title: Effect of B-vitamins and n-3 PUFA supplementation for 5 years on blood pressure in patients with CVD. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side-effects from 33 randomized controlled trials. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Effect of homocysteine-lowering B vitamin treatment on angiographic progression of coronary artery disease: a Western Norway B Vitamin Intervention Trial (WENBIT) substudy. B Vitamins and Magnetic Resonance Imaging–Detected Ischemic Brain Lesions in Patients With Recent Transient Ischemic Attack or Stroke: The VITAmins TO Prevent Stroke (VITATOPS) MRI-Substudy Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. Folic Acid Therapy Reduces the First Stroke Risk Associated With Hypercholesterolemia Among Hypertensive Patients Bread cofortified with folic acid and vitamin B-12 improves the folate and vitamin B-12 status of healthy older people: a randomized controlled trial. National Institutes of Health State-of-the-Science Conference Statement: Multivitamin/Mineral Supplements and Chronic Disease Prevention Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial. The effect of folic acid supplementation on carotid intima-media thickness in patients with cardiovascular risk: a randomized, placebo-controlled trial. Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence Paracetamol use in early life and asthma: prospective birth cohort study Multivitamin-mineral use is associated with reduced risk of cardiovascular disease mortality among women in the United States. Homocysteine-Lowering Treatment With Folic Acid, Cobalamin, and Pyridoxine Does Not Reduce Blood Markers of Inflammation, Endothelial Dysfunction, or Hypercoagulability in Patients With Previous Transient Ischemic Attack or Stroke: A Randomized Substudy of the VITATOPS Trial Effects of combined enalapril and folic acid therapy on the serum uric acid levels in hypertensive patients: a multicenter, randomized, double-blind, parallel-controlled clinical trial. GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). Dose-dependent effects of folic acid on plasma homocysteine in a randomized trial conducted among 723 individuals with coronary heart disease. B Vitamin and/or n-3 Fatty Acid Supplementation and Health-Related Quality of Life: Ancillary Findings from the SU.FOL.OM3 Randomized Trial Effect of Vitamin B12 and Folic Acid Supplementation on Bone Mineral Density and Quantitative Ultrasound Parameters in Older People with an Elevated Plasma Homocysteine Level: B-PROOF, a Randomized Controlled Trial Homocysteine lowering and cardiovascular events after acute myocardial infarction. Folic Acid-Based Intervention in Non-ST Elevation Acute Coronary Syndromes Homocysteine-Lowering Therapy and Stroke Risk, Severity, and Disability: Additional Findings From the HOPE 2 Trial A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. Vitamin Intervention for Stroke Prevention Trial: An Efficacy Analysis GRADE guidelines: 5. Rating the quality of evidence--publication bias. Treatment With B Vitamins and Incidence of Cancer in Patients With Previous Stroke or Transient Ischemic Attack: Results of a Randomized Placebo-Controlled Trial Effect of folic acid on endothelial function following acute myocardial infarction. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Homocysteine Lowering by Folate-Rich Diet or Pharmacological Supplementations in Subjects with Moderate Hyperhomocysteinemia The SU.FOL.OM3 Study: a secondary prevention trial testing the impact of supplementation with folate and B-vitamins and/or Omega-3 PUFA on fatal and non fatal cardiovascular events, design, methods and participants characteristics Lowered risks of hypertension and cerebrovascular disease after vitamin/mineral supplementation: the Linxian Nutrition Intervention Trial. Effect of Homocysteine-Lowering Treatment With Folic Acid and B Vitamins on Risk of Type 2 Diabetes in Women B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial Effect of physiological doses of oral vitamin B12 on plasma homocysteine: a randomized, placebo-controlled, double-blind trial in India Effect of 3 y of folic acid supplementation on the progression of carotid intima-media thickness and carotid arterial stiffness in older adults. The China Stroke Secondary Prevention Trial (CSSPT) Protocol: A Double-Blinded, Randomized, Controlled Trial of Combined Folic Acid and B Vitamins for Secondary Prevention of Stroke B vitamin and/or ω-3 fatty acid supplementation and cancer: ancillary findings from the supplementation with folate, vitamins B6 and B12, and/or omega-3 fatty acids (SU.FOL.OM3) randomized trial. Homocysteine lowering with folic acid and B vitamins in vascular disease. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease: The Renal Substudy of the China Stroke Primary Prevention Trial. Low-dose B vitamins supplementation ameliorates cardiovascular risk: a double-blind randomized controlled trial in healthy Chinese elderly A dose-finding trial of the effect of long-term folic acid intervention: implications for food fortification policy. Homocysteine, vitamin B12 and folate levels in Iranian patients with ischemic stroke Efficacy of folic acid when added to statin therapy in patients with hypercholesterolemia following acute myocardial infarction: a randomised pilot trial. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. Cancer incidence and mortality after treatment with folic acid and vitamin B12. Homocysteine-lowering vitamins do not lower plasma S-adenosylhomocysteine in older people with elevated homocysteine concentrations. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial VITATOPS, the VITAmins TO Prevent Stroke Trial: Rationale and Design of a Randomised Trial of B-Vitamin Therapy in Patients with Recent Transient Ischaemic Attack or Stroke (NCT00097669) (ISRCTN74743444) Mesna as a nonvitamin intervention to lower plasma total homocysteine concentration: implications for assessment of the homocysteine theory of atherosclerosis. Effect of vitamin B-12 and n-3 polyunsaturated fatty acids on plasma homocysteine, ferritin, C-reaction protein, and other cardiovascular risk factors: a randomized controlled trial. Cardiovascular effects of B-vitamins and/or N-3 fatty acids: the SU.FOL.OM3 trial. Uremic hyperhomocysteinemia: a randomized trial of folate treatment for the prevention of cardiovascular events. Secondary prevention with folic acid: effects on clinical outcomes. Homocysteine-lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease. Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B6 and B12 in high-risk patients: the Heart Outcomes Prevention Evaluation (HOPE)-2 trial. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Multivitamin use and the risk of myocardial infarction: a population-based cohort of Swedish women. Hyperhomocysteinemia in Japanese patients with convalescent stage ischemic stroke: Effect of combined therapy with folic acid and mecobalamine Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. B vitamin treatments modify the risk of myocardial infarction associated with a MTHFD1 polymorphism in patients with stable angina pectoris. Plasma total homocysteine: instigator or indicator of cardiovascular disease? Coronary blood flow in patients with stable coronary artery disease treated long term with folic acid and vitamin B12 Plasma homocysteine levels and mortality in patients with coronary artery disease. Effect of folate supplementation on serum homocysteine and plasma total antioxidant capacity in hypercholesterolemic adults under lovastatin treatment: a double-blind randomized controlled clinical trial. Complementary effects of multivitamin and omega-3 fatty acid supplementation on indices of cardiovascular health in individuals with elevated homocysteine. Homocysteine and all-cause mortality in hypertensive adults without pre-existing cardiovascular conditions Effect of Long-Term Homocysteine Reduction with B Vitamins on Arterial Wall Inflammation Assessed by Fluorodeoxyglucose Positron Emission Tomography: A Randomised Double-Blind, Placebo-Controlled Trial Effect of folic acid supplementation on cancer risk among adults with hypertension in China: A randomized clinical trial Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial.
