Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial

Vermeulen, E.G.; Stehouwer, C.D.A.; Twisk, J.W.R.; Berg, M. van den; Jong, SC de; Mackaay, A. J. C.; Campen, Cmc van; Visser, F. C.; Jakobs, C.; Bulterijs, EJ; Rauwerda, J. A.

doi:10.1016/s0140-6736(99)07391-2

Cited by 295 publications

(165 citation statements)

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“…It is compatible with the previous report by Mangoni et al (Mangoni et al 2002) that 4 weeks of folic acid intervention (5 mg/day) did not change the PWV significantly in healthy cigarette smokers. It is also compatible with the previous report by Vermeulen et al that 2 years of folic acid intervention (5 mg folic acid + 250 mg vitamin B6/day) did not change the ABI significantly in healthy siblings of patients with premature atherothrombotic disease (Vermeulen et al 2000). Via lowering the tHcy (Homocysteine Lowering Trialists' Collaboration 1998; Vermeulen et al 2000;Wald et al 2001) or directly improving endovascular dysfunction (Mangoni et al 2002), folic acid may improve the PWV and ABI, but 3 months does not seem long enough to detect any significant changes.…”

Section: Discussionsupporting

confidence: 93%

“…Intervention consisted of folic acid 1 mg/ day per o.s. or an identical-looking placebo for 3 months since tHcy reduction is known to be maximal at a folic acid dosage of 1 mg/day (a minimum of 0.8 mg/day has been reported as necessary to achieve the maximum reduction in the tHcy level) (Vermeulen et al 2000). The primary endpoint was the change in the plasma tHcy level, and the secondary endpoint was changes in the pulse wave velocity (PWV), ankle-brachial pressure index (ABI), and high-sensitive C-reactive protein (hsCRP) levels.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, it is inferred that the MTHFR C677T TT genotype is an independent risk factor for atherosclerosis via mild hyperhomocysteinemia. In addition, B vitamin supplementation such as folic acid has been shown to lower homocysteine levels (Homocysteine Lowering Trialists' Collaboration 1998; Vermeulen et al 2000;Wald et al 2001). The MTHFR C677T homozygote could therefore be a target of effective prevention by folic acid supplementation from the viewpoint of high-risk approach.…”

Section: Introductionmentioning

confidence: 99%

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Assessment of tailor-made prevention of atherosclerosis with folic acid supplementation: randomized, double-blind, placebo-controlled trials in each MTHFR C677T genotype

et al. 2005

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This study aimed at assessing the effect of folic acid supplementation quantitatively in each MTHFR C677T genotype and considered the efficiency of tailormade prevention of atherosclerosis. Study design was genotype-stratified, randomized, double-blind, placebocontrolled trials. The setting was a Japanese company in the chemical industry. Subjects were 203 healthy men after exclusion of those who took folic acid or drugs known to effect folic acid metabolism. Intervention was folic acid 1 mg/day p.o. for 3 months. The primary endpoint was plasma total homocysteine level (tHcy). In all three genotypes, there were significant tHcy decreases. The greatest decrease was in the TT homozygote [6.61 (3.47-9.76) lmol/l] compared with other genotypes [CC: 2.59 (1.81-3.36), CT: 2.64 (2.16-3.13)], and there was a significant trend between the mutated allele number and the decrease. The tHcy were significantly lowered in all the genotypes, but the amount of the decrease differed significantly in each genotype, which was observed at both 1 and 3 months. Using these timeseries data, the largest benefit obtained by the TT homozygote was appraised as 2.4 times compared with the CC homozygote. Taking into account the high allele frequency of this SNP, this quantitative assessment should be useful when considering tailor-made prevention of atherosclerosis with folic acid.

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Assessment of tailor-made prevention of atherosclerosis with folic acid supplementation: randomized, double-blind, placebo-controlled trials in each MTHFR C677T genotype

et al. 2005

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“…Another nonrandomized study also suggests that a homocysteine-lowering treatment would decrease the risk of atherothrombotic disease (Peterson and Spence, 1998). Furthermore, a 2-year, double-blind, randomized, placebo-controlled therapeutic trial in 158 healthy siblings of hyperhomocysteinemic patients with premature atherothrombotic disease folic acid plus vitamin B 6 treatment was associated with a decreased occurrence of abnormal exercise electrocardiography tests, which is consistent with a decreased risk of atherosclerotic events (Vermeulen et al, 2000). Additional experimental and large-scale clinical designs with optimal dose and duration of homocysteine-lowering treatment are needed to definitively prove that homocysteine is responsible for the increased risk of cardiovascular disease, mostly of atherosclerosis.…”

Section: Hyperhomocysteinemia: An Expected Causal Risk Factor For Athmentioning

confidence: 83%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

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SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

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“…Among these 59 surrogate endpoint trials that had a subsequent clinical endpoint trial, in 24 cases the clinical endpoint trial results validated the positive surrogate trials, while in 20 the subsequent clinical endpoint trial was negative (Table 3). 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 A negative surrogate endpoint trial was less likely to be followed by a positive outcome trial and we identified only 3 such examples ( P =0.02, Figure 2). …”

Section: Resultsmentioning

confidence: 99%

Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990–2011

Bikdeli

Punnanithinont

Akram

et al. 2017

JAHA

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BackgroundSurrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes.Methods and ResultsWe identified cardiovascular trials with primary surrogate endpoints published in the New England Journal of Medicine, Lancet, and JAMA: Journal of the American Medical Association from 1990 to 2011 and determined the trends in publication of surrogate endpoint trials and the success of the trials in meeting their primary endpoints. We tracked for publication of clinical outcome trials on the interventions tested in surrogate trials. We screened 3016 articles and identified 220 surrogate endpoint trials. From the total of 220 surrogate trials, 157 (71.4%) were positive for their primary endpoint. Only 59 (26.8%) surrogate trials had a subsequent clinical outcomes trial. Among these 59 trials, 24 outcomes trial results validated the positive surrogates, whereas 20 subsequent outcome trials were negative following positive results on a surrogate. We identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit. Findings were consistent in a sample cohort of 383 screened articles inclusive of 37 surrogate endpoint trials from 6 other high‐impact journals.ConclusionsAlthough cardiovascular surrogate outcomes trials frequently show superiority of the tested intervention, they are infrequently followed by a prominent outcomes trial. When there was a high‐profile clinical outcomes study, nearly half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it.

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Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial

Cited by 295 publications

References 30 publications

Assessment of tailor-made prevention of atherosclerosis with folic acid supplementation: randomized, double-blind, placebo-controlled trials in each MTHFR C677T genotype

Assessment of tailor-made prevention of atherosclerosis with folic acid supplementation: randomized, double-blind, placebo-controlled trials in each MTHFR C677T genotype

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990–2011

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