Effects of Homocysteine-Lowering With Folic Acid Plus Vitamin B-12 vs Placebo on Mortality and Major Morbidity in Myocardial Infarction Survivors A Randomized Trial

JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 06/2010; 303(24):2486-94. DOI: 10.1001/jama.2010.840
Source: PubMed


Blood homocysteine levels are positively associated with cardiovascular disease, but it is uncertain whether the association is causal.
To assess the effects of reducing homocysteine levels with folic acid and vitamin B(12) on vascular and nonvascular outcomes.
Double-blind randomized controlled trial of 12,064 survivors of myocardial infarction in secondary care hospitals in the United Kingdom between 1998 and 2008.
2 mg folic acid plus 1 mg vitamin B(12) daily vs matching placebo.
First major vascular event, defined as major coronary event (coronary death, myocardial infarction, or coronary revascularization), fatal or nonfatal stroke, or noncoronary revascularization.
Allocation to the study vitamins reduced homocysteine by a mean of 3.8 micromol/L (28%). During 6.7 years of follow-up, major vascular events occurred in 1537 of 6033 participants (25.5%) allocated folic acid plus vitamin B(12) vs 1493 of 6031 participants (24.8%) allocated placebo (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.97-1.12; P = .28). There were no apparent effects on major coronary events (vitamins, 1229 [20.4%], vs placebo, 1185 [19.6%]; RR, 1.05; 95% CI, 0.97-1.13), stroke (vitamins, 269 [4.5%], vs placebo, 265 [4.4%]; RR, 1.02; 95% CI, 0.86-1.21), or noncoronary revascularizations (vitamins, 178 [3.0%], vs placebo, 152 [2.5%]; RR, 1.18; 95% CI, 0.95-1.46). Nor were there significant differences in the numbers of deaths attributed to vascular causes (vitamins, 578 [9.6%], vs placebo, 559 [9.3%]) or nonvascular causes (vitamins, 405 [6.7%], vs placebo, 392 [6.5%]) or in the incidence of any cancer (vitamins, 678 [11.2%], vs placebo, 639 [10.6%]).
Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12) supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence. Identifier: ISRCTN74348595.

