Issue 318 Stroke & prevention - B vitamins

In a nutshell Arbor Clinical Nutrition Updates 2010 (Mar);318:1-5 ISSN 1446-5450

The association between

elevated Hcy, the B vitamins Premium edition
linked to it, and stroke incidence
and severity appears strong. This issue is for the personal use of Premium subscribers only
(except where being used within the terms of an institutional subscription).
So far, a dozen RCTs, (almost Previous issues
all in patients with significant Premium subscribers may obtain all past issues of the Updates by logging
atherosclerosis), have tried to into our web site at www.nutritionupdates.org.
prevent stroke by reducing Hcy
through various combinations
of folate, B12 and B6. In only one
trial did this clearly succeed.

NUTRITION RESEARCH REVIEW

Study 1: B vitamins and stroke severity Graph 1: Hazard ratio for stroke, active vs placebo
A new study from Turkey looked at vitamin B12 and (Study 2)
folate levels in relation to outcome of acute stroke.
HR
Subjects and method: Longitudinal observational
1.4
study of 109 patients with acute stroke, (¾ were
ischaemic, ¼ haemorrhagic. Baseline vitamin levels 1.2
were compared with initial clinical stroke severity 1.0
(Glasgow coma scale) and hospital mortality at 7 days.
0.8

Results: The mean initial vitamin levels were each 0.6

significantly lower in those who subsequently died 0.4
within 7 days than in those who survived, both for
0.2
vitamin B12 (186 vs 278 pmol/L, p=0.001) and folate 0.75 0.57 0.66 0.72 0.91 0.95
(17.6 vs 21.1 pmol/L, p=0.003). A similar relationship 0
was seen between the baseline levels of the two Any with initial Non- Fatal Functl.
vitamins and worse initial Glasgow coma scale. stroke Hcy fatal depend.
>13.8 ≤ 13.8
Ref. Bayir A. et al. Acute-phase vitamin B12 and folic acid levels in patients with (µmol/L)
ischemic and hemorrhagic stroke: is there a relationship with prognosis? Neurol
Res. 2010 Mar;32(2):115-118.

