moreover VISP
compared high dose Hcy-vitamins not with placebo
but with low dose And control subjects in WAFACS
were allowed to take multivitamin supplements up to
RDA level 61
atherosclerosis thrombogenesis hypertension and
impaired cerebro-arterial function a good deal of
which is contributed to by oxidative stress 29 30 36-39
For example a solid body of work shows the
relationship between Hcy and carotid intima-media
thickness (CIMT) 40-42 a measure of atherosclerosis
generally but also specifically related to stroke
risk 43-45 Whilst not all observational data has founda strong connection 46 47 a number of RCTs have
demonstrated improved CIMT after elevated Hcy was
lowered through vitamin supplements 48-53 though not
all have done so 54 New Study 3 did not demonstrate
this but when its data was added to other trial results
in meta-analysis this conclusion was supported
Another interesting light on mechanism comes from a
new Canadian study which showed that excess Hcy
can inhibit the expected migration of progenitor cells
from bone marrow to repair vascular endothelium
damaged in stroke patients
55
Mechanisms involving the Hcy-vitamins which do
not involve Hcy are less clear although some animal
evidence suggests folate may have some such
role 56 57 including in endothelial function 58 and
perhaps riboflavin in traumatic brain injury 59
This brings us to the third and most important
question can any damage caused by excess Hcy
be corrected by supplementation New Study 2 is a
fresh analysis of the HOPE-2 trial showing that the
25 protection against stroke incidence had a non-
significant trend to being for non-fatal strokes andparticularly in those subjects with higher baseline Hcy
HOPE-2 is best seen in the context of other RCTs that
have looked at this question Eleven have published
their results so far 60-71 Various combinations and
permutations of these eleven form the basis of no less
than three separate meta-analyses 72-74 That these
meta-analyses did not reach complete consensus is
perhaps not surprising bearing in mind that they did
not include all the same data - see Graph 2
Looking at that Graph it is hard to find strong support
for the idea that giving vitamins to reduce Hcy
prevents stroke Although 711 RCTs showed a risk
reduction in only one was this clearly significant That
was the HOPE-2 trial the largest on patients with past
history of diabetes or vascular disease 63 On the other
hand results from the even more recently completed
SEARCH trial of 12064 heart attack survivors 75 (as yet
unpublished) failed to show any stroke prevention 76
Some might take comfort from the sub-grouping
data in the Wang meta-analysis 74 which showed a
protective effect in patients without a stroke history
(ie primary prevention which was true of all trials barone) in those whose treatment lasted more than 3 yearsand which successfully reduced their Hcy levels
On the other hand Wangrsquos analysis was too early to
include the 2 RCT results published in 2008 (n=8532)
both lasting over 3 years but with negative results 60 61
20
07500 15
Bazzano 73
Cochrane 72
Wang 74
10 125050025
089
086
075
WENBIT60
088
WAFACS 61114
NORVIT 62
085
HOPE-2 63076
ASFAST 64045
Haemo-
dialysis 65
055
VISP 66 67104
GOES
68065
FOLARDA 69
End stage
renal 70
117
LINXIAN 71063
Overall
Durationgt 3612
Hcy reducgt 20
No strokehistory
306
3090
5442
3749
5522
315
88
3680
593
283
510
3318
077
082
071
RCTs
Meta-analyses
18086
13806
16841
9748
9018
12165
N =
N =
meta-analyses trial
incl in x1 x3x2
Graph 2 RR for stroke RCTs o Hcy lowering
vitamin supplements vs control
892019 Arbor B Vitamins and Stroke Prevention
httpslidepdfcomreaderfullarbor-b-vitamins-and-stroke-prevention 45
Reerences1 Saacutenchez-Moreno C et al Stroke roles o B vitamins homocysteine and antioxidants Nutr Res Rev 2009 Jun22(1)49-67 2 McNulty H et al Homocysteine B-vitamins and CVD Proc Nutr Soc 2008May67(2)232-73 McNulty H et al Ribolavin lowers homocysteine in individuals homozygous or the MTHFR 677C-gtT polymorphism Circulation 2006 Jan 3113(1)74-80 4 Narang AP et al Homocysteine--risk actor or ischemic stroke Indian JPh ysiol Pharmacol 2009 Jan-Mar53(1)34-85 Dhamija RK et al Homocysteine and lipoprotein (a) correlation in ischemic stroke patients J Neurol Sci 2009 Jun 15281(1-2)64-8
6 Khan U et al Homocysteine and its relationship to stroke subtypes in a UK black population the south London ethnicity and stroke study Stroke 2008Nov39(11)2943-97 Yang LK et al Correlations between olate B12 homocysteine levels and radiological markers o neuropathology in elderly post-stroke patients J Am CollNutr 2007 Jun26(3)272-88 Homocysteine Studies Collaboration Homocysteine and risk o ischemic heartdi sease and stroke a meta-analysis JAMA 2002 Oct 23-30288(16)2015- 229 Wald DS et al Homocysteine and cardiovascular disease evidence oncausality rom a meta-analysis BMJ 2002 Nov 23325(7374)120210 Kelly PJ et al Homocysteine MTHFR 677C--gtT polymorphism and risk o ischemic stroke results o a meta-analysis Neurology 2002 Aug 2759(4)529-3611 Weng LC et al Is ischemic stroke risk related to olate status or other nutr ients correlated with olate intake Stroke 2008 Dec39(12)3152-812 Larsson SC et al Folate vitamin B6 vitamin B12 and methionine intakes and risk o stroke subtypes in male smokers Am J Epidemiol 2008 Apr 15167(8)954-61
13 Weikert C et al B vitamin plasma levels and the risk o ischemic stroke andtransient ischemic attack in a German cohort Stroke 2007 Nov38(11)2912-814 Van Guelpen B et al Folate vitamin B12 and risk o ischemic and hemorrhagic stroke a prospective nested case-reerent study o plasmaconcentrations and dietary intake Stroke 2005 Jul36(7)1426-3115 Pieters B et al Periventricular white matter lucencies relate to low vitaminB12 levels in patients with small vessel stroke Stroke 2009 May40(5)1623-616 He K et al Folate vitamin B6 and B12 intakes in relation to risk o stroke among men Stroke 2004 Jan35(1)169-7417 Kelly PJ et al Inlammation homocysteine and vitamin B6 status ater ischemic stroke Stroke 2004 Jan35(1)12-518 Robinson K et al Low circulating olate and vitamin B6 concentrations risk actors or stroke peripheral vascular disease and coronary artery diseaseEur opean COMAC Group Circulation 1998 Feb 1097(5)437-4319 Gariballa S et al Ribolavin status in acute ischaemic stroke Eur J Clin Nutr 2007 Oct61(10)1237-40 20 Ross RK et al Prospective evaluation o dietary and other predictors o atal