abstract: Certain epidemiological and experimental studies suggest that n-3 fatty acids and folate can reduce blood pressure ( BP ) . We investigated the effect of a daily supplementation with dietary doses of B-vitamins or n-3 fatty acids for 5 years on BP in patients with a history of CVD who participated in the Supplémentation en Folates et Omega-3 trial . The patients ( n 2501 ; 1987 men and 514 women ) were r and omly assigned in a 2 × 2 factorial design to one of four groups : B-vitamins ( 5-methyl-THF ( 560 μg ) ; vitamin B₆ ( 3 mg ) and vitamin B₁₂ ( 20 μg ) ) and a placebo capsule for n-3 fatty acids ; n-3 fatty acids ( 600 mg of EPA and DHA at a ratio of 2:1 ) and a placebo capsule for B-vitamins ; both B-vitamins and n-3 fatty acids ; or placebo capsules for both treatments . The patients took two capsules daily in a double-blind manner for a median duration of 4·7 years . At baseline and annual examination for 5 years , the patients underwent a clinical examination where BP and clinical and biological parameters were assessed . No effect of supplementation with either n-3 PUFA or B-vitamins  on BP was observed in crude and adjusted multivariate models . Change in BP was not associated with change in homocysteine . In conclusion , the present results do not support the routine use of dietary supplements containing B-vitamins , or of n-3 fatty acids , to reduce BP in people with prior CVD During the past 25 years , 24 r and omized trials of intravenous ( IV ) fibrinolytic treatment have been reported , involving a total of some 6000 patients in the acute phase of myocardial infa rct ion . Most tested IV streptokinase ( SK ) , but a few tested IV urokinase ( UK ) . In the past 2 or 3 years numerous small r and omized trials of intracoronary ( IC ) SK have been started , 9 of which , involving a total of about 1000 such patients , have been reported . Because all of these IV and IC trials were small ( the largest including only 747 patients ) , their separate results appear contradictory and unreliable . But , an overview of the data from these trials indicates that IV treatment produces a highly significant ( 22 % + /- 5 % , P less than 0.001 ) reduction in the odds of death , an even larger reduction in the odds of reinfa rct ion , and an absolute frequency of serious adverse effects to set against this that is much smaller than the absolute mortality reduction . The apparent size of the mortality reduction in the IV trials was similar whether anticoagulants were compulsory or optional , whether treatment was in a coronary care unit or an ordinary ward and , surprisingly , whether treatment began early ( less than 6 h from onset of symptoms ) or late ( generally 12 - 24 h ) . In addition , there was no evidence that UK was more effective than the less expensive SK , or that , despite their technical complexity , the new IC regimes were more effective than the old IV regimes . Even the IV schedules that have been studied in r and omized trials were , however , quite complex , and the IC schedules were far more so . Perhaps partly because of this , none of them is widely used . If so , then some much simpler , and hence more widely practicable , IV SK regimes should be developed and tested . For example , a simple one hour high-dose IV SK infusion , without anticoagulation , will successfully convert virtually all of the available plasminogen into plasmin . But , it may be several years before the net effects on mortality of any more widely practicable IV SK regimes can be agreed unless many of the hospitals that do not wish routinely to use IC regimes or the complex previous IV regimes will collaborate in multicentre r and omized trials that can , if necessary , continue rapid intake until some tens of thous and s of patients have been r and omized , and some thous and s of deaths have been observed among the control and treated patients . The same , of course , may be true for any other fibrinolytic regimes ( e.g. infusion of tissue plasminogen activator ) if their net effects on mortality are comparable to those of IV SK Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading , despite our best efforts to improve the design and analysis of studies . Mendelian r and omization-the r and om assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures . The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies . Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian r and omization and are described . The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study , that polymorphisms may have several phenotypic effects associated with disease , the lack of suitable polymorphisms for study ing modifiable exposures of interest , and canalization-the buffering of the effects of genetic variation during development . Nevertheless , Mendelian r and omization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to underst and ing and preventing the adverse effects on human health of modifiable exposures Total plasma homocysteine ( tHcy ) is an independent risk factor for coronary artery disease , and tHcy is lowered by B vitamins . To assess the effect of homocysteine-lowering B-vitamin treatment on angiographic progression of coronary artery disease , this sub study of the Western Norway B Vitamin Intervention Trial ( WENBIT ) included patients who had undergone percutaneous coronary intervention . The patients were r and omized to daily oral treatment with folic acid , vitamin B(12 ) , and vitamin B(6 ) or placebo in a 2 x 2 factorial design . The coronary angiograms obtained at baseline and follow-up were evaluated . The primary angiographic end points were the changes in minimum lumen diameter and diameter stenosis .  A total of 348 subjects ( 288 men ) with a mean + /- SD age of 60 + /- 10.2 years were followed up for a median of 10.5 months ( twenty-fifth , seventy-fifth percentile 9.2 , 11.8 ) . The baseline median plasma tHcy level was 10.0 mumol/L ( twenty-fifth , seventy-fifth percentile 8.1 , 11.0 ) , and treatment with folic acid/vitamin B(12 ) lowered the tHcy levels by 22 % . At follow-up , we found 309 lesions with a significant decrease from baseline in the minimum lumen diameter of a mean of -0.16 + /- 0.4 mm and an increase in the diameter stenosis of 4.4 + /- 0.7 % . Treatment with folic acid/vitamin B(12 ) or vitamin B(6 ) was not associated with a change in diameter stenosis or minimum lumen diameter . In a post hoc analysis , folic acid/vitamin B(12 ) treatment was significantly associated with rapid progression ( odds ratio 1.84 , 95 % confidence interval 1.07 to 3.18 ) . In conclusion , vitamin B treatment showed no beneficial effect on the angiographic progression of coronary artery disease , and the post hoc analyses suggested that folic acid/vitamin B(12 ) treatment might promote more rapid progression Background and Purpose — Elevated concentrations of homocysteine are associated with cerebral small vessel disease ( CSVD ) . b-vitamin supplementation with folate and vitamins b12 and b6 reduces homocysteine concentrations . In a sub study of the VITAmins TO Prevent Stroke ( VITATOPS ) trial , we assessed the hypothesis that the addition of once-daily supplements of b vitamins would reduce the progression of CSVD-related brain lesions . Methods — A total of 359 patients with recent stroke or transient ischemic attack , who were r and omly allocated to double-blind treatment with placebo or b vitamins , underwent brain MRI at r and omization and after 2 years of b-vitamin supplementation . MR images were analyzed blinded to treatment allocation . Outcomes related to the prespecified hypothesis were progression of white matter hyperintensities and incident lacunes . We also explored the effect of b-vitamin supplementation on the incidence of other ischemic abnormalities . Results — After 2 years of treatment with b vitamins or placebo , there was no significant difference in white matter hyperintensities volume change ( 0.08 vs 0.13cm3 ; P=0.419 ) and incidence of lacunes ( 8.0 % vs 5.9 % , P=0.434 ; odds ratio=1.38 ) . In a sub analysis of patients with MRI evidence of severe CSVD at baseline , b-vitamin supplementation was associated with a significant reduction in white matter hyperintensities volume change ( 0.3 vs 1.7cm3 ; P=0.039 ) . Conclusions — Daily b-vitamin supplementation for 2 years did not significantly reduce the progression of brain lesions result ing from presumed CSVD in all patients with recent stroke or transient ischemic attack but may do so in the subgroup of patients with recent stroke or transient ischemic attack and severe CSVD . Clinical Trial Registration — http://vitatops.highway1.com.au/. Unique identifier : NCT00097669 and IS RCT N74743444 CONTEXT Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease . Oral administration of folic acid and vitamin B(12 ) can lower plasma total homocysteine levels . OBJECTIVE To assess the effect of treatment with folic acid and vitamin B(12 ) and the effect of treatment with vitamin B(6 ) as secondary prevention in patients with coronary artery disease or aortic valve stenosis . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999 - 2006 . A total of 3096 adult participants undergoing coronary angiography ( 20.5 % female ; mean age , 61.7 years ) were r and omized . At baseline , 59.3 % had double- or triple-vessel disease , 83.7 % had stable angina pectoris , and 14.9 % had acute coronary syndromes . INTERVENTIONS Using a 2 x 2 factorial design , participants were r and omly assigned to 1 of 4 groups receiving daily oral treatment with folic acid , 0.8 mg , plus vitamin B(12 ) , 0.4 mg , plus vitamin B(6 ) , 40 mg ( n = 772 ) ; folic acid plus vitamin B(12 ) ( n = 772 ) ; vitamin B(6 ) alone ( n = 772 ) ; or placebo ( n = 780 ) . MAIN OUTCOME MEASURES The primary end point was a composite of all-cause death , nonfatal acute myocardial infa rct ion , acute hospitalization for unstable angina pectoris , and nonfatal thromboembolic stroke . RESULTS Mean plasma total homocysteine concentration was reduced by 30 % after 1 year of treatment in the groups receiving folic acid and vitamin B(12 ) . The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention . During a median 38 months of follow-up , the primary end point was experienced by a total of 422 participants ( 13.7 % ) : 219 participants ( 14.2 % ) receiving folic acid/vitamin B(12 ) vs 203 ( 13.1 % ) not receiving such treatment ( hazard ratio , 1.09 ; 95 % confidence interval , 0.90 - 1.32 ; P = .36 ) and 200 participants ( 13.0 % ) receiving vitamin B(6 ) vs 222 ( 14.3 % ) not receiving vitamin B(6 ) ( hazard ratio , 0.90 ; 95 % confidence interval , 0.74 - 1.09 ; P = .28 ) . CONCLUSIONS This trial did not find an effect of treatment with folic acid/vitamin B(12 ) or vitamin B(6 ) on total mortality or cardiovascular events . Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00354081 IMPORTANCE Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data . OBJECTIVE 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 . DESIGN , SETTING , AND PARTICIPANTS The China Stroke Primary Prevention Trial , a r and omized , 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 infa rct ion ( MI ) participated in the study . INTERVENTIONS Eligible participants , stratified by MTHFR C677 T genotypes ( CC , CT , and TT ) , were r and omly 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 ) . MAIN OUTCOMES AND MEASURES 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 . RESULTS 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 . CONCLUSIONS AND RELEVANCE 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 . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00794885 CONTEXT Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine . OBJECTIVE To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas . DESIGN , SETTING , AND PARTICIPANTS A double-blind , placebo-controlled , 2-factor , phase 3 , r and omized clinical trial conducted at 9 clinical centers between July 6 , 1994 , and October 1 , 2004 . Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma . INTERVENTION Participants were r and omly assigned in a 1:1 ratio to receive 1 mg/d of folic acid ( n = 516 ) or placebo ( n = 505 ) , and were separately r and omized to receive aspirin ( 81 or 325 mg/d ) or placebo . Follow-up consisted of 2 colonoscopic surveillance cycles ( the first interval was at 3 years and the second at 3 or 5 years later ) . MAIN OUTCOME MEASURES The primary outcome measure was occurrence of at least 1 colorectal adenoma . Secondary outcomes were the occurrence of advanced lesions ( > or = 25 % villous features , high- grade dysplasia , size > or = 1 cm , or invasive cancer ) and adenoma multiplicity ( 0 , 1 - 2 , or > or =3 adenomas ) . RESULTS During the first 3 years , 987 participants ( 96.7 % ) underwent colonoscopic follow-up , and the incidence of at least 1 colorectal adenoma was 44.1 % for folic acid ( n = 221 ) and 42.4 % for placebo ( n = 206 ) ( unadjusted risk ratio [ RR ] , 1.04 ; 95 % confidence interval [ CI ] , 0.90 - 1.20 ; P = .58 ) . Incidence of at least 1 advanced lesion was 11.4 % for folic acid ( n = 57 ) and 8.6 % for placebo ( n = 42 ) ( unadjusted RR , 1.32 ; 95 % CI , 0.90 - 1.92 ; P = .15 ) . A total of 607 participants ( 59.5 % ) underwent a second follow-up , and the incidence of at least 1 colorectal adenoma was 41.9 % for folic acid ( n = 127 ) and 37.2 % for placebo ( n = 113 ) ( unadjusted RR , 1.13 ; 95 % CI , 0.93 - 1.37 ; P = .23 ) ; and incidence of at least 1 advanced lesion was 11.6 % for folic acid ( n = 35 ) and 6.9 % for placebo ( n = 21 ) ( unadjusted RR , 1.67 ; 95 % CI , 1.00 - 2.80 ; P = .05 ) . Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers . There was no significant effect modification by sex , age , smoking , alcohol use , body mass index , baseline plasma folate , or aspirin allocation . CONCLUSIONS Folic acid at 1 mg/d does not reduce colorectal adenoma risk . Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00272324 Background and Purpose — We sought to determine whether folic acid supplementation can independently reduce the risk of first stroke associated with elevated total cholesterol levels in a sub analysis using data from the CSPPT ( China Stroke Primary Prevention Trial ) , a double-blind , r and omized controlled trial . Methods — A total of 20 702 hypertensive adults without a history of major cardiovascular disease were r and omly assigned to a double-blind daily treatment of an enalapril 10-mg and a folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone . The primary outcome was first stroke . Results — The median treatment duration was 4.5 years . For participants not receiving folic acid treatment ( enalapril-only group ) , high total cholesterol ( ≥200 mg/dL ) was an independent predictor of first stroke when compared with low total cholesterol ( < 200 mg/dL ; 4.0 % versus 2.6 % ; hazard ratio , 1.52 ; 95 % confidence interval , 1.18–1.97 ; P=0.001 ) . Folic acid supplementation significantly reduced the risk of first stroke among participants with high total cholesterol ( 4.0 % in the enalapril-only group versus 2.7 % in the enalapril – folic acid group ; hazard ratio , 0.69 ; 95 % confidence interval , 0.56–0.84 ; P<0.001 ; number needed to treat , 78 ; 95 % confidence interval , 52–158 ) , independent of baseline folate levels and other important covariates . By contrast , among participants with low total cholesterol , the risk of stroke was 2.6 % in the enalapril-only group versus 2.5 % in the enalapril – folic acid group ( hazard ratio , 1.00 ; 95 % confidence interval , 0.75–1.30 ; P=0.982 ) . The effect was greater among participants with elevated total cholesterol ( P for interaction=0.024 ) . Conclusions — Elevated total cholesterol levels may modify the benefits of folic acid therapy on first stroke . Folic acid supplementation reduced the risk of first stroke associated with elevated total cholesterol by 31 % among hypertensive adults without a history of major cardiovascular diseases . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00794885 BACKGROUND M and atory fortification of flour with folic acid has reduced the number of neural tube defects in North America . Concerns that high intakes of folic acid might mask vitamin B-12 deficiency in older persons have delayed the introduction of fortification in many European countries . Cofortification of flour with folic acid and vitamin B-12 could simultaneously improve folate and vitamin B-12 status . OBJECTIVE The objective was to estimate the effect of the consumption of bread fortified with modest amounts of folic acid and vitamin B-12 on folate and vitamin B-12 status in healthy older persons living in the Netherl and s , where folic acid fortification is not taking place . DESIGN Men and women aged 50 - 75 y were r and omly assigned in this 12-wk double-blind , placebo-controlled trial to consume bread fortified with 138 mug folic acid and 9.6 mug vitamin B-12 daily ( n = 72 ) or unfortified bread ( n = 70 ) . RESULTS The consumption of fortified bread increased serum folate concentrations by 45 % ( mean : 6.3 nmol/L ; 95 % CI : 4.5 , 8.1 nmol/L ) and serum vitamin B-12 concentrations by 49 % ( mean : 102 pmol/L ; 95 % CI : 82 , 122 pmol/L ) relative to the placebo group . Fortified bread increased erythrocyte folate concentrations by 22 % and holotranscobalamin concentrations by 35 % ; it decreased homocysteine concentrations by 13 % and methylmalonic acid concentrations by 10 % . Consumption of fortified bread decreased the proportion of individuals with marginal serum vitamin B-12 concentrations ( < 133 pmol/L ) from 8 % at enrollment to 0 % after 12 wk . CONCLUSION Bread fortified with modest amounts of folic acid and vitamin B-12 will improve folate and vitamin B-12 status and a considerable proportion of vitamin B-12 deficiency in older people . This trial was registered at clinical trials.gov as NCT00353353 National Institutes of Health ( NIH ) consensus and state-of-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1 ) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality ( AHRQ ) , 2 ) presentations by investigators working in areas relevant to the conference questions during a 2-day public session , 3 ) questions and statements from conference attendees during open discussion periods that are part of the public session , and 4 ) closed deliberations by the panel during the remainder of the second day and the morning of the third . This statement is an independent report of the panel and is not a policy statement of the NIH or the federal government . The statement reflects the panel 's assessment of medical knowledge available at the time the statement was written . Thus , it provides a snapshot in time of the state of knowledge on the conference topic . When reading the statement , keep in mind that new knowledge is inevitably accumulating through medical research . At least half of American adults take a dietary supplement , the majority of which are multivitamin/multimineral ( MVM ) supplements . As more and more Americans seek strategies for maintaining good health and preventing disease , and as the marketplace