Study 2: Is there any HOPE for stroke?
A new analysis of the HOPE-2 trial focused on the
stroke outcomes, including severity.
Subjects and method: Multi-national RCT on 5,522
patients with known CVD, randomised to receive either
placebo or supplements (folic acid 2.5 mg, vitamin
B6 50 mg, vitamin B12 1,000 µg) designed to lower
homocysteine (Hcy) levels, daily for 5 years.
Results: Compared with placebo, the vitamin-
supplemented group had 25% fewer strokes, non-fatal
ones in particular. Amongst those who had strokes,
the severity (as judged by neurological deficit at 24 hrs
or functional dependence at 7 days) was not improved
by supplementation. See Graph.
Ref. Saposnik G. et al. Homocysteine-lowering therapy and stroke risk, severity, and
disability: additional findings from the HOPE 2 trial. Stroke. 2009 Apr;40(4):1365-72.
Study 3: B vitamins and carotid arterial function
A recent Australian trial tested the impact of B vitamin
supplements on carotid arteries and combined this
with a meta-analysis of previous similar RCTs.
Subjects and method: 162 patients with previous
stroke (from the VITATOPS trial) randomised to receive
either placebo or a B vitamin supplement (folic acid 2
mg, vitamin B6 25 mg, vitamin B12 500 µg) for a mean
of 3.9 yrs. Carotid intima-medial thickness (CIMT) and
brachial flow-mediated dilation (FMD) were measured.
In addition a meta-analysis was conducted on this
trial combined with a further 6 previous RCTs on CIMT
(n=768, no other trials on stroke patients) and 20 other
RCTs on FMD (n=1,282, only one other trial on stroke
patients).
Results: There was no significant change in CIMT or
FMD in their own trial. The meta-analysis showed a
COMMENTARY
The connection between homocysteine (Hcy) and
stroke is one aspect of the broader and controversial
`Hcy hypothesis’ - 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-vitamins’ 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 15.7) 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=9.8) 7.
Three meta-analyses (curiously, each published in
2002) confirmed this association. One included 30
observational studies involving 1,113 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=1.59 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 14
studies involving 1,769 stroke cases) was 1.79 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 (e.g. 7, 11-14), somewhat fewer reports of lower
vitamin B12 (e.g. 13, 15, 16) and much fewer of lower
vitamin B6 (e.g. 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 on
Hcy 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.
decrease in CIMT (0.10 mm, 95% CI: 0.01-0.20 mm)
and increase in FMD (by 1.4%, 0.7-2.1%), mainly seen
in trials of less than 9 weeks duration.
Ref. Potter K. et al. The effect of long-term homocysteine-lowering on carotid
intima-media thickness and flow-mediated vasodilation in stroke patients: a
randomized controlled trial and meta-analysis. BMC Cardiovasc Disord. 2008 Sep
20;8:24.
Methionine Nucleotide
synthesis
(DNA, RBC etc.)
Vit.B12
THF
Methionine Methionine MTHFR
synthase
Folate
Methyl
SAM cycle
cycle
NADPH
(S-Adenosyl-
donation
(nerves
methionine) Vit.B2
DNA etc.)
5-methyl
THF NADP+
Homocysteine
Vit.B6
Cysteine
Excreted or converted
to other a/a
Super simplified Hcy biochemistry lesson
Methyl donation and nucleotide synthesis are both vital
functions served by the conversion of methionine to, and
regeneration from, Hcy, involving the folate cycle. Vitamin
deficiency can lead to Hcy accumulation.
A meta-analysis in 2002 of 19 studies reported the OR
for (ischaemic) stroke in the TT genotype to be 1.23 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 that
such 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 the
vitamins 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 (e.g. 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 have
preferred 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,
atherosclerosis, thrombogenesis, hypertension and Graph 2: RR for stroke: RCTs of Hcy lowering
impaired cerebro-arterial function, a good deal of vitamin supplements vs control
which is contributed to by oxidative stress 29, 30, 36-39.
RCTs
For example, a solid body of work shows the # meta-analyses trial
relationship between Hcy and carotid intima-media incl. in: x1 x2 x3
thickness (CIMT) 40-42, a measure of atherosclerosis N=
generally but also specifically related to stroke 0.85
WENBIT 60 3,090
risk 43-45. Whilst not all observational data has found
a strong connection 46, 47, a number of RCTs have 1.14
WAFACS 61 5,442
demonstrated improved CIMT after elevated Hcy was
0.88
lowered through vitamin supplements 48-53, though not NORVIT 62 3,749
all have done so 54. New Study 3 did not demonstrate 0.76
this, but when its data was added to other trial results HOPE-2 63 5,522
in meta-analysis, this conclusion was supported. 0.45
ASFAST 64 315
Another interesting light on mechanism comes from a Haemo- 0.55
88
new Canadian study which showed that excess Hcy dialysis 65
1.04
can inhibit the expected migration of progenitor cells VISP 66, 67 3,680
from bone marrow to repair vascular endothelium 0.65
damaged in stroke patients 55. GOES 68 593
3.06
Mechanisms involving the Hcy-vitamins which do FOLARDA 69 283
not involve Hcy are less clear, although some animal End stage 1.17
510
evidence suggests folate may have some such renal 70
role 56, 57, including in endothelial function 58, and 0.63
LINXIAN 71 3,318
perhaps riboflavin in traumatic brain injury 59.
Meta-analyses
This brings us to the third and most important N= 0.89
question: can any damage caused by excess Hcy Cochrane 72 18,086 20%
be corrected by supplementation? New Study 2 is a
fresh analysis of the HOPE-2 trial, showing that the 0.86
25% protection against stroke incidence had a non- Bazzano 73 13,806
significant trend to being for non-fatal strokes and
particularly in those subjects with higher baseline Hcy. Wang 74 16,841
0.82
Overall
HOPE-2 is best seen in the context of other RCTs that
have looked at this question. Eleven have published Duration 0.71
9,748
their results so far 60-71. Various combinations and > 36/12
permutations of these eleven form the basis of no less Hcy reduc 0.77
9,018
than three separate meta-analyses 72-74. That these > 20%
meta-analyses did not reach complete consensus is No stroke 0.75
12,165
perhaps not surprising, bearing in mind that they did history
not include all the same data - see Graph 2.
0.0 0.25 0.50 0.75 1.0 1.25 1.5
Looking at that Graph, it is hard to find strong support
for the idea that giving vitamins to reduce Hcy
prevents stroke. Although 7/11 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 Some potential limitations of these trial data have been
hand, results from the even more recently completed raised. One is that these supplements in the doses
SEARCH trial of 12,064 heart attack survivors 75 (as yet used would be ineffective, or the effect too weak to be
unpublished) failed to show any stroke prevention 76. detected with the sample sizes tested, in people with
the kind of advanced atherosclerotic disease that was
Some might take comfort from the sub-grouping true of the subjects in all these trials except one 77.
data in the Wang meta-analysis 74, which showed a Let alone in patients who recently had a stroke, which
protective effect in patients without a stroke history was the basis of the VISP trial (included in all three
(i.e. primary prevention, which was true of all trials bar meta-analyses) - that is secondary prevention, hardly
one), in those whose treatment lasted more than 3 years comparable with the other RCTs. Moreover, VISP
and which successfully reduced their Hcy levels. compared high dose Hcy-vitamins not with placebo
On the other hand, Wang’s analysis was too early to but with low dose. And control subjects in WAFACS
include the 2 RCT results published in 2008 (n=8,532), were allowed to take multivitamin supplements up to
both lasting over 3 years but with negative results 60, 61. RDA level 61.
Other potential limitations of the existing trial data
include any masking effect of concurrent treatment
(e.g. statins), or the Hcy metabolic situation being
different 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 (e.g. 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, (e.g.1, 33, 83).
Whilst considering these different viewpoints,
and maybe even whether it might be worth giving
supplements to prevent stroke on a ‘no harm in trying’
basis, we should also think about their safety. On the
whole, the supplement regimes used in these trials have
been 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=1.30, 95% CI: 1.00–1.68) 62.
HOPE‑2 found that more of the vitamin subjects were
hospitalised for unstable angina (RR=1.24; 95% CI:
1.04-1.49), 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 SU.FOL.OM3 study on some 2,500 patients
who had CHD or stroke within the previous year 83, and
VITATOPS, with a target of 8,000 patients who had
recent transient ischaemic attack 84. The FAVORIT and
HOST trials may also offer some less direct information 77.
This is definitely a `watch this space’ topic.
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