stro ke in Shanghai China Circulation 1997 Jul 196(1)50-5 21 Biswas A et al Homocystine levels polymorphisms and the risk o ischemic stroke in young Asian Indians J Stroke Cerebrovasc Dis 2009 Mar- Apr18(2)103-10 22 Saacutenchez-Mariacuten B et al [Prevalence o methylenetetrahydroolate reductaseC677T mutation among patients with acute ischemic cerebrovascular disease in Ara gon] An Med Interna 2006 Apr23(4)153-5 23 Panigrahi I et al Role o MTHFR C677T polymorphism in ischemic strokeNeu rol India 2006 Mar54(1)48-50 24 Cantu C et al Hyperhomocysteinemia low olate and vitamin B12concentrations and methylene tetrahydroolate reductase mutation in cerebralvenous thrombosis Stroke 2004 Aug35(8)1790-4 25 Lim PS et al Polymorphism in methylenetetrahydroolate reductase gene its impact on plasma homocysteine levels and carotid atherosclerosis in ESRD patients receiving hemodialysis Nephron 2001 Mar87(3)249-56 26 Demuth K et al Opposite eects o plasma homocysteine and the methylenetetrahydroolate reductase C677T mutation on carotid artery geometry in a symptomatic adults Arterioscler Thromb Vasc Biol 1998 Dec18(12)1838-43 27 Ho GY et al Methylenetetrahydroolate reductase polymorphisms and homocysteine-lowering eect o vitamin therapy in Singaporean stroke patientsStroke 2006 Feb37(2)456-60 28 Terwecoren A et al Ischemic stroke and hyperhomocysteinemia truth or myt h Acta Neurol Belg 2009 Sep109(3)181-8 29 Pezzini A et al Homocysteine and cerebral ischemia pathogenic andther apeutical implications Curr Med Chem 200714(3)249-6330 Hankey GJ et al Clinical useulness o plasma homocysteine in vascular dise ase Med J Aust 2004 Sep 20181(6)314-831 Stanger O et al DACH-LIGA homocystein (german austrian and swiss homocysteine society) consensus paper on the rational clinical use o homocysteine olic acid and B-vitamins in cardiovascular and thromboticdiseases guidelines and recommendations Clin Chem Lab Med 2003Nov 41(11)1392-40332 Herrmann W et al Hyperhomocysteinaemia a critical review o old and new
aspects Curr Drug Metab 2007 Jan8(1)17-3133 Ntaios GC et al Vitamins and stroke the homocysteine hypothesis still indou bt Neurologist 2008 Jan14(1)2-434 Lonn E Homocysteine in the prevention o ischemic heart disease stroke andvenous thromboembolism therapeutic target or just another distraction Curr Opin Hematol 2007 Sep14(5)481-735 Wierzbicki AS Homocysteine and cardiovascular disease a review o theevidence Diab Vasc Dis Res 2007 Jun4(2)143-50
Other potential limitations of the existing trial data
include any masking effect of concurrent treatment
(eg statins) or the Hcy metabolic situation beingdifferent in the RCTs on renal failure patients 77-79 Another possible issue is the baseline status of the
Hcy-vitamins and ability to absorb them For example
people living in areas with folate-fortified flour (higher
baseline status) or with B12
malabsorption may show
less protective effect from those supplements
74 79 80
What all of this might mean is that we have not as yet
narrowed down the population group in whom Hcy
lowering prevents stroke For example we lack trials
on patients with high Hcy who have not yet displayed
clinical atherosclerosis Others have argued (both
for stroke and heart disease) that the benefits of Hcy
lowering may take years to be seen and that we do
not have enough of that kind of long term data Or
that the effect of genetic polymorphism has not been
adequately taken into account or that benefit may
be confined to even higher risk patients (such as
atherosclerotic smokers) 81 82
In short given all these consideration and at least
one substantial trial having positive results there are
certainly those who do not believe we should rule
these treatments out just yet (eg 78-82 )
At the same time it would be fair to say that the
majority view is that despite the very strong
epidemiological data such a frankly disappointing
set of trial results means that current evidence simply
does not justify using these vitamins for stroke
prevention certainly not in a routine way (eg1 33 83 )
Whilst considering these different viewpoints
and maybe even whether it might be worth giving
supplements to prevent stroke on a lsquono harm in tryingrsquo
basis we should also think about their safety On the
whole the supplement regimes used in these trials havebeen considered safe (and cheap) interventions 28
There were two exceptions NORVIT reported a
rise of borderline statistical significance in non-
fatal myocardial infarction (but not in stroke) in the
vitamin group (OR=130 95 CI 100ndash168) 62
HOPE-2 found that more of the vitamin subjects werehospitalised for unstable angina (RR=124 95 CI
104-149) compared with placebo 63 In the absence
of confirmation of such increased risk from other
trials it is hard to know what significance to place
on this (There is also the question of whether folate
might sometimes promote cancer growth - a complex
subject that will be the topic of a later issue)
Two further large RCTs involving Hcy-vitamins and
stroke prevention are due to report in the next several
years the SUFOLOM3 study on some 2500 patients
who had CHD or stroke within the previous year 83 and
VITATOPS with a target of 8000 patients who had
recent transient ischaemic attack 84 The FAVORIT and
HOST trials may a lso offer some less direct information 77
This is definitely a `watch this spacersquo topic
892019 Arbor B Vitamins and Stroke Prevention
httpslidepdfcomreaderfullarbor-b-vitamins-and-stroke-prevention 55
Disclaimer copyright terms of use and subscribing