offers an increasing number of products to fulfill that desire , it is important that consumers have the best possible information to make their choices . Assessing the available scientific evidence on the benefits of MVM supplement use for chronic disease prevention , identifying the gaps in the evidence , and recommending an appropriate research agenda to meet the shortfalls are subjects considered in this report . The word vitamine was coined in 1912 , as an abbreviated term meant to capture the notion of important factors in the diet , or vital amines . This was preceded more than 150 years earlier by British navy physician James Lind 's discoveryin the first recorded controlled trialthat citrus juice , a good source of what was found 2 centuries later to be vitamin C , could prevent scurvy in sailors . In 1913 , the first vitamin was isolated : thiamin , the deficiency of which caused beriberi . Thirteen vitamins and 15 essential minerals have now been identified as important to human nutrition . Large-scale fortification of diets began in the United States with the addition of iodine to table salt in 1924 to prevent goiter , followed by the addition of vitamin D to milk in 1933 to prevent rickets and the addition of thiamin , riboflavin , niacin , and iron to flour in 1941 . Multivitamin/multimineral products providing more than vitamins A and D became available in pharmacies and grocery stores in the mid-1930s . In the early 1940s , the first MVM tablet was introduced . Although clinical deficiency of vitamins or minerals , other than iron , is now uncommon in the United States , growth in supplement use has accelerated rapidly with marketing spurred by cl aims some based on scientific studies that chronic conditions could be prevented or treated by supplement use . Annual sales of supplements to Americans are now reported at about $ 23 billion , a substantial share of which is spent on vitamins and minerals . Because of such widespread use of MVM , increasing public and medical confusion over apparently contradictory results from studies , and reports of possible adverse effects from overuse in certain circumstances , the Office of Dietary Supplements and the Office of Medical Applications of Research of the NIH convened a State-of-the-Science Conference on Multivitamin/Mineral Supplements and Chronic Disease Prevention , held on 1517 May 2006 , in Bethesda , Maryl and . The goal of the conference was to assess the evidence available on MVM use and outcomes for chronic disease prevention in the generally healthy population of adults and to make recommendations for future research . The conference focused on vitamins and minerals and did not deal with botanicals , hormones , or other supplements . It also did not address the treatment of vitamin or mineral deficiencies . Except for considerations of safety , the conference also did not review issues of primary relevance to pregnant women or children . Specifically , the conference explored the following key questions : 1 ) What are the current patterns and prevalence of the public 's use of MVM supplements ? 2 ) What is known about the dietary nutrient intake of MVM users versus nonusers ? 3 ) What is the efficacy of single vitamin/mineral supplement use in chronic disease prevention ? 4 ) What is the efficacy of MVM  in chronic disease prevention in the general population of adults ? 5 ) What is known about the safety of MVM  for the generally healthy population ? and 6 ) What are the major knowledge gaps and research opportunities regarding MVM use ? During the first 2 days of the conference , experts presented information on each of the key questions . After weighing the scientific evidence , including the data presented by the speakers and a formal evidence report commissioned through AHRQ , an independent panel prepared and presented a draft of this state-of-the-science statement addressing the conference questions . The evidence report prepared for the conference is available at www.ahrq.gov/clinic/tp/multivittp.htm . For the purpose of this statement , the term MVM refers to any supplement containing 3 or more vitamins and minerals but no herbs , hormones , or drugs , with each component at a dose less than the tolerable upper level determined by the Food and Nutrition Boardthe maximum daily intake likely to pose no risk for adverse health effects . Our review also included studies of the relationship of single-nutrient supplements and 2-nutrient supplements to certain disease outcomes . The term primary prevention refers to preventing the development of disease in a person who does not have the disease in question . The chronic conditions assessed include cancer ; age-related sensory loss ; and cardiovascular , endocrine , neurologic , musculoskeletal , gastroenterologic , renal , and pulmonary diseases . A word is warranted about the nature of the evidence base considered by the panel . The range of vitamins and minerals of possible interest was so broad that the conference planning committee chose to focus the evidence report on nutrients for which the potential for impact had been most strongly suggested and on conditions for which supplements were thought to have the most potential influence . The planning committee also limited the scope of the evidence report to consideration of r and omized , controlled trials ( RCTs ) , which are generally considered the gold st and ard for evidence -based decision making . These are studies in which participants are allocated by chance alone to receive or not to receive 1 of 2 or more clinical interventions . For example , while folate supplementation was initially shown to decrease the risk for neural tube defects in animal studies , outcome data in nonhuman models were not considered sufficient evidence on which to base policy recommendations . At the next level of evidence , observational studies in humans suggested efficacy of folate supplementation to prevent such defects . However , these were criticized because they were not r and omized and were potentially subject to bias . Not until these findings were confirmed by RCTs in humans was public policy implemented , including fortification of cereal grains with folate . An observational study is one in which the exposure or treatment of interest is not assigned to the participant by the investigator . Such studies suggested that -carotene intake might protect against the development of some types of cancer . However , RCTs of -carotene supplementation not only showed no benefit , they also found an increased risk for lung cancer in persons who smoked cigarettes or who were exposed to asbestos . These examples illustrate both the risk of relying only on observational studies and the advantage of RCTs in identifying both benefits and risks of MVM supplementation . Limiting the focus of our statement to RCTs has some inherent limitations , given the potential of other types of studies to provide important insights . Observational studies , for example , are particularly useful for generating hypotheses , defining adverse effects , and documenting long-term treatment consequences . They are often essential precursors to the well-conducted RCTs important for policy formation . Our principal recommendations focus on the compelling research activities that must be supported to better inform the decisions that millions of Americans are making each day to use or not to use MVM supplements to prevent chronic disease . At the same time , mindful of the constraints of the available evidence base , we have also taken care not to make premature recommendations about whether generally healthy Americans should or should not take MVM supplements . Because of the need for more reliable information on MVMs , we have made strong recommendations for research and for increased U.S. Food and Drug Administration ( FDA ) oversight of the MVM industry . 