Efficacy Of Folic Acid Therapy Research Articles

Doubly bi-allelic variants of MTHFR and MTHFD1 in a Chinese patient with hyperhomocysteinemia and failure of folic acid therapy.

Background: Hyperhomocysteinemia (HHcy) is a risk factor for thromboembolic disease. Defects in one-carbon metabolism (1-CM)-related genes, such as methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase 1 (MTHFD1), can cause HHcy and may also affect the efficacy of folic acid therapy. The details of mechanisms are yet to be further investigated. Method: We described a Chinese family with hereditary HHcy. The proband suffered from severe thromboembolic disease and experienced failure of folic acid therapy. Two sons of the proband were also diagnosed with HHcy but were sensitive to folic acid therapy. Whole-exome sequencing (WES) was conducted to evaluate the genetic lesion of this family. Results: Compound heterozygous variants (a common polymorphism, p. A222V, and a novel variant, p. C631*fs*1) of the MTHFR gene and a homozygous missense variant (p. K134R) of the MTHFD1 gene were identified in the proband. The two sons, with successful intervention, only harbored the homozygous p. A222V variant of the MTHFR gene. Conclusion: The clinical manifestations and genetic research synergistically confirmed the diagnosis of HHcy and clarified the failure of folic acid therapy in the proband caused by doubly bi-allelic variants of the MTHFR and MTHFD1 genes. Our study increased our understanding of the molecular basis of 1-CM-related gene defects on folic acid therapy in HHcy.

Using the optimal method-explained variance weighted genetic risk score to predict the efficacy of folic acid therapy to hyperhomocysteinemia.

Genetic risk score (GRS) is a useful way to explore genetic architectures and the relationships of complex diseases. Several studies had revealed many single nucleotide polymorphisms (SNPs) associated with the efficacy of folic acid treatment to hyperhomocysteinemia (HHcy). We aimed to construct and screen out the optimal predictive model based on four GRSs and traditional risk factors. Four GRSs enrolled four SNPs (MTHFR rs1801131, MTHFR rs1801133, MTRR rs1801394, BHMT rs3733890) were presented as follows: (a) simple count genetic risk score (SC-GRS), (b) direct logistic regression genetic risk score (DL-GRS), (c) polygenic genetic risk score (PG-GRS), and (d) explained variance weighted genetic risk score (EV-GRS). We performed a prospective cohort study including 638 HHcy patients. Then we evaluated the associations of four GRSs with folic acid's efficacy and the performance of four GRSs. Four GRSs were independently associated with efficacy of treatment (p < 0.05). When combining GRSs with traditional risk factors, the AUC of the four models were all above 0.900 in the training set (Tradition + SC-GRS: 0.909, Tradition + DL-GRS: 0.909, Tradition + PG-GRS: 0.904, Tradition + EV-GRS: 0.910). And EV-GRS got the highest AUC. When evaluating the models in the testing set, we got the same conclusion that EV-GRS was optimal among four GRSs with the highest AUC (0.878) and the highest increase of AUC (0.008). A more precise predictive model combing the optimal GRS with traditional risk factors was constructed to predict the efficacy of folic acid therapy to HHcy.

Combining genetic risk score with artificial neural network to predict the efficacy of folic acid therapy to hyperhomocysteinemia

Artificial neural network (ANN) is the main tool to dig data and was inspired by the human brain and nervous system. Several studies clarified its application in medicine. However, none has applied ANN to predict the efficacy of folic acid treatment to Hyperhomocysteinemia (HHcy). The efficacy has been proved to associate with both genetic and environmental factors while previous studies just focused on the latter one. The explained variance genetic risk score (EV-GRS) had better power and could represent the effect of genetic architectures. Our aim was to add EV-GRS into environmental factors to establish ANN to predict the efficacy of folic acid therapy to HHcy. We performed the prospective cohort research enrolling 638 HHcy patients. The multilayer perception algorithm was applied to construct ANN. To evaluate the effect of ANN, we also established logistic regression (LR) model to compare with ANN. According to our results, EV-GRS was statistically associated with the efficacy no matter analyzed as a continuous variable (OR = 3.301, 95%CI 1.954–5.576, P < 0.001) or category variable (OR = 3.870, 95%CI 2.092–7.159, P < 0.001). In our ANN model, the accuracy was 84.78%, the Youden’s index was 0.7073 and the AUC was 0.938. These indexes above indicated higher power. When compared with LR, the AUC, accuracy, and Youden’s index of the ANN model (84.78%, 0.938, 0.7073) were all slightly higher than the LR model (83.33% 0.910, 0.6687). Therefore, clinical application of the ANN model may be able to better predict the folic acid efficacy to HHcy than the traditional LR model. When testing two models in the validation set, we got the same conclusion. This study appears to be the first one to establish the ANN model which added EV-GRS into environmental factors to predict the efficacy of folic acid to HHcy. This model would be able to offer clinicians a new method to make decisions and individual therapeutic plans.