Your use o these Updates in any orm or ormat constitutes your agreement to our disclaimer and terms o use which can be ound on our web site atwwwnutritionupdatesorgsubterms_premphp You can also obtain the disclaimer and terms o use by emailing us at upTarborcomcom
copy Copyright Arbor Communications PTL 2010 All rights reserved This document may NOT be orwarded onto others without our written permission
I you want to receive the Clinical Nutrition Updates on an ongoing basis please register at wwwnutritionupdatesorgsub Or send a request email to
upDarborcomcom This is a FREE service to health proessionals and students Include details o your name email address country institution (i
relevant) and proessional background The Updates are available in English Spanish Portuguese Italian French Turkish Korean and Russian
36 Osanai T et al Novel pro-atherogenic molecule coupling actor 6 iselevated in patients with stroke a possible linkage to homocysteine Ann Med 201042(1)79-8637 Kumar M et al Homocysteine decreases blood low to the brain due tovascular resistance in carotid artery Neurochem Int 2008 Dec53(6-8)214-938 Stanger O et al Clinical use and rational management o homocysteine olic acid and B vitamins in cardiovascular and thrombotic diseases Z Kardiol 2004 Jun 93(6)439-5339 Guilland JC et al [Hyperhomocysteinemia an independent risk actor or a simple marker o vascular disease 1 Basic data] Pathol Biol (Paris) 2003
Mar51(2)101-10 40 Baptista AP et al Inlammation homocysteine and carotid intima-mediathickness Rev Port Cardiol 2008 Jan27(1)39-48 41 Sabaliauskene Z et al [Hyperhomocysteinemia in patients with atherosclerotic extracranial disease o the carotid artery] Klin Lab Diagn 2006 Jun (6)20-2 35 42 Wang H et al Serum level o homocysteine is correlated to carotid artery athe rosclerosis in Chinese with ischemic stroke Neurol Res 2006 Jan28(1)25-30 43 Silvestrini M et al Carotid wall thickness and stroke risk in patients with asymptomatic internal carotid stenosis Atherosclerosis 2010 Jan 4 Epub 44 Cobble M et al Carotid intima-media thickness knowledge and applicationto everyday practice Postgrad Med 2010 Jan122(1)10-8 45 Sahoo R et al Common carotid intima-media thickness in acute ischemic stro ke A case control study Neurol India 2009 Sep-Oct57(5)627-30 46 Ntaios G et al Homocysteine and carotid intima-media thickness in ischemic stro ke patients are not correlated Neuropsychiatr Dis Treat 2008 Apr4( 2)477-9 47 Held C et al Correlations between plasma homocysteine and olate
concentrations and carotid atherosclerosis in high-risk individuals baseline datarom the Homocysteine and Atherosclerosis Reduction Trial (HART) Vasc Med 2008 Nov13(4)245-53 48 Nanayakkara PW et al Eect o a treatment strategy consisting o pravastatinvitamin E and homocysteine lowering on carotid intima-media thicknessendothelial unction and renal unction in patients with mild to moderatechronic kidney disease results rom the Anti-Oxidant Therapy in Chronic RenalInsuiciency (ATIC) Study Arch Intern Med 2007 Jun 25167(12)1262-70 49 Fernaacutendez-Miranda C et al Eect o olic acid treatment on carotid intima- media thickness o patients with coronary disease Int J Cardiol 2007 Jun12118(3)345-950 Hodis HN et al High-dose B vitamin supplementation and progressiono subclinical atherosclerosis a randomized controlled trial Stroke 2009Mar 40(3)730-651 Vianna AC et al Uremic hyperhomocysteinemia a randomized trial o olate treatment or the prevention o cardiovascular events Hemodial Int 2007 Apr 11(2)210-6
52 Tungkasereerak P et al Eect o short-term olate and vitamin B supplementation on blood homocysteine level and carotid artery wall thickness inchronic hemodialysis patients J Med Assoc Thai 2006 Aug89(8)1187-9353 Till U et al Decrease o carotid intima-media thickness in patients at risk tocerebral ischemia ater supplementation with olic acid Vitamins B6 and B12 Atherosclerosis 2005 Jul181(1)131-554 van Dijk RA et al Long-term homocysteine-lowering treatment with olic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiness a 2-year randomized placebo-controlled trial Arterioscler Thromb VascBiol 2001 Dec21(12)2072-955 Alam MM et al Homocysteine reduces endothelial progenitor cells in stroke patients through apoptosis J Cereb Blood Flow Metab 2009 Jan29(1)157-6556 Hwang IK et al Folic acid deiciency increases delayed neuronal death DNAdamage platelet endothelial cell adhesion molecule-1 immunoreactivity and gliosis in the hippocampus ater transient cerebral ischemia J Neurosci Res 2008 Jul86(9)2003-1557 Huang GW et al [Eects o olic acid vitamin B(6) and vitamin B(12) on learning and memory unction in cerebral ischemia rats] Zhonghua Yu Fang Yi Xue Za Zhi 2007 May41(3)212-458 Doshi SN et al Folic acid improves endothelial unction in coronary artery disease via mechanisms largely independent o homocysteine loweringCirculation 2002 Jan 1105(1)22-659 Hoane MR et al Administration o ribolavin improves behavioral outcome and reduces edema ormation and glial ibrillary acidic protein expression ater trau matic brain injury J Neurotrauma 2005 Oct22(10)1112-2260 Ebbing M et al Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins ater coronary angiography a randomizedcontrolled trial JAMA 2008 Aug 20300(7)795-804
61 Albert CM et al Eect o olic acid and B vitamins on risk o cardiovascular events and total mortality among women at high risk or cardiovascular disease a randomized trial JAMA 2008 May 7299(17)2027-3662 Boslashnaa KH et al Homocysteine lowering and cardiovascular events ater acute myocardial inarction N Engl J Med 2006 Apr 13354(15)1578-8863 Lonn E et al Homocysteine lowering with olic acid and B vitamins invascular disease N Engl J Med 2006 Apr 13354(15)1567-7764 Zoungas S et al Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renalailure a multicenter randomized controlled trial J Am Coll Cardiol 2006 Mar