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    • "In the intervention groups, the dose of folic acid ranged from 0.5 to 40 mg/day, the dose of vitamin B6 ranged from 3 to 250 mg/day, and the dose of vitamin B12 ranged from 6 to 2000 µg/day. In the meta-analysis, the trial outcome was MACE in 23 trials [20]–[36], [38]–[43], total mortality in 20 trials [21]–[31], [33], [35], [37]–[43], cardiac death in 15 trials [21]–[23], [25]–[27], [29]–[31], [34]–[36], [39], [42], [43], MI in 19 trials [21]–[31], [33], [35], [37]–[39], [41]–[43], and stroke in 18 trials [22], [23], [25]–[31], [33]–[35], [37]–[39], [41]–[43]. We restricted the inclusion criteria to RCTs with a minimum follow-up of 6 months to ensure a reliable conclusion. "
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    ABSTRACT: Background Observational studies suggest that B vitamin supplementation reduces cardiovascular risk in adults, but this association remains controversial. This study aimed to summarize the evidence from randomized controlled trials (RCTs) investigating B vitamin supplementation for the primary or secondary prevention of major adverse cardiovascular outcomes and to perform a cumulative meta-analysis to determine the evidence base. Methodology and Principal Findings In April 2013, we searched PubMed, Embase, and the Cochrane Library to identify relevant RCTs. We included RCTs investigating the effect of B vitamin supplementation on cardiovascular outcome. Relative risk (RR) was used to measure the effect using a random-effect model. Statistical heterogeneity scores were assessed using the Q statistic. We included data on 57,952 individuals from 24 RCTs: 12 primary prevention trials and 12 secondary prevention trials. In 23 of these trials, 10,917 major adverse cardiovascular events (MACE) occurred; in 20 trials, 7,203 deaths occurred; in 15 trials, 3,422 cardiac deaths occurred; in 19 trials, 3,623 myocardial infarctions (MI) occurred; and in 18 trials, 2,465 strokes occurred. B vitamin supplementation had little or no effect on the incidence of MACE (RR, 0.98; 95% confidence interval [CI]: 0.93–1.03; P = 0.37), total mortality (RR, 1.01; 95% CI: 0.97–1.05; P = 0.77), cardiac death (RR, 0.96; 95% CI: 0.90–1.02; P = 0.21), MI (RR, 0.99; 95% CI: 0.93–1.06; P = 0.82), or stroke (RR, 0.94; 95% CI: 0.85–1.03; P = 0.18). Conclusion/Significance B vitamin supplementation, when used for primary or secondary prevention, is not associated with a reduction in MACE, total mortality, cardiac death, MI, or stroke.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Most of the current homocysteine-lowering therapies are based on the supplementation of folic acid that can facilitate the remethylation of homocysteine [4]. However, clinical trials showed that folic acid does not have beneficial effects on cardiovascular outcomes [5,6]. It is thus necessary to develop a non-folic acid homocysteine-lowering approach for hyperlipidemia, because the lack of benefit of homocysteine-lowering therapy suggests that folic acid-based treatment that is still most widely used may increase the cardiovascular risk that has already been elevated in the hyperlipidemic setting. "
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    ABSTRACT: Elevated homocysteine is a cardiovascular risk factor in hyperlipidemia. Transsulfuration pathway provides an endogenous pathway for homocysteine conversion to antioxidant glutathione (GSH). Salvianolic acid A (Sal A) contains two molecules of caffeic acid and one molecule of danshensu that is capable of enhancing homocysteine transsulfuration, which led to the hypothesis that Sal A has activatory effect on transsulfuration pathway and this effect may have beneficial effects on both homocysteine and redox status in hyperlipidemia.Methods and results: To test this hypothesis, we developed a rat model of hyperlipidemia induced by high-fat diet for 16 weeks, during which rats were treated with 1 mg/kg salvianolic acid A (Sal A) for the final 4 weeks. Activities of key enzymes and metabolite profiling in the transsulfuration pathway revealed that hyperlipidemia led to elevated plasma homocysteine levels after 16-week dietary treatment, which was associated with reduced activities of homocysteine transsulfuration enzymes, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE). The impaired transsulfuration pathway prevented homocysteine transsulfuration to cysteine, resulting in cysteine deficiency and subsequent reduction in GSH pool size. The redox status was altered in the setting of hyperlipidemia as indicated by GSH/GSSG ratio. Sal A treatment increased hepatic CBS and CSE activities, which was associated with reduced accumulation in circulating homocysteine levels and attenuated decline in hepatic cysteine content in hyperlipidemic rats. Sal A also led to an increase in GSH pool size, which subsequently caused a restored GSH/GSSG ratio. The activatory effect of Sal A on CBS was also observed in normal rats and in in vitro experiment. Our results suggest that activation of transsulfuration pathway by Sal A is a promising homocysteine-lowering approach that has beneficial effects on redox homeostasis in hyperlipidemic settings.
    Full-text · Article · Dec 2013 · Nutrition & Metabolism
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    • "Seven trials [7-9,11,17,18,20] included patients with chronic kidney disease. Eight trials [12-14,16,19,21,22,24] included patients with cardiovascular disease or stroke. One trial [10] included healthy individuals. "
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    ABSTRACT: B vitamins have been extensively used to reduce homocysteine levels; however, it remains uncertain whether B vitamins are associated with a reduced risk of stroke. Our aim was to evaluate the effects of B vitamins on stroke. We systematically searched PubMed, EmBase, and the Cochrane Central Register of Controlled Trials to identify studies for our analysis. Relative risk (RR) was used to measure the effect of B-vitamin supplementation on the risk of stroke. The analysis was further stratified based on factors that could affect the treatment effects. Of the 13,124 identified articles, we included 18 trials reporting data on 57,143 individuals and 2,555 stroke events. B-vitamin supplementation was not associated with a significant reduction in the risk of stroke (RR, 0.91, 95%CI: 0.82-1.01, P = 0.075; RD, -0.003, 95%CI: -0.007-0.001, P = 0.134). Subgroup analyses suggested that B-vitamin supplementation might reduce the risk of stroke if included trials had a man/woman ratio of more than 2 or subjects received dose of folic acid less than 1 mg. Furthermore, in a cumulative meta-analysis for stroke, the originally proposed nonsignificant B-vitamin effect was refuted by the evidence accumulated up to 2006. There is a small effect with borderline statistical significance based on data gathered since 2007. Our study indicates that B-vitamin supplementation is not associated with a lower risk of stroke based on relative and absolute measures of association. Subgroup analyses suggested that B-vitamin supplementation can effectively reduce the risk of stroke if included trials had a man/woman ratio of more than 2 or subjects received dose of folic acid less than 1 mg.
    Full-text · Article · Nov 2013 · PLoS ONE
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