Efficacy of folic acid therapy for the association between high serum vitamin B12 level with all cause mortality among hypertensive population: the CSPPT randomized clinical trial post-hoc analysis

Abstract Background While higher vitamin B12 level was found to be co-related with mortality in various population, the effectiveness of folic acid therapy for this association remained unknown. Purpose 1: Explore the association between high B12 level and all cause mortality in hypertensive population. 2: To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing all cause mortality than enalapril alone among targeted population. Methods Current study used post hoc analysis to examin data from the china stroke primary prevention trial (CSPPT), a randomized, double-blind, multi-center clinical trial. After excluded those lack of vitamin B12 data and with extreme B12 value, 20,204 participants (mean age 60 [SD. 8.54]; 59.16% male gender; total mean serum vitamin B12 level 410.51 [SD. 124.85] pg/ml) were included in present study.10,093 participants were treated with enalpril alone and 10,111 patients took the combine use of enalapril and folic acid. The primary outcome was all cause mortality, which collected based on hospital issued death certificate and investigation during follow up period. Results Over the medium follow-up time of 4.5 years, 308 death occurred in enalapril group and 295 death happened in enalapril-folic acid group. Differences were observed regarding sex, center, smoking &amp; drinking status at baseline. In enalapril group, high vitamin B12 level presented positive linear association with all cause mortality and was found to be significantly differences (P=0.018). Whereas no association between high vitamin B12 level and all cause mortality were observed in enalapril and folic acid group. (P=0.448). KM curves and tertile analysis of vitamin B12 level also showed same finding. Sensitivity analysis were processed to ensure the accuracy of the study result. Conclusion The present study not only explored that higher vitamin B12 level will increase all cause mortality in hypertensive population, but also found that high vitamin B12 level loses its co-relationship with all cause mortality after folic acid therapy, which potentially reflected the benefits of long-term, low-dose folic acid supplementation. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Key R&amp;D Projects, Jiangxi National Key Research and Development Program Smoothing curveKM curve

Identifying gene-environment interactions on the efficacy of folic acid therapy for hyperhomocysteinemia based on prediction model

Various genetic and environmental factors or their interactions may result in the failure of folic acid therapy for hyperhomocysteinemia (HHcy). We hypothesized that an optimal predictive model of gene-environment interactions could be constructed to predict the efficacy of folic acid therapy in HHcy. A prospective cohort study of 638 HHcy patients was performed. The patients were treated with oral folic acid (5 mg/d) for 90 days. We used conditional inference tree model to stratify the failure risk of folic acid therapy synthesizing information from a weighted genetic risk score (wGRS) and environmental exposures, simultaneously interpreting the gene-environment interaction network in predicting the efficacy of HHcy. We detected high-order interactions between medical history of stroke, coronary heart disease (CHD), wGRS, and baseline total homocysteine (tHcy) on the failure risk of folic acid therapy. The wGRS in fourth quartile had 3.73-fold increased failure risk of folic acid treatment (odds ratio = 3.73, 95% confidence interval: 1.47-9.45). Stroke was identified as the key discriminator among the variables examined. A total of 3.3% of participants in failure group were at the lowest failure risk of folic acid therapy (nonstroke, non-CHD, baseline tHcy ≤ 31.1 μmol/L, wGRS ≤ 1.05). Individuals with stroke but with wGRS > 1.05 were at the highest failure risk of folic acid therapy (91.0% of participants in failure group). Medical history of stroke, CHD, wGRS, and baseline tHcy were consistently identified as significant risk factors for the failure risk of folic acid therapy. The multiple interactions between genetic and environmental factors can be visually presented via the conditional inference tree model.