2147(6)1108-1665 Righetti M et al Homocysteine-lowering vitamin B treatment decreasescardiovascular events in hemodialysis patients Blood Puri 200624(4)379-8666 Spence JD et al Vitamin Intervention For Stroke Prevention trial an eicacy ana lysis Stroke 2005 Nov36(11)2404-967 Toole JF et al Lowering homocysteine in patients with ischemic stroketo prevent recurrent stroke myocardial inarction and death the VitaminIntervention or Stroke Prevention (VISP) randomized controlled trial JAMA 2004Feb 4291(5)565-7568 Liem A et al Secondary prevention with olic acid results o the Goesextension study Heart 2005 Sep91(9)1213-469 Liem AH et al Eicacy o olic acid when added to statin therapy in patientswith hypercholesterolemia ollowing acute myocardial inarction a randomised pilot trial Int J Cardiol 2004 Feb93(2-3)175-970 Wrone EM et al Randomized trial o olic acid or prevention o cardiovascular events in end-stage renal disease J Am Soc Nephrol 2004Feb 15(2)420-6
71 Mark SD et al Lowered risks o hypertension and cerebrovascular disease ater vitaminmineral supplementation the Linxian Nutrition Intervention Trial Am J Epidemiol 1996 Apr 1143(7)658-6472 Martiacute-Carvajal AJ et al Homocysteine lowering interventions or preventingcardiovascular events Cochrane Database Syst Rev 2009 Oct 7(4)CD00661273 Bazzano LA et al Eect o olic acid supplementation on risk o cardiovascular diseases a meta-analysis o randomized controlled trials JAMA 2006 Dec 13296(22)2720-674 Wang X et al Eicacy o olic acid supplementation in stroke prevention a met a-analysis Lancet 2007 Jun 2369(9576)1876-8275 SEARCH Study Collaborative Group et al Study o the eectiveness o additional reductions in cholesterol and homocysteine (SEARCH) characteristicso a randomized trial among 12064 myocardial inarction survivors Am Heart J 2007 Nov154(5)815-23 82376 Amritage J et al SEARCH Study Collaborative Group SEARCH (Study o the Eectiveness o Additional Reductions in Cholesterol and Homocysteine) randomized comparison o olic acid 2 mg plus vitamin b12 1 mg daily versus
placebo or 7 years in 12064 myocardial inarction survivors Circulation 2008Nov 118(22)2309-231777 Marcus J et al Homocysteine lowering and cardiovascular disease risk lost in translation Can J Cardiol 2007 Jul23(9)707-1078 Pietrzik K Opinion on the COCHRANE Review lsquorsquoHomocysteine-lowering interventions or preventing cardiovascular events European Nutraceutical As sociation website at httpwwwenaonlineorg79 Spence JD Perspective on the eicacy analysis o the Vitamin Intervention or Stro ke Prevention trial Clin Chem Lab Med 200745(12)1582-580 Ueland PM et al Homocysteine and olate status in an era o olic acidortiication balancing beneits risks and B-vitamins Clin Chem 2008May54(5)779-8181 Wald DS et al Folic acid homocysteine and cardiovascular disease judging causality in the ace o inconclusive trial evidence BMJ 2006 Nov 25333(7578)1114-782 Nainggolan L Folic acid modestly protects against cardiovascular eventsHea rtwire 2006 reproduced in Medscape web site wwwmedscapecom83 Bazzano LA Folic acid supplementation and cardiovascular disease the stateo t he art Am J Med Sci 2009 Jul338(1)48-984 Galan P et al The SUFOLOM3 Study a secondary prevention trial testingthe impact o supplementation with olate and B-vitamins andor Omega-3 PUFAon atal and non atal cardiovascular events design methods and participantscharacteristics Trials 2008 Jun 1093585 VITATOPS Trial Study Group et al VITATOPS the VITAmins TO prevent stroke trial rationale and design o a randomised trial o B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669)(ISRCTN74743444) Int J Stroke 2007 May2(2)144-50
892019 Arbor B Vitamins and Stroke Prevention
httpslidepdfcomreaderfullarbor-b-vitamins-and-stroke-prevention 45
Reerences1 Saacutenchez-Moreno C et al Stroke roles o B vitamins homocysteine and antioxidants Nutr Res Rev 2009 Jun22(1)49-67 2 McNulty H et al Homocysteine B-vitamins and CVD Proc Nutr Soc 2008May67(2)232-73 McNulty H et al Ribolavin lowers homocysteine in individuals homozygous or the MTHFR 677C-gtT polymorphism Circulation 2006 Jan 3113(1)74-80 4 Narang AP et al Homocysteine--risk actor or ischemic stroke Indian JPh ysiol Pharmacol 2009 Jan-Mar53(1)34-85 Dhamija RK et al Homocysteine and lipoprotein (a) correlation in ischemic stroke patients J Neurol Sci 2009 Jun 15281(1-2)64-8
6 Khan U et al Homocysteine and its relationship to stroke subtypes in a UK black population the south London ethnicity and stroke study Stroke 2008Nov39(11)2943-97 Yang LK et al Correlations between olate B12 homocysteine levels and radiological markers o neuropathology in elderly post-stroke patients J Am CollNutr 2007 Jun26(3)272-88 Homocysteine Studies Collaboration Homocysteine and risk o ischemic heartdi sease and stroke a meta-analysis JAMA 2002 Oct 23-30288(16)2015- 229 Wald DS et al Homocysteine and cardiovascular disease evidence oncausality rom a meta-analysis BMJ 2002 Nov 23325(7374)120210 Kelly PJ et al Homocysteine MTHFR 677C--gtT polymorphism and risk o ischemic stroke results o a meta-analysis Neurology 2002 Aug 2759(4)529-3611 Weng LC et al Is ischemic stroke risk related to olate status or other nutr ients correlated with olate intake Stroke 2008 Dec39(12)3152-812 Larsson SC et al Folate vitamin B6 vitamin B12 and methionine intakes and risk o stroke subtypes in male smokers Am J Epidemiol 2008 Apr 15167(8)954-61
13 Weikert C et al B vitamin plasma levels and the risk o ischemic stroke andtransient ischemic attack in a German cohort Stroke 2007 Nov38(11)2912-814 Van Guelpen B et al Folate vitamin B12 and risk o ischemic and hemorrhagic stroke a prospective nested case-reerent study o plasmaconcentrations and dietary intake Stroke 2005 Jul36(7)1426-3115 Pieters B et al Periventricular white matter lucencies relate to low vitaminB12 levels in patients with small vessel stroke Stroke 2009 May40(5)1623-616 He K et al Folate vitamin B6 and B12 intakes in relation to risk o stroke among men Stroke 2004 Jan35(1)169-7417 Kelly PJ et al Inlammation homocysteine and vitamin B6 status ater ischemic stroke Stroke 2004 Jan35(1)12-518 Robinson K et al Low circulating olate and vitamin B6 concentrations risk actors or stroke peripheral vascular disease and coronary artery diseaseEur opean COMAC Group Circulation 1998 Feb 1097(5)437-4319 Gariballa S et al Ribolavin status in acute ischaemic stroke Eur J Clin Nutr 2007 Oct61(10)1237-40 20 Ross RK et al Prospective evaluation o dietary and other predictors o atal
