Hyperhomocysteinemia in Japanese patients with convalescent stage ischemic stroke: Effect of combined therapy with folic acid and mecobalamine
Authors: Kei Satoh
Hidemi Yoshida
Norifumi Metoki
Yoshihiro Sato
Izumi Kondo
Masahide Kaji
Journal: Journal of the Neurological Sciences (2002)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Hyperhomocysteinemia; vascular diseases; ischemic stroke; folic acid supplementation; Vitamin B(12)

Abstract:  Hyperhomocysteinemia is considered to be a risk factor for vascular diseases including ischemic stroke. It has been shown that plasma homocysteine level can be lowered by folic acid supplementation. Vitamin B(12) may be also beneficial when included in the supplement regimen with folic acid. We have examined in Japanese patients with ischemic stroke the homocysteine-lowering potential of a combination therapy with folic acid and vitamin B(12). Patients with ischemic stroke were randomized into three groups and each group received vitamin B(12) (1500 microg/day, n = 63), folic acid (5 mg/day, n = 64), or both vitamin B(12) and folic acid (n = 64) for 8 weeks. Plasma levels of homocysteine and these vitamins were followed. Significant reduction in plasma homocysteine was observed in all three groups, and the combination therapy yielded the most remarkable result, i.e., plasma total homocysteine was reduced by 38.5% and this was significantly larger than the reduction in other two groups (22.4% and 10.9% in the groups received folic acid and vitamin B(12), respectively). Vitamin B(12) synergizes with folic acid in reducing plasma homocysteine in Japanese patients with ischemic stroke and the combined therapy may be particularly effective in the secondary prevention. 

Retracted: No

PubPeer comments:
 19 citations on Web of Science, most recently in August 2019. This paper should have been retracted. This trial report was included in the systematic review published three years ago that identified serious and wide-ranging problems with 33 publications of randomized trials by this group of investigators (Neurology 2016:87:2391-402). 28 of the 33 trial reports have been retracted. All of the 33 trial reports with Sato as a first author have been retracted, except those in the Journal of Neurological Sciences. There is now a context of multiple ( 90) retractions of work by this group of researchers for a wide range of reasons that include fabrication, authorship misconduct, duplicate data reporting, plagiarism and unresolved concerns about data integrity J Neurol Sci and its publisher, together with all the other journals and publishers of the 33 trials, were notified by the editor of Neurology about the concerns with this paper in September 2016. In addition to the concerns already published in Neurology, concerns specific to this paper, which were sent to J Neurol Sci in May 2018, are: Ethical oversight Ethics oversight was reported to be from the Human Investigation Committee of the Kurume University Hospital, for a study conducted at Kurume University Medical Center, April 1997-August 2000. It is now known that there was no such committee in existence at Kurume University at the time the study was purportedly conducted (Stroke. 2019;50:e247). Thus, the study, if it was conducted, was undertaken without ethical approval and oversight. Authorship Drs Kaji, Kondo, Metoki, Satoh were u2018honorary authorsu2019 on papers published by Dr Sato that have now been retracted Improbable randomization The baseline data in the randomized groups are improbably similar. Among the 12 reported comparisons of baseline variables reported in the treatment groups, all P values are 0.6 u2013 the chance of this occurring by randomization is P=0.00002. For the 5 continuous variables, the chance that all baseline comparisons would yield P values 0.6 is P=0.01. Improbable participant retention None of the 191 participants with a previous stroke withdrew during the 8-week study Implausible data Table 1 reports the baseline data for the biochemical variables plasma homocysteine, serum folate and serum cobalamin in the randomized groups. Table 2 reports the percent change and final absolute value for each variable in the treatment groups. All participants completed the trial. Using the provided data for mean baseline value and mean % change to calculate the final absolute value yields discrepancies between the calculated final value and the reported final value for all but one of the results. Many of the discrepancies are substantial (implausible data shown in bold text in Table A).  Impossible data The % change in homocysteine is also reported in each of two infarction subgroups within each treatment group in the text of Section 3.2 of the Results section. Table 1 reports the number of participants in each subgroup within each treatment group. The sum of the number of participants in the infarction subgroups (group A 38+25, group B 40+24, group C 38+26) = those of the whole group (A = 63, B=64, C=64) in each case. The mean % change in the whole group should = the sum of the mean % change x n of each subgroup, divided by the total n. As shown in the Table B below, this is not the case for Groups B and C. These data are mathematically impossible even when maximum rounding is applied.  , 
 On 14 June 2020 the publisher informed us that this paper was to be retracted. 9 months later, it has not been. It has been cited 24 times (Scopus). Lengthy delays in publication of retraction notices are not in the best interests of readers. , 
 It is now 21 months since Elsevier communicated, via COPE, its undertaking to retract this paper. Recent requests for an update on the retraction to Elsevier, COPE, and the journal did not receive a response. The society associated with the journal, the World Federation of Neurology, responded but was unable to provide any information. , 
 See also https: retractionwatch.com 2022 06 23 an-elsevier-journal-said-it-would-retract-10-papers-two-years-ago-it-still-hasnt ,