Association between BHMT and CBS gene promoter methylation with the efficacy of folic acid therapy in patients with hyperhomocysteinemia.

Both betaine homocysteine methyltransferase (BHMT) and cystathionine β-synthase (CBS) are major enzymes in the metabolism of plasma homocysteine (Hcy). Abnormal methylation levels of BHMT and CBS are positively associated with Hcy levels. The present study is performed to explore the association between the methylation levels in the promoter regions of the BHMT and CBS genes and the efficacy of folic acid therapy in patient with hyperhomocysteinemia (HHcy). A prospective cohort study recruiting HHcy (Hcy ≥ 15 μmol/L) patients was performed. The subjects were treated with oral folic acid (5 mg/d) for 90 days, and the patients were divided into the success group (Hcy < 15 μmol/L) and the failure group (Hcy ≥ 15 μmol/L) according to their Hcy levels after treatment. In the logistic regression model with adjusted covariates, the patients with lower total methylation levels in the BHMT and CBS promoter regions exhibited 1.627-fold and 1.671-fold increased risk of treatment failure compared with higher methylation individuals, respectively. Similarly, subjects who had lower methylation levels (<methylation mean) in BHMT CpG1 had 1.792 times higher risks. Stratified analysis by sex found that lower CBS methylation levels were associated with a 2.128-fold increased risk for treatment failure in males with HHcy. Lower levels of BHMT or CBS promoter total methylation might be associated with increased the risk of treatment failure. These studies suggest that lower levels of BHMT and CBS methylation are all predictors of failure in folic acid therapy for HHcy. However, due to some limitations of this study, such as the small number of the loci tested, further large-scale studies are necessary to verify our observations.

Prediction model for the efficacy of folic acid therapy on hyperhomocysteinaemia based on genetic risk score methods.

No risk assessment tools for the efficacy of folic acid treatment for hyperhomocysteinaemia (HHcy) have been developed. We aimed to use two common genetic risk score (GRS) methods to construct prediction models for the efficacy of folic acid therapy on HHcy, and the best gene-environment prediction model was screened out. A prospective cohort study enrolling 638 HHcy patients was performed. We used a logistic regression model to estimate the associations of two GRS methods with the efficacy. Performances were compared using area under the receiver operating characteristic curve (AUC). The simple count genetic risk score (SC-GRS) and weighted genetic risk score (wGRS) were found to be independently associated with the efficacy of folic acid treatment for HHcy. Using the SC-GRS, per risk allele increased with a 1·46-fold increased failure risk (P < 0·001) after adjustment for traditional risk factors, including age, sex, BMI, smoking, alcohol consumption, history of diabetes, history of hypertension, history of hyperlipidaemia, history of stroke and history of CHD. When used the wGRS, the association was strengthened (OR = 2·08, P < 0·001). Addition of the SC-GRS and wGRS to the traditional risk model significantly improved the predictive ability by AUC (0·859). A precise gene-environment predictive model with good performance was developed for predicting the treatment failure rate of folic acid therapy for HHcy.

Genetic polymorphisms of key enzymes in folate metabolism affect the efficacy of folate therapy in patients with hyperhomocysteinaemia.

The aim of this study is to analyse the efficacy rate of folate for the treatment of hyperhomocysteinaemia (HHcy) and to explore how folate metabolism-related gene polymorphisms change its efficacy. This study also explored the effects of gene-gene and gene-environment interactions on the efficacy of folate. A prospective cohort study enrolling HHcy patients was performed. The subjects were treated with oral folate (5 mg/d) for 90 d. We analysed the efficacy rate of folate for the treatment of HHcy by measuring homocysteine (Hcy) levels after treatment. Unconditioned logistic regression was conducted to analyse the association between SNP and the efficacy of folic acid therapy for HHcy. The efficacy rate of folate therapy for HHcy was 56·41 %. The MTHFR rs1801133 CT genotype, TT genotype and T allele; the MTHFR rs1801131 AC genotype, CC genotype and C allele; the MTRR rs1801394 GA genotype, GG genotype and G allele; and the MTRR rs162036 AG genotype and AG+GG genotypes were associated with the efficacy of folic acid therapy for HHcy (P<0·05). No association was seen between other SNP and the efficacy of folic acid. The optimal model of gene-gene interactions was a two-factor interaction model including rs1801133 and rs1801394. The optimal model of gene-environment interaction was a three-factor interaction model including history of hypertension, history of CHD and rs1801133. Folate supplementation can effectively decrease Hcy level. However, almost half of HHcy patients failed to reach the normal range. The efficacy of folate therapy may be genetically regulated.