stro ke in Shanghai China Circulation 1997 Jul 196(1)50-5 21 Biswas A et al Homocystine levels polymorphisms and the risk o ischemic stroke in young Asian Indians J Stroke Cerebrovasc Dis 2009 Mar- Apr18(2)103-10 22 Saacutenchez-Mariacuten B et al [Prevalence o methylenetetrahydroolate reductaseC677T mutation among patients with acute ischemic cerebrovascular disease in Ara gon] An Med Interna 2006 Apr23(4)153-5 23 Panigrahi I et al Role o MTHFR C677T polymorphism in ischemic strokeNeu rol India 2006 Mar54(1)48-50 24 Cantu C et al Hyperhomocysteinemia low olate and vitamin B12concentrations and methylene tetrahydroolate reductase mutation in cerebralvenous thrombosis Stroke 2004 Aug35(8)1790-4 25 Lim PS et al Polymorphism in methylenetetrahydroolate reductase gene its impact on plasma homocysteine levels and carotid atherosclerosis in ESRD patients receiving hemodialysis Nephron 2001 Mar87(3)249-56 26 Demuth K et al Opposite eects o plasma homocysteine and the methylenetetrahydroolate reductase C677T mutation on carotid artery geometry in a symptomatic adults Arterioscler Thromb Vasc Biol 1998 Dec18(12)1838-43 27 Ho GY et al Methylenetetrahydroolate reductase polymorphisms and homocysteine-lowering eect o vitamin therapy in Singaporean stroke patientsStroke 2006 Feb37(2)456-60 28 Terwecoren A et al Ischemic stroke and hyperhomocysteinemia truth or myt h Acta Neurol Belg 2009 Sep109(3)181-8 29 Pezzini A et al Homocysteine and cerebral ischemia pathogenic andther apeutical implications Curr Med Chem 200714(3)249-6330 Hankey GJ et al Clinical useulness o plasma homocysteine in vascular dise ase Med J Aust 2004 Sep 20181(6)314-831 Stanger O et al DACH-LIGA homocystein (german austrian and swiss homocysteine society) consensus paper on the rational clinical use o homocysteine olic acid and B-vitamins in cardiovascular and thromboticdiseases guidelines and recommendations Clin Chem Lab Med 2003Nov 41(11)1392-40332 Herrmann W et al Hyperhomocysteinaemia a critical review o old and new
aspects Curr Drug Metab 2007 Jan8(1)17-3133 Ntaios GC et al Vitamins and stroke the homocysteine hypothesis still indou bt Neurologist 2008 Jan14(1)2-434 Lonn E Homocysteine in the prevention o ischemic heart disease stroke andvenous thromboembolism therapeutic target or just another distraction Curr Opin Hematol 2007 Sep14(5)481-735 Wierzbicki AS Homocysteine and cardiovascular disease a review o theevidence Diab Vasc Dis Res 2007 Jun4(2)143-50
Other potential limitations of the existing trial data
include any masking effect of concurrent treatment
(eg statins) or the Hcy metabolic situation beingdifferent in the RCTs on renal failure patients 77-79 Another possible issue is the baseline status of the
Hcy-vitamins and ability to absorb them For example
people living in areas with folate-fortified flour (higher
baseline status) or with B12
malabsorption may show
less protective effect from those supplements
74 79 80
What all of this might mean is that we have not as yet
narrowed down the population group in whom Hcy
lowering prevents stroke For example we lack trials
on patients with high Hcy who have not yet displayed
clinical atherosclerosis Others have argued (both
for stroke and heart disease) that the benefits of Hcy
lowering may take years to be seen and that we do
not have enough of that kind of long term data Or
that the effect of genetic polymorphism has not been
adequately taken into account or that benefit may
be confined to even higher risk patients (such as
atherosclerotic smokers) 81 82
In short given all these consideration and at least
one substantial trial having positive results there are
certainly those who do not believe we should rule
these treatments out just yet (eg 78-82 )
At the same time it would be fair to say that the
majority view is that despite the very strong
epidemiological data such a frankly disappointing
set of trial results means that current evidence simply
does not justify using these vitamins for stroke
prevention certainly not in a routine way (eg1 33 83 )
Whilst considering these different viewpoints
and maybe even whether it might be worth giving
supplements to prevent stroke on a lsquono harm in tryingrsquo
basis we should also think about their safety On the
whole the supplement regimes used in these trials havebeen considered safe (and cheap) interventions 28
There were two exceptions NORVIT reported a
rise of borderline statistical significance in non-
fatal myocardial infarction (but not in stroke) in the
vitamin group (OR=130 95 CI 100ndash168) 62
HOPE-2 found that more of the vitamin subjects werehospitalised for unstable angina (RR=124 95 CI
104-149) compared with placebo 63 In the absence
of confirmation of such increased risk from other
trials it is hard to know what significance to place
on this (There is also the question of whether folate
might sometimes promote cancer growth - a complex
subject that will be the topic of a later issue)
Two further large RCTs involving Hcy-vitamins and
stroke prevention are due to report in the next several
years the SUFOLOM3 study on some 2500 patients
who had CHD or stroke within the previous year 83 and
VITATOPS with a target of 8000 patients who had
recent transient ischaemic attack 84 The FAVORIT and
HOST trials may a lso offer some less direct information 77
This is definitely a `watch this spacersquo topic
892019 Arbor B Vitamins and Stroke Prevention
httpslidepdfcomreaderfullarbor-b-vitamins-and-stroke-prevention 55
Disclaimer copyright terms of use and subscribing
Your use o these Updates in any orm or ormat constitutes your agreement to our disclaimer and terms o use which can be ound on our web site atwwwnutritionupdatesorgsubterms_premphp You can also obtain the disclaimer and terms o use by emailing us at upTarborcomcom
