Elsevier

The Lancet Neurology

Volume 16, Issue 9, September 2017, Pages 750-760
The Lancet Neurology

Personal View
B vitamins in stroke prevention: time to reconsider

https://doi.org/10.1016/S1474-4422(17)30180-1Get rights and content

Summary

B vitamin therapy lowers plasma total homocysteine concentrations, and might be a beneficial intervention for stroke prevention; however, cyanocobalamin (a form of vitamin B12) can accelerate decline in renal function and increase the risk of cardiovascular events in patients with impaired renal function. Although early trials did not show benefit in reduction of stroke, these results might have been due to harm in participants with impaired renal function. In patients with diabetic nephropathy, cyanocobalamin is harmful, whereas B vitamins appear to reduce cardiovascular events in study participants with normal renal function. Our meta-analysis of individual patient data from two large trials of B vitamin therapy (VISP and VITATOPS) indicates that patients with impaired renal function who are exposed to high-dose cyanocobalamin do not benefit from therapy with B vitamins for the prevention of stroke (risk ratio 1·04, 95% CI 0·84–1·27), however, patients with normal renal function who are not exposed to high-dose cyanocobalamin benefit significantly from this treatment (0.78, 0·67–0·90; interaction p=0·03). The potential benefits of B vitamin therapy with folic acid and methylcobalamin or hydroxycobalamin, instead of cyanocobalamin, to lower homocysteine concentrations in people at high risk of stroke warrant further investigation.

Introduction

Stroke is an important cause of death and a leading cause of disability worldwide; however, it is also a preventable condition. Epidemiological evidence and Mendelian randomisation studies indicate that high homocysteine concentrations in the blood are a risk factor for stroke. Some clinical trials of B vitamins to lower homocysteine concentrations have shown a reduction in stroke incidence, but not a reduction in the incidence of myocardial infarction; whereas other studies have shown no benefit of this intervention. After the report of findings from the VISP trial,1 the NORVIT trial,2 and the HOPE-2 trial,3 most physicians consider that therapy with B vitamins is not useful. However, reports from the CSPPT study published in 20154 and 20165, 6 have shed new light on this controversial topic.

The term folate therapy has been used to refer collectively to all vitamin therapies that lower plasma homocysteine concentrations; however, several nutrients are involved in the metabolism of homocysteine. Folate, cobalamin, and betaine are all involved in remethylation of homocysteine to methionine, whereas pyridoxine (vitamin B6) is required for trans-sulfuration to cystathionine (figure 1).7

Total homocysteine, which is composed of homocysteine, its dimer homocystine, and mixed cysteine-homocysteine disulfide, is the biochemical compound usually assessed in plasma.8 Studies have investigated various combinations of folic acid, cyanocobalamin (vitamin B12) and pyridoxine for the prevention of stroke. The accumulation of cyanide in renal failure9 might interfere with the decyanation of cyanocobalamin, which is an important metabolic process for the activation of cobalamin.10

In this Personal View, we review the evidence on vitamin B supplementation and risk of stroke from clinical trials, and propose that the reason why early trials did not show a reduction in stroke incidence was because of the harmful effects of cyanocobalamin in participants with renal impairment. The adverse effects of cyanocobalamin might have obscured the benefit of B vitamins observed in participants with normal renal function in these early trials.

Section snippets

Epidemiological evidence

Early observations in patients with homocystinuria (a metabolic disease caused by an inherited deficiency in cystathionine synthase), who have high concentrations of total homocysteine in blood, led McCully11 to propose that high total homocysteine concentrations contribute to thrombosis and vascular disease. Subsequently, less elevated concentrations of total homocysteine were also found to increase the risk of vascular disease. In 1986, Boers and colleagues12 reported that about 40% of

Evidence from clinical trials

In the VISP trial,1 which included 3680 participants with ischaemic stroke in the USA, investigators reported no significant reduction in the primary outcome (recurrent stroke) or the secondary outcome (coronary heart disease and cardiovascular death) following daily treatment over a 2 year period with 25 mg folic acid, 25 mg pyridoxine, and 400 μg cyanocobalamin.1 A caveat of the VISP trial was that participants with low concentrations of serum cyanocobalamin at baseline received injections of

Low folate consumption

Populations in which folate consumption is low might benefit from vitamin B supplementation. A genetic analysis and a meta-analysis2 of randomised controlled trials suggest that folate status modifies the association between total homocysteine, the MTHFR 677C→T polymorphism, and risk of stroke. Evidence from regions with established policies of population folate supplementation, such as the USA, suggests that lowering of homocysteine concentrations is of little or no benefit for the prevention

B vitamins might be harmful in people with impaired renal function

Patients with kidney disease accounted for a considerable proportion of participants included in the VISP1 and NORVIT2 clinical trials of B vitamins for vascular prevention, because many were elderly individuals, and increasing age is associated with declining renal function (appendix).

A meta-analysis39 of 11 randomised controlled trials of B vitamin therapy in 10 951 patients with chronic kidney disease (n=4389), end stage kidney disease (n=2452), and functioning kidney transplants (n=4110)

Meta-analysis

Results from several meta-analyses30, 31, 36, 49 suggest that B vitamin therapy to lower homocysteine concentration is associated with a reduced incidence of stroke.

Figure 4, Figure 5 show the results of our meta-analysis conducted for the purpose of this Personal View, which conformed to the Quality of Reporting of Meta-analyses guidelines.62 For this analysis, we included individual patient data from the VISP1 and VITATOPS37 trials to ensure that participants can be separated into two groups:

Risk of stroke versus risk of myocardial infarction

Although some studies have reported a reduction of coronary restenosis63 and improved survival (free of a composite event that included revascularisation) after percutaneous coronary intervention,64 most studies have shown no reduction in the incidence of coronary events after B vitamin therapy to lower homocysteine concentrations. Lowering of total homocysteine concentrations might preferentially reduce stroke incidence, compared with myocardial infarction, because thromboembolism and small

Conclusions and future directions

The evidence covered in this Personal View is summarised in the panel. The high burden of stroke is expected to increase because of the ageing of the population, the decline in renal function associated with ageing, the high prevalence of metabolic vitamin B12 deficiency in elderly individuals,79 the very high prevalence of elevated concentrations of total homocysteine (in about 40% of elderly patients presenting with stroke or transient ischaemic attack80), the quadrupling of stroke risk in

Search strategy and selection criteria

We searched MEDLINE, PubMed, and the Cochrane Library, for articles published between January, 1966, and December, 2016, using the MESH terms “cardiovascular disease”, “cerebrovascular accident”, “cerebrovascular disease”, “stroke” and “folic acid”, “folate”, “multivitamin”, “vitamin”, “chronic kidney disease”, “end-stage renal disease”, “advanced chronic kidney disease”, and “dialysis”. We also did manual searches of bibliographies of all relevant trials and review articles. The search was

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