Correction to: Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men.

HomeStrokeVol. 49, No. 3Correction to: Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection to: Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men Originally published1 Mar 2018https://doi.org/10.1161/STR.0000000000000166Stroke. 2018;49:e141This article corrects the followingEffect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive MenIn the article by Zhou et al, “Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men,” which published online ahead of print December 22, 2017, and appeared in the January 2018 issue of the journal (Stroke. 2018;49:114–120. DOI: 10.1161/STROKEAHA.117.018273), a correction is needed.On page 115, the sentence “We then excluded 133 participants because of missingdata on smoking status and baseline folate levels,” should be “We then excluded 113 participants because of missing data on smoking status and baseline folate levels.”On page 115, Figure 1 has been replaced as shown in this correction notice (“n=133” was changed to “n=113”).This correction has been made to the current online version of the article, which is available at http://stroke.ahajournals.org/content/49/1/114. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesEffect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive MenZiyi Zhou, et al. Stroke. 2018;49:114-120 March 2018Vol 49, Issue 3 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/STR.0000000000000166PMID: 29483365 Originally publishedMarch 1, 2018 PDF download Advertisement

Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men.

We aimed to examine whether the efficacy of folic acid therapy in the primary prevention of stroke is jointly affected by smoking status and baseline folate levels in a male population in a post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial). Eligible participants of the CSPPT were randomly assigned to a double-blind daily treatment of a combined enalapril 10-mg and folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. In total, 8384 male participants of the CSPPT were included in the current analyses. The primary outcome was first stroke. The median treatment duration was 4.5 years. In the enalapril-alone group, the first stroke risk varied by baseline folate levels and smoking status (never versus ever). Specifically, there was an inverse association between folate levels and first stroke in never smokers (P for linear trend=0.043). However, no such association was found in ever smokers. A test for interaction between baseline folate levels and smoking status on first stroke was significant (P=0.045). In the total sample, folic acid therapy significantly reduced the risk of first stroke in never smokers with folate deficiency (hazard risk, 0.36; 95% confidence interval, 0.16-0.83) and in ever smokers with normal folate levels (hazard risk, 0.69; 95% confidence interval, 0.48-0.99). Baseline folate levels and smoking status can interactively affect the risk of first stroke. Our data suggest that compared with never smokers, ever smokers may require a higher dosage of folic acid to achieve a greater beneficial effect on stroke. Our findings need to be confirmed by future randomized trials. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Efficacy of Folic Acid Therapy in Patients with Hyperhomocysteinemia

ABSTRACTBackground: Increased plasma homocysteine (Hcy) levels are a risk factor for stroke and can be reduced with folic acid therapy. Therefore, it is extremely important for patients with hyperhomocysteinemia (HHcy) to obtain the normal level of Hcy after folate intervention. Thus far, few studies have reported the effective rate defined as percentage of patients who achieved normal plasma Hcy levels after folic acid therapy. Objectives: The present study aimed to investigate the effective rate of folic acid for the treatment of HHcy and the impact of plasma baseline Hcy levels and the compliance of oral folic acid on the efficacy.Methods: A total of 858 patients with HHcy were treated with oral folic acid (5 mg/d) for 3 months. Fasting blood samples collected at baseline and at the end of treatment were assayed for plasma Hcy levels.Results: After 3 months of treatment, the plasma Hcy levels of 484 patients were reduced to below the normal levels (15 μmol/L), corresponding to an effective rate of 56.41%. The average of Hcy levels decreased by 28.05%. The effective rates of folic acid therapy in a mild Hcy elevated group and an intermediate Hcy elevated group were 61.34% and 27.78%, respectively (p = 0.000). The effective rates among patients with good and poor compliance of oral folic acid were 65.29% and 35.18%, respectively (p = 0.000).Conclusions: More than 40% patients with HHcy failed to reach the normal range (5–15 μmol/L) after 3 months of folic acid supplementation. Further prospective studies are warranted to explore the reasons for failure.