copy Copyright Arbor Communications PTL 2010 All rights reserved This document may NOT be orwarded onto others without our written permission
I you want to receive the Clinical Nutrition Updates on an ongoing basis please register at wwwnutritionupdatesorgsub Or send a request email to
upDarborcomcom This is a FREE service to health proessionals and students Include details o your name email address country institution (i
relevant) and proessional background The Updates are available in English Spanish Portuguese Italian French Turkish Korean and Russian
36 Osanai T et al Novel pro-atherogenic molecule coupling actor 6 iselevated in patients with stroke a possible linkage to homocysteine Ann Med 201042(1)79-8637 Kumar M et al Homocysteine decreases blood low to the brain due tovascular resistance in carotid artery Neurochem Int 2008 Dec53(6-8)214-938 Stanger O et al Clinical use and rational management o homocysteine olic acid and B vitamins in cardiovascular and thrombotic diseases Z Kardiol 2004 Jun 93(6)439-5339 Guilland JC et al [Hyperhomocysteinemia an independent risk actor or a simple marker o vascular disease 1 Basic data] Pathol Biol (Paris) 2003
Mar51(2)101-10 40 Baptista AP et al Inlammation homocysteine and carotid intima-mediathickness Rev Port Cardiol 2008 Jan27(1)39-48 41 Sabaliauskene Z et al [Hyperhomocysteinemia in patients with atherosclerotic extracranial disease o the carotid artery] Klin Lab Diagn 2006 Jun (6)20-2 35 42 Wang H et al Serum level o homocysteine is correlated to carotid artery athe rosclerosis in Chinese with ischemic stroke Neurol Res 2006 Jan28(1)25-30 43 Silvestrini M et al Carotid wall thickness and stroke risk in patients with asymptomatic internal carotid stenosis Atherosclerosis 2010 Jan 4 Epub 44 Cobble M et al Carotid intima-media thickness knowledge and applicationto everyday practice Postgrad Med 2010 Jan122(1)10-8 45 Sahoo R et al Common carotid intima-media thickness in acute ischemic stro ke A case control study Neurol India 2009 Sep-Oct57(5)627-30 46 Ntaios G et al Homocysteine and carotid intima-media thickness in ischemic stro ke patients are not correlated Neuropsychiatr Dis Treat 2008 Apr4( 2)477-9 47 Held C et al Correlations between plasma homocysteine and olate
concentrations and carotid atherosclerosis in high-risk individuals baseline datarom the Homocysteine and Atherosclerosis Reduction Trial (HART) Vasc Med 2008 Nov13(4)245-53 48 Nanayakkara PW et al Eect o a treatment strategy consisting o pravastatinvitamin E and homocysteine lowering on carotid intima-media thicknessendothelial unction and renal unction in patients with mild to moderatechronic kidney disease results rom the Anti-Oxidant Therapy in Chronic RenalInsuiciency (ATIC) Study Arch Intern Med 2007 Jun 25167(12)1262-70 49 Fernaacutendez-Miranda C et al Eect o olic acid treatment on carotid intima- media thickness o patients with coronary disease Int J Cardiol 2007 Jun12118(3)345-950 Hodis HN et al High-dose B vitamin supplementation and progressiono subclinical atherosclerosis a randomized controlled trial Stroke 2009Mar 40(3)730-651 Vianna AC et al Uremic hyperhomocysteinemia a randomized trial o olate treatment or the prevention o cardiovascular events Hemodial Int 2007 Apr 11(2)210-6
52 Tungkasereerak P et al Eect o short-term olate and vitamin B supplementation on blood homocysteine level and carotid artery wall thickness inchronic hemodialysis patients J Med Assoc Thai 2006 Aug89(8)1187-9353 Till U et al Decrease o carotid intima-media thickness in patients at risk tocerebral ischemia ater supplementation with olic acid Vitamins B6 and B12 Atherosclerosis 2005 Jul181(1)131-554 van Dijk RA et al Long-term homocysteine-lowering treatment with olic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiness a 2-year randomized placebo-controlled trial Arterioscler Thromb VascBiol 2001 Dec21(12)2072-955 Alam MM et al Homocysteine reduces endothelial progenitor cells in stroke patients through apoptosis J Cereb Blood Flow Metab 2009 Jan29(1)157-6556 Hwang IK et al Folic acid deiciency increases delayed neuronal death DNAdamage platelet endothelial cell adhesion molecule-1 immunoreactivity and gliosis in the hippocampus ater transient cerebral ischemia J Neurosci Res 2008 Jul86(9)2003-1557 Huang GW et al [Eects o olic acid vitamin B(6) and vitamin B(12) on learning and memory unction in cerebral ischemia rats] Zhonghua Yu Fang Yi Xue Za Zhi 2007 May41(3)212-458 Doshi SN et al Folic acid improves endothelial unction in coronary artery disease via mechanisms largely independent o homocysteine loweringCirculation 2002 Jan 1105(1)22-659 Hoane MR et al Administration o ribolavin improves behavioral outcome and reduces edema ormation and glial ibrillary acidic protein expression ater trau matic brain injury J Neurotrauma 2005 Oct22(10)1112-2260 Ebbing M et al Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins ater coronary angiography a randomizedcontrolled trial JAMA 2008 Aug 20300(7)795-804
61 Albert CM et al Eect o olic acid and B vitamins on risk o cardiovascular events and total mortality among women at high risk or cardiovascular disease a randomized trial JAMA 2008 May 7299(17)2027-3662 Boslashnaa KH et al Homocysteine lowering and cardiovascular events ater acute myocardial inarction N Engl J Med 2006 Apr 13354(15)1578-8863 Lonn E et al Homocysteine lowering with olic acid and B vitamins invascular disease N Engl J Med 2006 Apr 13354(15)1567-7764 Zoungas S et al Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renalailure a multicenter randomized controlled trial J Am Coll Cardiol 2006 Mar