1 . What Are the Current Patterns and Prevalence of the Public 's Use of MVM Supplements ? More than half of American adults take dietary supplements in the belief that they will make them feel better , give them greater energy , improve their health , and prevent and treat disease . The use of supplements has been steadily increasing , and growth appears likely to continue . Currently , users spend more than $ 23 billion per year on supplements , and among this supplement-using population , MVM is the major category of supplements , used by about one third of Americans . Uncertainty remains in estimating prevalence of use because of problems defining these products ; increasing complexity in the formulation of supplements , including more non-MVM components and specialized formulas ; and varying frequency of use . It appears that use is higher BACKGROUND Elevated plasma homocysteine concentrations are a risk factor for osteoporotic fractures . Lowering homocysteine with combined vitamin B-12 and folic acid supplementation may reduce fracture risk . OBJECTIVE This study [ B-vitamins for the PRevention Of Osteoporotic Fractures ( B-PROOF ) ] aim ed to determine whether vitamin B-12 and folic acid supplementation reduces osteoporotic fracture incidence in hyperhomocysteinemic elderly individuals . DESIGN This was a double-blind , r and omized , placebo-controlled trial in 2919 participants aged ≥65 y with elevated homocysteine concentrations ( 12 - 50 μmol/L ) . Participants were assigned to receive daily 500 μg vitamin B-12 plus 400 μg folic acid or placebo supplementation for 2 y. Both intervention and placebo tablets also contained 600 IU vitamin D3 . The primary endpoint was time to first osteoporotic fracture . Exploratory prespecified subgroup analyses were performed in men and women and in individuals younger than and older than age 80 y. Data were analyzed according to intention-to-treat and per- protocol principles . RESULTS Osteoporotic fractures occurred in 61 persons ( 4.2 % ) in the intervention group and 75 persons ( 5.1 % ) in the placebo group . Osteoporotic fracture risk was not significantly different between groups in the intention-to-treat analyses ( HR : 0.84 ; 95 % CI : 0.58 , 1.21 ) or per- protocol analyses ( HR : 0.81 ; 95 % CI : 0.54 , 1.21 ) . For persons aged > 80 y , in per- protocol analyses , osteoporotic fracture risk was lower in the intervention group than in the placebo group ( HR : 0.27 ; 95 % CI : 0.10 , 0.74 ) . The total number of adverse events ( including mortality ) did not differ between groups . However , 63 and 42 participants in the intervention and placebo groups , respectively , reported incident cancer ( HR : 1.56 ; 95 % CI : 1.04 , 2.31 ) . CONCLUSIONS These data show that combined vitamin B-12 and folic acid supplementation had no effect on osteoporotic fracture incidence in this elderly population . Exploratory subgroup analyses suggest a beneficial effect on osteoporotic fracture prevention in compliant persons aged > 80 y. However , treatment was also associated with increased incidence of cancer , although the study was not design ed for assessing cancer outcomes . Therefore , vitamin B-12 plus folic acid supplementation can not be recommended at present for fracture prevention in elderly people . The B-PROOF study was registered with the Netherl and s Trial Register ( trialregister.nl ) as NTR1333 and at clinical trials.gov as NCT00696414 INTRODUCTION Observational studies have suggested a causal relationship between hyperhomocysteinemia and cardiovascular complications such as stroke and ischemic heart disease . The Homocysteine Lowering Trialists ' Collaboration has shown that daily administration of folic acid can significantly decrease homocysteine levels up to 25 % . Aim of this study was to investigate the effect of daily supplementation of folic acid ( 5 mg ) on IMT after 18 months of treatment in patients with at least one cardiovascular risk factor . METHODS We enrolled 103 patients with at least one cardiovascular risk factor who were r and omized to receive either a daily dose of 5 mg folic acid ( group I , n=53 ) or placebo ( group II , n=50 ) for 18 months . RESULTS After 18 months of folic acid supplementation , homocysteine levels were significantly reduced in the active treatment group compared to a non-significant increase in the placebo group . Folic acid levels were markedly increased in the former group and non-significantly reduced in the latter . Significant regression of carotid IMT was observed ( 0.961+/-0.092 to 0.933+/-0.077 mm , p<0.001 ) compared to significant IMT progression in the placebo group ( 0.964+/-0.099 to 0.984+/-0.094 mm ) . CONCLUSION Folic acid supplementation results in significant IMT reduction after 18 months in patients with at least one cardiovascular risk Background Osteoporosis is a major health problem , and the economic burden is expected to rise due to an increase in life expectancy throughout the world . Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12 and folate status are associated with an increased fracture risk . As vitamin B12 and folate intake and status play a large role in homocysteine metabolism , it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration . Methods / Design The B-PROOF ( B-Vitamins for the PRevention Of Osteoporotic Fractures ) study is a r and omized double-blind placebo-controlled trial . The intervention comprises a period of two years , and includes 2919 subjects , aged 65 years and older , independently living or institutionalized , with an elevated homocysteine concentration ( ≥ 12 μmol/L ) . One group receives daily a tablet with 500 μg vitamin B12 and 400 μg folic acid and the other group receives a placebo tablet . In both tablets 15 μg ( 600 IU ) vitamin D is included . The primary outcome of the study is osteoporotic fractures . Measurements are performed at baseline and after two years and cover bone health i.e. bone mineral density and bone turnover markers , physical performance and physical activity including falls , nutritional intake and status , cognitive function , depression , genetics and quality of life . This large multi-center project is carried out by a consortium from the Erasmus MC ( Rotterdam , the Netherl and s ) , VUmc ( Amsterdam , the Netherl and s ) and Wageningen University , ( Wageningen , the Netherl and s ) , the latter acting as coordinator . Discussion To our best knowledge , the B-PROOF study is the first intervention study in which the effect of vitamin B12 and folic acid supplementation on osteoporotic fractures is studied in a general elderly population . We expect the first longitudinal results of the B-PROOF intervention in the second semester of 2013 . The results of this intervention will provide evidence on the efficacy of vitamin B12 and folate supplementation in the prevention of osteoporotic fractures . Trial Registration The B-PROOF study is registered with the Netherl and s Trial ( NTR NTR1333 ) and with Clinical Trials.gov ( NCT00696514 ) Objective To determine if use of paracetamol in early life is an independent risk factor for  childhood asthma .  Design Prospect i ve birth cohort study . Setting Melbourne Atopy Cohort Study . Participants 620 children with a family history of allergic disease , with paracetamol use prospect ively documented on 18 occasions from birth to 2 years of age , followed until age 7 years . Main outcome measures The primary outcome was childhood asthma , ascertained by question naire at 6 and 7 years . Secondary outcomes were infantile wheeze , allergic rhinitis , eczema , and skin prick test positivity . Results Paracetamol had been used in 51 % ( 295/575 ) of children by 12 weeks of age and in 97 % ( 556/575 ) by 2 years . Between 6 and 7 years , 80 % ( 495/620 ) were followed up ; 30 % ( 148 ) had current asthma . Increasing frequency of paracetamol use was weakly associated with increased risk of childhood asthma ( crude odds ratio 1.18 , 95 % confidence interval 1.00 to 1.39 , per doubling of days of use ) . However , after adjustment for frequency of respiratory infections , this association essentially disappeared ( odds ratio 1.08 , 0.91 to 1.29 ) . Paracetamol use for non-respiratory causes was not associated with asthma ( crude odds ratio 0.95 , 0.81 to 1.12 ) . Conclusions In children with a family history of allergic diseases , no association was found between early paracetamol use and risk of subsequent allergic disease after adjustment for respiratory infections or when paracetamol use was restricted to non-respiratory tract infections . These findings suggest that early paracetamol use does not increase the risk of asthma BACKGROUND Multivitamin-mineral ( MVM ) products are the most commonly used supplements in the United States , followed by multivitamin ( MV ) products . Two r and omized clinical trials ( RCTs ) did not show an effect of MVMs or MVs on cardiovascular disease ( CVD ) mortality ; however , no clinical trial data are available for women with MVM supplement use and CVD mortality . OBJECTIVE The objective of this research was to examine the association between MVM and MV use and CVD-specific mortality among US adults without CVD . METHODS A nationally representative sample of adults from the restricted data NHANES III ( 1988 - 1994 ; n = 8678 ; age ≥40 y ) were matched with mortality data reported by the National Death Index through 2011 to examine associations between MVM and MV use and CVD mortality by using Cox proportional hazards models , adjusting for multiple potential confounders . RESULTS We observed no significant association between CVD mortality and users of MVMs or MVs compared with nonusers ; however , when users were classified by the reported length of time products were used , a significant association was found with MVM  use of > 3 y compared with nonusers ( HR : 0.65 ; 95 % CI : 0.49 , 0.85 ) . This finding was largely driven by the significant association among women ( HR : 0.56 ; 95 % CI : 0.37 , 0.85 ) but not men ( HR : 0.79 ; 95 % CI : 0.44 , 1.42 ) . No significant association was observed for MV products and CVD mortality in fully adjusted models . CONCLUSIONS In this nationally representative data set with detailed information on supplement use and CVD mortality data ∼20 y later , we found an association between  MVM  use of > 3 y and reduced CVD mortality risk for women when models