Folic acid therapy reduces the risk of mortality associated with heavy proteinuria among hypertensive patients

We aimed to evaluate whether proteinuria and estimated glomerular filtration rate (eGFR) levels can modify the efficacy of folic acid therapy on the risk of all-cause mortality among hypertensive patients in the China Stroke Primary Prevention Trial, a randomized, double-blind, and controlled trial. A total of 20 702 hypertensive patients without a history of major cardiovascular diseases were randomly assigned to a double-blind daily treatment of a single tablet containing 10-mg enalapril and 0.8-mg folic acid (n = 10 348), or 10-mg enalapril alone (n = 10 354). All-cause mortality, a prespecified endpoint of the China Stroke Primary Prevention Trial, was the main outcome in this analysis. Over a median treatment duration of 4.5 years, in the enalapril alone group, both heavy proteinuria [vs. absent, 10.8 vs. 2.7%; hazard ratio = 3.30; 95% confidence interval (CI): 2.10-5.18] and lower eGFR levels (<60 vs. ≥90 ml/min per 1.73 m, 13.0 vs. 2.2%; hazard ratio = 1.93; 95% CI: 1.19-3.12) were significantly associated with increased risk of all-cause mortality. Folic acid supplementation significantly reduced the risk of all-cause mortality in patients with heavy proteinuria (6.4% in the enalapril-folic acid vs. 10.8% in the enalapril alone group, hazard ratio = 0.49; 95% CI: 0.26-0.94), but not in those with absent or mild proteinuria (2.8 vs. 2.9%, hazard ratio = 0.99; 95% CI: 0.84-1.17; P for interaction = 0.040). However, eGFR levels did not significantly modify the effect of folic acid supplementation in reducing the risk of all-cause mortality (P for interaction = 0.228). Among hypertensive patients without a history of major cardiovascular diseases, folic acid therapy could reduce the mortality risk associated with heavy proteinuria.

Folic acid therapy reduces serum uric acid in hypertensive patients: a substudy of the China Stroke Primary Prevention Trial (CSPPT)1–3

Background: The effect of folic acid supplementation on uric acid (UA) concentrations is still inconclusive.Objective: We aimed to test the efficacy of folic acid therapy in reducing serum UA in hypertensive patients.Design: A total of 15,364 hypertensive patients were randomly assigned to a double-blind daily treatment with a single tablet that contained 10 mg enalapril and 0.8 mg folic acid (n = 7685) or 10 mg enalapril alone (n = 7679). The main outcome was the change in serum UA, which was defined as UA at the exit visit minus that at baseline. Secondary outcomes were as follows: 1) controlled hyperuricemia (UA concentration <357 µmol/L after treatment) and 2) new-onset hyperuricemia in participants with normal UA concentrations (<357 µmol/L).Results: After a median of 4.4 y of treatment, the mean ± SD UA concentration increased by 34.7 ± 72.5 µmol/L in the enalapril-alone group and by 30.7 ± 71.8 µmol/L in the enalapril–folic acid group, which resulted in a mean group difference of −4.0 µmol/L (95% CI: −6.5, −1.6 µmol/L; P = 0.001). Furthermore, compared with enalapril alone, enalapril–folic acid treatment showed an increase in controlled hyperuricemia (30.3% compared with 25.6%; OR: 1.31; 95% CI: 1.01, 1.70) and a decrease in new-onset hyperuricemia (15.0% compared with 16.3%; OR: 0.89; 95% CI: 0.79, 0.99). A greater beneficial effect was observed in subjects with hyperuricemia (P-interaction = 0.07) or higher concentrations of total homocysteine (tHcy) (P-interaction = 0.02) at baseline. Furthermore, there was a significant inverse relation (P < 0.001) between the reduction of tHcy and the change in UA concentrations.Conclusions: Enalapril–folic acid therapy, compared with enalapril alone, can significantly reduce the magnitude of the increase of UA concentrations in hypertensive adults. This trial was registered at clinicaltrials.gov as NCT00794885.

Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease: The Renal Substudy of the China Stroke Primary Prevention Trial.

The efficacy of folic acid therapy on renal outcomes has not been previously investigated in populations without folic acid fortification. To test whether treatment with enalapril and folic acid is more effective in slowing renal function decline than enalapril alone across a spectrum of renal function at baseline from normal to moderate chronic kidney disease (CKD) among Chinese adults with hypertension. In this substudy of eligible China Stroke Primary Prevention Trial (CSPPT), 15 104 participants with an estimated glomerular filtration rate (eGFR) 30 mL/min/1.73 m2 or greater, including 1671 patients with CKD, were recruited from 20 communities in Jiangsu province in China. Participants were randomized to receive a single tablet daily containing 10 mg enalapril and 0.8 mg folic acid (n = 7545) or 10 mg enalapril alone (n = 7559). The primary outcome was the progression of CKD, defined as a decrease in eGFR of 30% or more and to a level of less than 60 mL/min/1.73 m2 if the baseline eGFR was 60 mL/min/1.73 m2 or more, or a decrease in eGFR of 50% or more if the baseline eGFR was less than 60 mL/min/1.73 m2; or end-stage renal disease. Secondary outcomes included a composite of the primary outcome and all-cause death, rapid decline in renal function, and rate of eGFR decline. Overall, 15 104 Chinese adults with a mean (range) age of 60 (45-75) years were recruited; median follow-up was 4.4 years. There were 164 and 132 primary events in the enalapril group and the enalapril-folic acid group, respectively. Compared with the enalapril group, the enalapril-folic acid group had a 21% reduction in the odds of the primary event (odds ratio [OR], 0.79; 95% CI, 0.62-1.00) and a slower rate of eGFR decline (1.28% vs 1.42% per year; P = .02). Among the participants with CKD at baseline, folic acid therapy resulted in a significant reduction in the risks for the primary event (OR, 0.44; 95% CI, 0.26-0.75), rapid decline in renal function (OR, 0.67; 95% CI, 0.47-0.96) and the composite event (OR, 0.62; 95% CI, 0.43-0.90), and a 44% slower decline in renal function (0.96% vs 1.72% per year, P < .001). Among those without CKD at baseline, there was no between-group difference in the primary end point. Enalapril-folic acid therapy, compared with enalapril alone, can significantly delay the progression of CKD among patients with mild-to-moderate CKD. clinicaltrials.gov Identifier: NCT00794885.

Abstract TMP86: Folic Acid Therapy Prevents Stroke in Countries Without Mandatory Folic Acid Food Fortification: A Meta-analysis of Randomized Controlled Trials

Background: Additional folic acid treatment appears to have a neutral effect on reducing vascular risk in countries that mandate fortification of food with folic acid (e.g. US and Canada). However, it is uncertain whether folic acid therapy reduces stroke risk in countries without folic acid food fortification. Objective: To comprehensively evaluate the efficacy of folic acid therapy on stroke prevention in countries without folic acid food fortification. Methods: Pubmed, EMBASE, and Clinicaltrials.gov from January 1966 to August 2015 were searched to identify relevant studies. Relative risk (RR) with 95% CI was used as a measure of the association between folic acid supplementation and risk of stroke, after pooling data across trials in a random-effects model. Results: The search identified 14 randomized controlled trials involving treatment with folic acid that had enrolled 71,334 participants, all of which stroke was reported as an outcome measure. Across all trials, folic acid therapy vs. control was associated with a lower risk of stroke (RR=0.84; 95% CI, 0.76-0.93; P=0.0007) and there was no heterogeneity among include trials (P for heterogeneity =0.27, I2=17%) (Figure). The RR of stroke in primary prevention trials was 0.81 (12 trials, 95% CI, 0.72-0.91; P=0.0006). Among 3 trials, which distinguished ischemic from hemorrhagic stroke as endpoints, folic acid therapy reduced risk of ischemic stroke (RR=0.77; 95% CI 0.67-0.90, P=0.0006), but had a neutral effect on hemorrhagic stroke (RR=0.92, 95% CI 0.66-1.28, P=0.61). Conclusion: Among people living in countries without mandatory folic acid food fortification, folic acid therapy reduces the occurrence of a stroke.