2147(6)1108-1665 Righetti M et al Homocysteine-lowering vitamin B treatment decreasescardiovascular events in hemodialysis patients Blood Puri 200624(4)379-8666 Spence JD et al Vitamin Intervention For Stroke Prevention trial an eicacy ana lysis Stroke 2005 Nov36(11)2404-967 Toole JF et al Lowering homocysteine in patients with ischemic stroketo prevent recurrent stroke myocardial inarction and death the VitaminIntervention or Stroke Prevention (VISP) randomized controlled trial JAMA 2004Feb 4291(5)565-7568 Liem A et al Secondary prevention with olic acid results o the Goesextension study Heart 2005 Sep91(9)1213-469 Liem AH et al Eicacy o olic acid when added to statin therapy in patientswith hypercholesterolemia ollowing acute myocardial inarction a randomised pilot trial Int J Cardiol 2004 Feb93(2-3)175-970 Wrone EM et al Randomized trial o olic acid or prevention o cardiovascular events in end-stage renal disease J Am Soc Nephrol 2004Feb 15(2)420-6
71 Mark SD et al Lowered risks o hypertension and cerebrovascular disease ater vitaminmineral supplementation the Linxian Nutrition Intervention Trial Am J Epidemiol 1996 Apr 1143(7)658-6472 Martiacute-Carvajal AJ et al Homocysteine lowering interventions or preventingcardiovascular events Cochrane Database Syst Rev 2009 Oct 7(4)CD00661273 Bazzano LA et al Eect o olic acid supplementation on risk o cardiovascular diseases a meta-analysis o randomized controlled trials JAMA 2006 Dec 13296(22)2720-674 Wang X et al Eicacy o olic acid supplementation in stroke prevention a met a-analysis Lancet 2007 Jun 2369(9576)1876-8275 SEARCH Study Collaborative Group et al Study o the eectiveness o additional reductions in cholesterol and homocysteine (SEARCH) characteristicso a randomized trial among 12064 myocardial inarction survivors Am Heart J 2007 Nov154(5)815-23 82376 Amritage J et al SEARCH Study Collaborative Group SEARCH (Study o the Eectiveness o Additional Reductions in Cholesterol and Homocysteine) randomized comparison o olic acid 2 mg plus vitamin b12 1 mg daily versus
placebo or 7 years in 12064 myocardial inarction survivors Circulation 2008Nov 118(22)2309-231777 Marcus J et al Homocysteine lowering and cardiovascular disease risk lost in translation Can J Cardiol 2007 Jul23(9)707-1078 Pietrzik K Opinion on the COCHRANE Review lsquorsquoHomocysteine-lowering interventions or preventing cardiovascular events European Nutraceutical As sociation website at httpwwwenaonlineorg79 Spence JD Perspective on the eicacy analysis o the Vitamin Intervention or Stro ke Prevention trial Clin Chem Lab Med 200745(12)1582-580 Ueland PM et al Homocysteine and olate status in an era o olic acidortiication balancing beneits risks and B-vitamins Clin Chem 2008May54(5)779-8181 Wald DS et al Folic acid homocysteine and cardiovascular disease judging causality in the ace o inconclusive trial evidence BMJ 2006 Nov 25333(7578)1114-782 Nainggolan L Folic acid modestly protects against cardiovascular eventsHea rtwire 2006 reproduced in Medscape web site wwwmedscapecom83 Bazzano LA Folic acid supplementation and cardiovascular disease the stateo t he art Am J Med Sci 2009 Jul338(1)48-984 Galan P et al The SUFOLOM3 Study a secondary prevention trial testingthe impact o supplementation with olate and B-vitamins andor Omega-3 PUFAon atal and non atal cardiovascular events design methods and participantscharacteristics Trials 2008 Jun 1093585 VITATOPS Trial Study Group et al VITATOPS the VITAmins TO prevent stroke trial rationale and design o a randomised trial o B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669)(ISRCTN74743444) Int J Stroke 2007 May2(2)144-50
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36 Osanai T et al Novel pro-atherogenic molecule coupling actor 6 iselevated in patients with stroke a possible linkage to homocysteine Ann Med 201042(1)79-8637 Kumar M et al Homocysteine decreases blood low to the brain due tovascular resistance in carotid artery Neurochem Int 2008 Dec53(6-8)214-938 Stanger O et al Clinical use and rational management o homocysteine olic acid and B vitamins in cardiovascular and thrombotic diseases Z Kardiol 2004 Jun 93(6)439-5339 Guilland JC et al [Hyperhomocysteinemia an independent risk actor or a simple marker o vascular disease 1 Basic data] Pathol Biol (Paris) 2003
Mar51(2)101-10 40 Baptista AP et al Inlammation homocysteine and carotid intima-mediathickness Rev Port Cardiol 2008 Jan27(1)39-48 41 Sabaliauskene Z et al [Hyperhomocysteinemia in patients with atherosclerotic extracranial disease o the carotid artery] Klin Lab Diagn 2006 Jun (6)20-2 35 42 Wang H et al Serum level o homocysteine is correlated to carotid artery athe rosclerosis in Chinese with ischemic stroke Neurol Res 2006 Jan28(1)25-30 43 Silvestrini M et al Carotid wall thickness and stroke risk in patients with asymptomatic internal carotid stenosis Atherosclerosis 2010 Jan 4 Epub 44 Cobble M et al Carotid intima-media thickness knowledge and applicationto everyday practice Postgrad Med 2010 Jan122(1)10-8 45 Sahoo R et al Common carotid intima-media thickness in acute ischemic stro ke A case control study Neurol India 2009 Sep-Oct57(5)627-30 46 Ntaios G et al Homocysteine and carotid intima-media thickness in ischemic stro ke patients are not correlated Neuropsychiatr Dis Treat 2008 Apr4( 2)477-9 47 Held C et al Correlations between plasma homocysteine and olate
concentrations and carotid atherosclerosis in high-risk individuals baseline datarom the Homocysteine and Atherosclerosis Reduction Trial (HART) Vasc Med 2008 Nov13(4)245-53 48 Nanayakkara PW et al Eect o a treatment strategy consisting o pravastatinvitamin E and homocysteine lowering on carotid intima-media thicknessendothelial unction and renal unction in patients with mild to moderatechronic kidney disease results rom the Anti-Oxidant Therapy in Chronic RenalInsuiciency (ATIC) Study Arch Intern Med 2007 Jun 25167(12)1262-70 49 Fernaacutendez-Miranda C et al Eect o olic acid treatment on carotid intima- media thickness o patients with coronary disease Int J Cardiol 2007 Jun12118(3)345-950 Hodis HN et al High-dose B vitamin supplementation and progressiono subclinical atherosclerosis a randomized controlled trial Stroke 2009Mar 40(3)730-651 Vianna AC et al Uremic hyperhomocysteinemia a randomized trial o olate treatment or the prevention o cardiovascular events Hemodial Int 2007 Apr 11(2)210-6