controlled for age , race , education , body mass index , alcohol , aspirin use , serum lipids , blood pressure , and blood glucose/glycated hemoglobin . Our results are consistent with the 1 available RCT in men , indicating no relation with MVM use and CVD mortality Background and Purpose — Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine ( total homocysteine [ tHcy ] ) accelerate cardiovascular disease by promoting vascular inflammation , endothelial dysfunction , and hypercoagulability . Methods — We conducted a r and omized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg , vitamin B12 0.5 mg , and vitamin B6 25 mg compared with placebo on laboratory markers of vascular inflammation , endothelial dysfunction , and hypercoagulability . Results — At 6 months after r and omization , there was no significant difference in blood concentrations of markers of vascular inflammation ( high-sensitivity C-reactive protein [ P=0.32 ] ; soluble CD40L [ P=0.33 ] ; IL-6 [ P=0.77 ] ) , endothelial dysfunction ( vascular cell adhesion molecule-1 [ P=0.27 ] ; intercellular adhesion molecule-1 [ P=0.08 ] ; von Willebr and factor [ P=0.92 ] ) , and hypercoagulability ( P-selectin [ P=0.33 ] ; prothrombin fragment 1 and 2 [ P=0.81 ] ; D-dimer [ P=0.88 ] ) among patients assigned vitamin therapy compared with placebo despite a 3.7-&mgr;mol/L ( 95 % CI , 2.7 to 4.7 ) reduction in total homocysteine ( tHcy ) . Conclusions — Lowering tHcy by 3.7 & mgr;mol/L with folic acid-based multivitamin therapy does not significantly reduce blood concentrations of the biomarkers of inflammation , endothelial dysfunction , or hypercoagulability measured in our study . The possible explanations for our findings are : ( 1 ) these biomarkers are not sensitive to the effects of lowering tHcy ( eg , multiple risk factor interventions may be required ) ; ( 2 ) elevated tHcy causes cardiovascular disease by mechanisms other than the biomarkers measured ; or ( 3 ) elevated tHcy is a noncausal marker of increased vascular risk Objective The efficacy of combined treatment consisting of enalapril and folic acid ( FA ) was compared to that of enalapril alone in reducing the serum uric acid ( UA ) levels in adult hypertensive patients in China . Methods Patients with mild to moderate hypertension ( n=480 ) were r and omly assigned to one of three treatment groups : ( 1 ) 10 mg enalapril ( control group ) , ( 2 ) 10 mg enalapril plus 0.4 mg FA ( low-FA group ) or ( 3 ) 10 mg enalapril plus 0.8 mg FA ( high-FA group ) daily for eight weeks . The primary outcome was the UA ratio ( week 8 UA : baseline UA ) . Results The final analysis included 450 patients ( 43.1 % men , 27 - 75 years of age ) . An adjusted multivariable regression analysis revealed no significant differences in the UA ratio between the three groups after eight weeks of treatment . In the subgroup analysis stratified according to the baseline UA level , the high-FA group demonstrated a significantly greater UA-lowering response among the patients with an elevated baseline UA concentration ( UA ≥310 μmol/L ) [ median UA ratio ( 25th percentile , 75th percentile ) : 0.94 ( 0.83 , 1.01 ) ] , compared with that observed in the control group [ 0.97 ( 0.90 , 1.00 ) , p=0.025 ] . Similar results were found in the participants with baseline hyperuricemia ( HUA ; UA : men > 420 μmol/L , women > 350 μmol/L ) . Conclusion In this sample of adult hypertensive patients , the administration of a daily dose of 10 mg of enalapril combined with 0.8 mg of FA had a greater beneficial effect on the serum UA levels than did that of 10 mg of enalapril alone in patients with either an elevated UA concentration or HUA In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias AIMS To determine the effects on homocysteine levels of two doses of folic acid compared to placebo , where the high dose is typical of that provided by pharmacological intervention and the low dose approximates that provided by dietary supplementation . METHODS AND RESULTS The PACIFIC study was a double-blind , placebo-controlled , factorial r and omized trial . Seven hundred and twenty-three individuals with a history of myocardial infa rct ion or unstable angina were recruited from 28 clinical cardiology centres in Australia and New Zeal and and r and omized to folic acid 2.0 mg daily , folic acid 0.2 mg daily or placebo . The primary outcome , homocysteine , was measured using a fluorescence polarization immunoassay . Compared to placebo , 2.0 mg folic acid  reduced homo-cysteine by 1.8 micromol x 1(-1 ) [ 95 % confidence interval ( CI ) 1.3 - 2.3 ] and 0.2 mg reduced homocysteine by 1.2 micromol x 1(-1 ) [ 95 % CI 0.8 - 1.7 ) . The higher dose reduced homocysteine significantly more than the lower dose ( P=001 ) . CONCLUSIONS Both doses of folic acid  reduced homocysteine , but the effects of the 2.0 mg dose were about one third greater than the 0.2 mg dose . Fortification of foods with folic acid should result in population -wide lower levels of homocysteine but high-dose pharmacological supplementation would produce greater reductions for high-risk individuals Background Despite growing attention to nutrition and quality of life in cardiovascular disease survivors , the impact of dietary factors according to disease type or to quality of life domain is poorly understood . We investigated the effects of B vitamin and /or n-3 fatty acid supplementation on health-related quality of life among survivors of stroke , myocardial infa rct ion , or unstable angina . Methods We performed ancillary analyses of the SU.FOL.OM3 trial ( 2003–2009 ; France ) . In total , 2,501 men ( mean age = 61 y ) and women ( mean age = 63 y ) were r and omized in a 2 × 2 factorial design to : 1 ) 0.56 mg 5-methyl-tetrahydrofolate , 3 mg vitamin B6 , 0.02 mg vitamin B12 ; 2 ) 600 mg eicosapentaenoic and docosahexaenoic acids in a 2∶1 ratio ; 3 ) B vitamins and n-3 fatty acids combined ; or 4 ) placebo . Health-related quality of life was evaluated at follow-up with the Medical Outcomes Study 36-Item Short Form Health Survey . Data from 2,029 individuals were used in this analysis . Results After 3.1±0.4 y , no effects of supplementation with either B vitamins  or n-3 fatty acids on quality of life ( physical or mental health domains ) were found . However , participants receiving B vitamins had slightly more activity limitations due to emotional problems compared with those not receiving B vitamins ( mean difference = 3.8 ; 95 % CI : 0.4 , 7.1 ) . A significant interaction of treatment by prior disease revealed an inverse association between n-3 fatty acids and vitality among myocardial infa rct ion survivors ( mean difference = 2.9 ; 95 % CI : 0.5 , 5.2 ) . Conclusions There were no beneficial effects of supplementation with relatively low doses of B vitamins or n-3 fatty acids on health-related quality of life in cardiovascular disease survivors . The adverse effects of B vitamins on activity limitations and of n-3 fatty acids on vitality among individuals with prior myocardial infa rct ion merit confirmation High plasma homocysteine ( Hcy ) levels are associated with increased osteoporotic fracture incidence . However , the mechanism remains unclear . We investigated the effect of Hcy-lowering vitamin B12 and folic acid treatment on bone mineral density ( BMD ) and calcaneal quantitative ultrasound ( QUS ) parameters . This r and omized , double-blind , placebo-controlled trial included participants aged ≥65 years with plasma Hcy levels between 12 and 50 µmol/L. The intervention comprised 2-year supplementation with either a combination of 500 µg B12 , 400 µg folic acid , and 600 IU vitamin D or placebo with 600 IU vitamin D only . In total , 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS .  Femoral neck ( FN ) BMD , lumbar spine ( LS ) BMD , calcaneal broadb and ultrasound attenuation ( BUA ) , and calcaneal speed of sound ( SOS ) were assessed . After 2 years , FN-BMD and BUA had significantly decreased , while LS-BMD significantly increased ( all p < 0.01 ) and SOS did not change in either treatment arm . No statistically significant differences between the intervention and placebo group were present for FN-BMD ( p = 0.24 ) , LS-BMD ( p = 0.16 ) , SOS ( p = 0.67 ) , and BUA ( p = 0.96 ) . However , exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons > 80 years ( estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group , p = 0.04 for difference ) . In conclusion , this study showed no overall effect of treatment with vitamin B12 and folic acid on BMD or QUS parameters in elderly , mildly hyperhomocysteinemic persons , but suggests a small beneficial effect on BUA in persons > 80 years who were compliant in taking the supplement BACKGROUND Homocysteine is a risk factor for cardiovascular disease . We evaluated the efficacy of homocysteine-lowering treatment with B vitamins for secondary prevention in patients who had had an acute myocardial infa rct ion . METHODS The trial included 3749 men and women who had had an acute myocardial infa rct ion within seven days before r and omization . Patients were r and omly assigned , in a two-by-two factorial