Issue 318 In a nutshell

The association between elevated Hcy, the B vitamins linked to it, and stroke incidence and severity appears strong. So far, a dozen RCTs, (almost all in patients with significant atherosclerosis), have tried to prevent stroke by reducing Hcy through various combinations of folate, B12 and B6. In only one trial did this clearly succeed.

Stroke & prevention - B vitamins
Arbor Clinical Nutrition Updates 2010 (Mar);318:1-5 ISSN 1446-5450

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Study 1: B vitamins and stroke severity A new study from Turkey looked at vitamin B12 and folate levels in relation to outcome of acute stroke. Subjects and method: Longitudinal observational study of 109 patients with acute stroke, (¾ were ischaemic, ¼ 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 significantly lower in those who subsequently died within 7 days than in those who survived, both for vitamin B12 (186 vs 278 pmol/L, p=0.001) and folate (17.6 vs 21.1 pmol/L, p=0.003). A similar relationship was seen between the baseline levels of the two vitamins and worse initial Glasgow coma scale.
Ref. Bayir A. et al. Acute-phase vitamin B12 and folic acid levels in patients with ischemic and hemorrhagic stroke: is there a relationship with prognosis? Neurol Res. 2010 Mar;32(2):115-118.

Graph 1: Hazard ratio for stroke, active vs placebo
(Study 2)

1.4 1.2 1.0 0.8 0.6 0.4 0.2 0
0.75 0.57 0.66 0.72 0.91 0.95

Any with initial Hcy stroke
>13.8 ≤ 13.8

Non- Fatal fatal

Functl. depend.

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 vitaminsupplemented 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

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.

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 metaanalysis 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.


(DNA, RBC etc.)

Nucleotide synthesis

Vit.B12 THF

Methyl donation
(nerves DNA etc.)

SAM (S-Adenosylmethionine)

Methionine cycle

Methionine synthase

Folate cycle
5-methyl THF




Homocysteine Vit.B6

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 metaanalyses 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 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 found a 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 nonsignificant trend to being for non-fatal strokes and particularly 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 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 hand, results from the even more recently completed SEARCH trial of 12,064 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 (i.e. primary prevention, which was true of all trials bar one), in those whose treatment lasted more than 3 years and which successfully reduced their Hcy levels. On the other hand, Wang’s analysis was too early to include the 2 RCT results published in 2008 (n=8,532), both lasting over 3 years but with negative results 60, 61.

Graph 2: RR for stroke: RCTs of Hcy lowering vitamin supplements vs control

# meta-analyses trial x1 x2 incl. in: x3 0.85 1.14 0.88 0.76 0.45 0.55 1.04 0.65 3.06 1.17 0.63



WAFACS 61 5,442 NORVIT 62 HOPE-2 63 ASFAST 64 Haemodialysis 65 VISP 66, 67 GOES 68 3,749 5,522 315 88 3,680 593

FOLARDA 69 283 End stage renal 70 LINXIAN 71 510 3,318

Cochrane 72 Bazzano 73 Wang 74 Overall Duration > 36/12 Hcy reduc > 20% No stroke history 0.0

N= 18,086 13,806 16,841

0.89 20% 0.86

0.71 0.77 0.75

9,748 9,018 12,165



0.75 1.0



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, hardly comparable 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.

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 nonfatal 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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