52 Tungkasereerak P et al Eect o short-term olate and vitamin B supplementation on blood homocysteine level and carotid artery wall thickness inchronic hemodialysis patients J Med Assoc Thai 2006 Aug89(8)1187-9353 Till U et al Decrease o carotid intima-media thickness in patients at risk tocerebral ischemia ater supplementation with olic acid Vitamins B6 and B12 Atherosclerosis 2005 Jul181(1)131-554 van Dijk RA et al Long-term homocysteine-lowering treatment with olic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiness a 2-year randomized placebo-controlled trial Arterioscler Thromb VascBiol 2001 Dec21(12)2072-955 Alam MM et al Homocysteine reduces endothelial progenitor cells in stroke patients through apoptosis J Cereb Blood Flow Metab 2009 Jan29(1)157-6556 Hwang IK et al Folic acid deiciency increases delayed neuronal death DNAdamage platelet endothelial cell adhesion molecule-1 immunoreactivity and gliosis in the hippocampus ater transient cerebral ischemia J Neurosci Res 2008 Jul86(9)2003-1557 Huang GW et al [Eects o olic acid vitamin B(6) and vitamin B(12) on learning and memory unction in cerebral ischemia rats] Zhonghua Yu Fang Yi Xue Za Zhi 2007 May41(3)212-458 Doshi SN et al Folic acid improves endothelial unction in coronary artery disease via mechanisms largely independent o homocysteine loweringCirculation 2002 Jan 1105(1)22-659 Hoane MR et al Administration o ribolavin improves behavioral outcome and reduces edema ormation and glial ibrillary acidic protein expression ater trau matic brain injury J Neurotrauma 2005 Oct22(10)1112-2260 Ebbing M et al Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins ater coronary angiography a randomizedcontrolled trial JAMA 2008 Aug 20300(7)795-804
61 Albert CM et al Eect o olic acid and B vitamins on risk o cardiovascular events and total mortality among women at high risk or cardiovascular disease a randomized trial JAMA 2008 May 7299(17)2027-3662 Boslashnaa KH et al Homocysteine lowering and cardiovascular events ater acute myocardial inarction N Engl J Med 2006 Apr 13354(15)1578-8863 Lonn E et al Homocysteine lowering with olic acid and B vitamins invascular disease N Engl J Med 2006 Apr 13354(15)1567-7764 Zoungas S et al Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renalailure a multicenter randomized controlled trial J Am Coll Cardiol 2006 Mar
2147(6)1108-1665 Righetti M et al Homocysteine-lowering vitamin B treatment decreasescardiovascular events in hemodialysis patients Blood Puri 200624(4)379-8666 Spence JD et al Vitamin Intervention For Stroke Prevention trial an eicacy ana lysis Stroke 2005 Nov36(11)2404-967 Toole JF et al Lowering homocysteine in patients with ischemic stroketo prevent recurrent stroke myocardial inarction and death the VitaminIntervention or Stroke Prevention (VISP) randomized controlled trial JAMA 2004Feb 4291(5)565-7568 Liem A et al Secondary prevention with olic acid results o the Goesextension study Heart 2005 Sep91(9)1213-469 Liem AH et al Eicacy o olic acid when added to statin therapy in patientswith hypercholesterolemia ollowing acute myocardial inarction a randomised pilot trial Int J Cardiol 2004 Feb93(2-3)175-970 Wrone EM et al Randomized trial o olic acid or prevention o cardiovascular events in end-stage renal disease J Am Soc Nephrol 2004Feb 15(2)420-6
71 Mark SD et al Lowered risks o hypertension and cerebrovascular disease ater vitaminmineral supplementation the Linxian Nutrition Intervention Trial Am J Epidemiol 1996 Apr 1143(7)658-6472 Martiacute-Carvajal AJ et al Homocysteine lowering interventions or preventingcardiovascular events Cochrane Database Syst Rev 2009 Oct 7(4)CD00661273 Bazzano LA et al Eect o olic acid supplementation on risk o cardiovascular diseases a meta-analysis o randomized controlled trials JAMA 2006 Dec 13296(22)2720-674 Wang X et al Eicacy o olic acid supplementation in stroke prevention a met a-analysis Lancet 2007 Jun 2369(9576)1876-8275 SEARCH Study Collaborative Group et al Study o the eectiveness o additional reductions in cholesterol and homocysteine (SEARCH) characteristicso a randomized trial among 12064 myocardial inarction survivors Am Heart J 2007 Nov154(5)815-23 82376 Amritage J et al SEARCH Study Collaborative Group SEARCH (Study o the Eectiveness o Additional Reductions in Cholesterol and Homocysteine) randomized comparison o olic acid 2 mg plus vitamin b12 1 mg daily versus
placebo or 7 years in 12064 myocardial inarction survivors Circulation 2008Nov 118(22)2309-231777 Marcus J et al Homocysteine lowering and cardiovascular disease risk lost in translation Can J Cardiol 2007 Jul23(9)707-1078 Pietrzik K Opinion on the COCHRANE Review lsquorsquoHomocysteine-lowering interventions or preventing cardiovascular events European Nutraceutical As sociation website at httpwwwenaonlineorg79 Spence JD Perspective on the eicacy analysis o the Vitamin Intervention or Stro ke Prevention trial Clin Chem Lab Med 200745(12)1582-580 Ueland PM et al Homocysteine and olate status in an era o olic acidortiication balancing beneits risks and B-vitamins Clin Chem 2008May54(5)779-8181 Wald DS et al Folic acid homocysteine and cardiovascular disease judging causality in the ace o inconclusive trial evidence BMJ 2006 Nov 25333(7578)1114-782 Nainggolan L Folic acid modestly protects against cardiovascular eventsHea rtwire 2006 reproduced in Medscape web site wwwmedscapecom83 Bazzano LA Folic acid supplementation and cardiovascular disease the stateo t he art Am J Med Sci 2009 Jul338(1)48-984 Galan P et al The SUFOLOM3 Study a secondary prevention trial testingthe impact o supplementation with olate and B-vitamins andor Omega-3 PUFAon atal and non atal cardiovascular events design methods and participantscharacteristics Trials 2008 Jun 1093585 VITATOPS Trial Study Group et al VITATOPS the VITAmins TO prevent stroke trial rationale and design o a randomised trial o B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669)(ISRCTN74743444) Int J Stroke 2007 May2(2)144-50