design , to receive one of the following four daily treatments : 0.8 mg of folic acid , 0.4 mg of vitamin B12 , and 40 mg of vitamin B6 ; 0.8 mg of folic acid and 0.4 mg of vitamin B12 ; 40 mg of vitamin B6 ; or placebo . The primary end point during a median follow-up of 40 months was a composite of recurrent myocardial infa rct ion , stroke , and sudden death attributed to coronary artery disease . RESULTS The mean total homocysteine level was lowered by 27 percent among patients given folic acid plus vitamin B12 , but such treatment had no significant effect on the primary end point ( risk ratio , 1.08 ; 95 percent confidence interval , 0.93 to 1.25 ; P=0.31 ) . Also , treatment with vitamin B6 was not associated with any significant benefit with regard to the primary end point ( relative risk of the primary end point , 1.14 ; 95 percent confidence interval , 0.98 to 1.32 ; P=0.09 ) . In the group given folic acid , vitamin B12 , and vitamin B6 , there was a trend toward an increased risk ( relative risk , 1.22 ; 95 percent confidence interval , 1.00 to 1.50 ; P=0.05 ) . CONCLUSIONS Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infa rct ion . A harmful effect from combined B vitamin treatment was suggested . Such treatment should therefore not be recommended . ( Clinical Trials.gov number , NCT00266487 . ) Homocysteinemia is a risk factor for cardiovascular diseases . Folic acid combined with vitamins B6 and B12 is effective in lowering homocysteine levels . This r and omized placebo-controlled study was design ed to determine the effect of a folic acid-based supplement on secondary prevention of clinical events in non-ST-segment elevation acute coronary syndromes . The study comprised 240 patients with either unstable angina or non-ST-elevation myocardial infa rct ion in the previous 2 weeks who were r and omized to a folate group ( n = 116 ) or a placebo group ( n = 124 ) . The folate group received 1 mg folic acid , 400 μg vitamin B12 , and 10 mg vitamin B6 daily . Clinical outcomes within 6 months were assessed . The composite endpoint of death , nonfatal acute coronary syndrome , and serious re-hospitalization was significantly higher in the folate group ; serious re-hospitalization alone was significantly higher in this group . Advanced age and diabetes increased susceptibility to the composite outcome . Folic acid-based supplementation is not beneficial and may even be harmful in the secondary prevention of cardiovascular events in patients with unstable angina and non-ST-elevation myocardial infa rct ion . Further studies on the safety of such supplements are suggested . Controlled Clinical Trials Registry no. IS RCT N30249553 Background and Purpose — Elevated total homocysteine is associated with a higher risk of cerebrovascular disease . It is not known whether lowering homocysteine impacts on stroke risk , both in terms of severity and ischemic vs hemorrhagic stroke subtypes . Our aim was to determine whether vitamin therapy reduces the risk of ischemic and hemorrhagic stroke , as well as stroke-related disability . Methods — We analyzed stroke outcomes among participants of the Heart Outcomes Prevention Evaluation 2 ( HOPE 2 ) trial that r and omized 5522 adults with known cardiovascular disease to a daily combination of 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 , or matching placebo  , for 5 years . Results — Among 5522 participants , stroke occurred in 258 ( 4.7 % ) individuals during a mean of 5 years of follow-up . The geometric mean homocysteine concentration decreased by 2.2 & mgr;mol/L in the vitamin therapy group and increased by 0.80 & mgr;mol/L in the placebo group . The incidence rate of stroke was 0.88 per 100 person-years in the vitamin therapy group and 1.15 per 100 person-years in the placebo group ( hazard ratio [ HR ] , 0.75 ; 95 % CI , 0.59–0.97 ) . Vitamin therapy also reduced the risk of nonfatal stroke ( HR , 0.72 ; 95 % CI , 0.54–0.95 ) but did not impact on neurological deficit at 24 hours ( P=0.45 ) or functional dependence at discharge or at 7 days ( OR , 0.95 ; 95 % CI , 0.57–1.56 ) . In subgroup analysis , patients aged younger than 69 years , from regions without folic acid food fortification , with higher baseline cholesterol and homocysteine levels , and those not receiving antiplatelet or lipid-lowering drugs at enrollment had a larger treatment benefit . Conclusions — Lowering of homocysteine with folic acid and vitamins B6 and B12 did reduce the risk of overall stroke , but not stroke severity or disability OBJECTIVE To assess prospect ively the risk of coronary heart disease associated with elevated plasma levels of homocyst(e)ine . DESIGN Nested case-control study using prospect ively collected blood sample s. SETTING Participants in the Physicians ' Health Study . PARTICIPANTS A total of 14,916 male physicians , aged 40 to 84 years , with no prior myocardial infa rct ion ( MI ) or stroke provided plasma sample s at baseline and were followed up for 5 years . Sample s from 271 men who subsequently developed MI were analyzed for homocyst(e)ine levels together with paired controls , matched by age and smoking . MAIN OUTCOME MEASURE Acute MI or death due to coronary disease . RESULTS Levels of homocyst(e)ine were higher in cases than in controls ( 11.1 + /- 4.0 [ SD ] vs 10.5 + /- 2.8 nmol/mL ; P = .03 ) . The difference was attributable to an excess of high values among men who later had MIs . The relative risk for the highest 5 % vs the bottom 90 % of homocyst(e)ine levels was 3.1 ( 95 % confidence interval , 1.4 to 6.9 ; P = .005 ) . After additional adjustment for diabetes , hypertension , aspirin assignment , Quetelet 's Index , and total/high-density lipoprotein cholesterol , this relative risk was 3.4 ( 95 % confidence interval , 1.3 to 8.8 ) ( P = .01 ) . Thirteen controls and 31 cases ( 11 % ) had values above the 95th percentile of the controls . CONCLUSIONS Moderately high levels of plasma homocyst(e)ine are associated with subsequent risk of MI independent of other coronary risk factors . Because high levels can often be easily treated with vitamin supplements , homocyst(e)ine may be an independent , modifiable risk factor Background and Purpose — The Vitamin Intervention for Stroke Prevention trial ( VISP ) intention-to-treat analysis did not show efficacy of combined vitamin therapy for recurrent vascular events in patients with nondisabling stroke . Reasons for lack of efficacy may have included folate fortification of grain products , inclusion of the recommended daily intake for B12 in the low-dose arm , treatment with parenteral B12 in patients with low B12 levels in both study arms , a dose of B12 too low for patients with malabsorption , supplementation with non study vitamins , and failure of patients with significant renal impairment to respond to vitamin therapy . We conducted an efficacy analysis limited to patients most likely to benefit from the treatment , based on hypotheses arising from evidence developed since VISP was initiated . The criteria for this subgroup were defined before any data analysis . Methods — For this analysis , we excluded patients with low and very high B12 levels at baseline ( < 250 and > 637 pmol/L , representing the 25th and 95th percentiles ) , to exclude those likely to have B12 malabsorption or to be taking B12 supplements outside the study and patients with significant renal impairment ( glomerular filtration rate < 46.18 ; the 10th percentile ) . Results — This subgroup represents 2155 patients ( 37 % female ) , with a mean age of 66±10.7 years . For the combined end point of ischemic stroke , coronary disease , or death , there was a 21 % reduction in the risk of events in the high-dose group compared with the low-dose group ( unadjusted P=0.049 ; adjusted for age , sex , blood pressure , smoking , and B12 level P=0.056 ) . In Kaplan – Meier survival analysis comparing 4 groups , patients with a baseline B12 level at the median or higher r and omized to high-dose vitamin had the best overall outcome , and those with B12 less than the median assigned to low-dose vitamin had the worst ( P=0.02 for combined stroke , death , and coronary events ; P=0.03 for stroke and coronary events ) . Conclusions — In the era of folate fortification , B12 plays a key role in vitamin therapy for total homocysteine . Higher doses of B12 , and other treatments to lower total homocysteine may be needed for some patients In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if a body of evidence is associated with a high risk of publication bias . Even when individual studies included in best- evidence summaries have a low risk of bias , publication bias can result in substantial overestimates of effect . Authors should suspect publication bias when available evidence comes from a number of small studies , most of which have been commercially funded . A number of approaches based on examination of the pattern of data are available to help assess publication bias . The most popular of these is the funnel plot ; all , however , have substantial limitations . Publication bias is likely frequent , and caution in the face of early