ACP Journal Club. In Chinese adults with hypertension, adding folic acid to enalapril reduced incident stroke.

Source Citation Huo Y, Li J, Qin X, et al; CSPPT Investigators. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: The CSPPT randomized clinical...

Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial.

Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data. To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension. The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20,702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study. Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10,348) or a tablet containing enalapril, 10 mg, alone (n = 10,354). The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death. During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events. Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels. clinicaltrials.gov Identifier: NCT00794885.

What is the Effect of Folic Acid Supplementation on the Incidence or Reduction of PhenytoinInduced Gingival Overgrowth? A Systematic Review

Background: Several published studies have reported both positive and negative effects regarding the administration of folic acid (FA) on either prevention, or reduction of phenytoin (PHT)-induced gingival overgrowth (PIGO). Several other published studies have evaluated the effect of FA supplementation upon gingival health. Objective: The primary objective is a systematic assessment review of studies evaluating the efficacy of FA therapy for the prevention or reduction of PIGO. Secondary objectives entail evaluation of the FA and seizure control, on the mechanism of Drug-IGO, and on FA supplementation and gingival health. Materials and methods: Electronic databases (a Medline via PubMed database, and Cochrane Central Register of Controlled Trials) search was conducted; other sources were searched such as Google Scholar and clinicaltrials.gov. Reference lists of retrieved articles were searched. Randomized placebo-controlled trials (RCTs) assessing the effect of topical or systemic administration of folic acid on gingival enlargement in phenytoin patients were included. Two reviewers (HH, RB) performed the study search, data extraction, and risk of bias assessment. The literature was reviewed regarding PHT-FA interaction, and FA supplementation to promote gingival health. Results: The main research was through Pubmed search, and done on February, 15, 2015. It resulted in eight items. Only five items were considered for screening. The other three items were not interventional. One extra title was found on Google Scholar website. The total RCTs included for the systematic review were six trials. Studies regarding FA and gingival health were also evaluated which produced another four items. Conclusion: FA supplementation may improve the gingival health status, and may delay the onset of PICO, as there are only at present a limited number of studies with a limited number of subjects, further studies are necessary to confirm or deny the positive effects of FA therapy. In PHT-treated epileptic patients properly managed, FA supplementation has a very limited risk in interfering with seizure control. Due to very limited toxicity and the potential for promoting gingival health, future FA supplementation therapy studies should be considered,

Folic Acid Therapy and Cardiovascular Disease in ESRD or Advanced Chronic Kidney Disease

The efficacy of folic acid therapy to lower homocysteine (Hcy) levels in an effort to reduce cardiovascular disease (CVD) risk in patients with ESRD or advanced chronic kidney disease (ACKD; creatinine clearance, <30 ml/min) remains inconclusive. We conducted a meta-analysis of relevant randomized trials to further examine this issue. This meta-analysis included 3886 patients with ESRD/ACKD from seven qualified randomized trials using folic acid therapy and with CVD reported as one of the end points. When pooling the seven trials, folic acid therapy reduced the risk of CVD by 15% (RR, 0.85; 95% CI, 0.76 to 0.96; P = 0.009). A greater beneficial effect was observed among those trials with a treatment duration >24 months (RR, 0.84; 95% CI, 0.72 to 0.98; P = 0.02), a decrease in Hcy level >20% (RR, 0.83; 95% CI, 0.73 to 0.95; P = 0.007), and no or partial folic acid fortification (RR, 0.80; 95% CI, 0.65 to 0.99; P = 0.04). The beneficial effect also was seen when Hcy levels decreased >20%, even in the presence of folic acid fortification (RR, 0.85; 95% CI, 0.73 to 0.99; P = 0.04). In the corresponding comparison groups, the estimated RRs were attenuated and insignificant. Folic acid therapy can reduce CVD risk in patients with ESRD/ACKD by 15%. A greater beneficial effect was observed among those trials with no or partial folic acid fortification or a decrease in Hcy level >20% regardless of folic acid fortification.