Table 2.

Summary of the evidence supporting B vitamins for stroke prevention

VISP[10] including all patients showed no benefit, nor did NORVIT[58]—both older populations with poorer renal function than in later major trials, receiving cyanocobalamin. In NORVIT, there was an increased risk of stroke among persons receiving cyanocobalamin.

In HOPE-2[59] (younger healthier population with better renal function than in NORVIT and VISP), B vitamins reduced the risk of stroke by 23%.

In SuFolOM3[60] (younger participants than in the other trials, with the best renal function of the studies and only 20 μg of cyanocobalamin), B vitamins reduced stroke by 43%.

In the VISP subgroup analysis[61] excluding patients with eGFR <46.18 and those who got B12 shots, a 34% reduction in the composite outcome of stroke/MI/vascular death was observed, comparing high-dose vitamin in patients with good vitamin B12 absorption vs. low-dose vitamin in patients with poor vitamin B12 absorption (baseline vitamin B12 below the median).

B vitamins including 1000 μg of cyanocobalamin were harmful in patients with diabetic nephropathy (DIVINe study),[62] accelerating decline in renal function and doubling cardiovascular events.

In VITATOPS, B vitamins with only 400 μg of cyanocobalamin were not beneficial in diabetics with eGFR <50 (HR = 0.88; 95% CI = 0.59,1.32; P= 0.54) but were beneficial in patients with eGFR >50 (HR = 0.82; 95% CI = 0.68, 0.98; P = 0.03)[9] If the harm from B vitamins in DIVINe were from folic acid, then there should have been harm among patients in the Chinese CSPPT trial[63] with impaired renal function and folic acid alone; instead folic acid improved renal function and reduced a composite event including overall mortality[64]; therefore, the harm in the other studies was due to either cyanocobalamin or vitamin B6.

Koyama’s work (increased cyanide levels in renal failure[65] and benefit of methylcobalamin not shown in the WENBIT study[66] with cyanocobalamin),[67] plus 2 plausible mechanisms for harm (thiocyanate increases LDL oxidation[68] and formation of thiocyanate consumes H2S), points to the cyanide in cyanocobalamin (or impaired decyanation of cyanocobalamin) in patients with impaired renal function as the likely problem.

Essentially, the null trials are explained by harm in participants with impaired renal function cancelling out the benefit among participants with good renal function.[9]

(Reproduced by permission of Lancet Neurology from: Spence JD, Yi Q, Hankey GJ. B vitamins in stroke prevention: time to reconsider. Lancet Neurol. 2017 Sep;16(9):750-60.)