results , particularly with small sample size and number of events , is warranted Background and Purpose — To determine the effect of B vitamin treatment on the incidence of cancer among patients with stroke or transient ischemic attack . Methods — A total of 8164 patients with recent stroke or transient ischemic attack were r and omly allocated to double-blind treatment with 1 tablet daily of placebo or B vitamins ( 2 mg folic acid , 25 mg vitamin B6 , 500 & mgr;g vitamin B12 ) and followed for a median of 3.4 years for any cancer as an adverse event . Results — There was no significant difference in the incidence of any cancer among participants assigned B vitamins compared with placebo ( 4.04 % versus 4.59 % ; risk ratio , 0.86 ; 95 % CI , 0.70–1.07 ) and no difference in cancer mortality ( 2.35 % versus 2.09 % ; risk ratio , 1.09 ; 0.81–1.46 ) . Among 1899 patients with diabetes , the incidence of cancer was higher among participants assigned B vitamins compared with placebo ( 5.35 % versus 3.28 % ; adjusted risk ratio , 2.21 ; 1.31–3.73 ) , whereas among 6168 patients without diabetes , the incidence of cancer was lower among participants assigned B vitamins compared with placebo ( 3.66 % versus 5.03 % ; adjusted risk ratio , 0.67 ; 0.51–0.87 ; P for interaction=0.0001 ) . Conclusions — Daily administration of folic acid , vitamin B6 , and vitamin B12 to 8164 patients with recent stroke or transient ischemic attack for a median of 3.4 years had no significant effect , compared with placebo , on cancer incidence or mortality . However , a post hoc subgroup analysis raises the hypothesis that folic acid treatment may increase the incidence of cancer among diabetics and reduce the incidence of cancer among nondiabetics with a history of stroke or transient ischemic attack . Clinical Trial Registration — URL : www . clinical trials.gov . Unique identifier : NCT00097669 . URL : www.controlled-trials.com . Unique identifier : IS RCT N74743444 The aim of this study was to test the influence of high-dose folic acid ( 10 mg/d ) on endothelial function in patients referred for coronary intervention after an acute myocardial infa rct ion ( AMI ) and determine its relation to homocysteine levels . Flow-mediated dilation ( FMD ) of the brachial artery was performed in 40 patients after AMI ( 16 with normal homocysteine levels and 24 patients with elevated levels [ > 11 micromol/L ] ) . Subjects were r and omized to receive first folic acid ( 10 mg/day ; group A ) or placebo ( group B ) for 6 weeks in a double-blind crossover trial with a 2-week washout . Plasma folate , total homocysteine and its subtypes ( oxidized , reduced , and protein-bound ) , FMD , and nitroglycerin-mediated dilation were assessed at baseline and at 6 and 14 weeks . In group A , folic acid improved FMD from 3.98 + /- 0.35 % to 6.44 + /- 0.56 % ( p < 0.001 ) . This effect persisted after the crossover with placebo ( 5.42 + /- 0.59 , p = 0.13 ) . In group B , placebo did not increase FMD ( 4.01 + /- 0.34 % vs 4.46 + /- 0.38 , p = 0.38 ) ; however , a significant increase was observed in the second active treatment period ( 6.49 + /- 0.56 % , p = 0.005 ) . In both groups , improved FMD neither correlated with basal levels of homocysteine and its subtypes nor with changes induced during the folate treatment . Nitroglycerin-mediated dilation did not change significantly in either group . Folic acid increased FMD in both normo- and hyperhomocysteinanemic groups ( p = 0.006 and p < 0.001 ) . In conclusion , 6-week treatment with high-dose folic acid improves endothelial function in post-AMI patients , independent from homocysteine status . Folic acid can be recommended to improve postinfa rct ion endothelial dysfunction in patients with normo- and hyperhomocysteinemia BACKGROUND Elevated plasma total homocysteine ( tHcy ) , low B-vitamin intake , and genetic polymorphisms related to tHcy metabolism may play roles in coronary heart disease ( CHD ) . More prospect i ve studies are needed . METHODS AND RESULTS We used a prospect i ve case-cohort design to determine whether tHcy-related factors are associated with incidence of CHD over an average of 3.3 years of follow-up in a biracial sample of middle-aged men and women . Age- , race- , and field center-adjusted CHD incidence was associated positively ( P<0.05 ) with tHcy in women but not men , and CHD was associated negatively ( P<0.05 ) with plasma folate ( women only ) , plasma pyridoxal 5'-phosphate ( both sexes ) , and vitamin supplementation ( women only ) . However , after accounting for other risk factors , only plasma pyridoxal 5'-phosphate was associated with CHD incidence ; the relative risk for the highest versus lowest quintile of pyridoxal 5'-phosphate was 0.28 ( 95 % CI=0.1 to 0.7 ) . There was no association of CHD with the C677 T mutation of the methylenetetrahydrofolate reductase gene or with 3 mutations of the cystathionine beta-synthase gene . CONCLUSIONS Our prospect i ve findings add uncertainty to conclusions derived mostly from cross-sectional studies that tHcy is a major , independent , causative risk factor for CHD . Our findings point more strongly to the possibility that vitamin B6 offers independent protection . R and omized trials , some of which are under way , are needed to better clarify the interrelationships of tHcy , B vitamins  , and cardiovascular disease Background / Objectives : To compare the efficacy of a diet rich in natural folate and of two different folic acid supplementation protocol s in subjects with “ moderate ” hyperhomocysteinemia , also taking into account C677 T polymorphism of 5,10-methylenetetrahydrofolate reductase ( MTHFR ) gene . Subjects/ Methods : We performed a 13 week open , r and omized , double blind clinical trial on 149 free living persons with mild hyperhomocyteinemia , with daily 200 μg from a natural folate-rich diet , 200 μg [6S]5-methyltetrahydrofolate ( 5-MTHF ) , 200 μg folic acid or placebo . Participants were stratified according to their MTHFR genotype . Results : Homocysteine ( Hcy ) levels were reduced after folate enriched diet , 5-MTHF or folic acid supplementation respectively by 20.1 % ( p < 0.002 ) , 19.4 % ( p < 0.001 ) and 21.9 % ( p < 0.001 ) , as compared to baseline levels and significantly as compared to placebo ( p < 0.001 , p < 0.002 and p < 0.001 , respectively for enriched diet , 5-MTHF and folic acid ) . After this enriched diet and the folic acid supplementation , Hcy in both genotype groups decreased approximately to the same level , with higher percentage decreases observed for the TT group because of their higher pre-treatment value . Similar results were not seen by genotype for 5-MTHF . A significant increase in RBC folate concentration was observed after folic acid and natural folate-rich food supplementations , as compared to placebo . Conclusions : Supplementation with natural folate-rich foods , folic acid and 5-MTHF reached a similar reduction in Hcy concentrations Background During the last decades , many basic and clinical research have pointed to the role of B vitamins ( folate , vitamins B6 and B12 ) and n-3 fatty acids as nutritional factors that might have a protective effect on the development of cardiovascular diseases ( CVD ) . Methods / design The SU.FOL.OM3 ( SUpplementation with FOlate , vitamin B6 and B12 and /or OMega-3 fatty acids ) trial is a r and omized double-blind , placebo-controlled , secondary -prevention trial design ed to test the efficacy of 5-methyl tetra-hydro-folates ( 5-MTHF ) supplementation , in combination with vitamin B6 and B12 and /or n-3 fatty acids , at nutritional doses , on fatal and non fatal ischemic CVD in a 2 × 2 factorial design . A total of 2501 patients aged between 45 and 80 years who had a past history , in the previous year , of myocardial infa rct ion ( n = 1151 ) or instable angina pectoris ( n = 711 ) or an ischemic stroke ( n = 639 ) were included . Subjects have to be supplemented and followed up for five years . Daily supplementation comprised nutritional doses of 5-MTHF ( 560 μg ) , vitamin B6 ( 3 mg ) and B12 ( 20 μg ) and /or n-3 fatty acids ( 600 mg with an EPA : DHA ratio of 2:1 ) . A factorial design 2 × 2 has been applied to investigate the separate effects of the B-vitamins , and the n-3 fatty acids , as well as their interaction as compared to the placebo . The primary endpoint is a combination of myocardial infa rct ion , ischemic stroke and cardiovascular death . Secondary endpoints are events of the composite endpoint taken separately , total mortality , and other cardiovascular events such as acute coronary syndromes , coronary revascularization , cardiac failure , arrhythmia ... Conclusion Baseline socio-demographic and medical characteristics of participants are totally comparable in the four r and omized groups . Trial registration Current Controlled Trials IS RCT A total of 3,318 men and women from a region in rural China were r and omized to receive daily either a multiple vitamin/mineral supplement or a placebo . Deaths that occurred in the participants were ascertained and classified according to cause over the 6-year period from 1985 to 1991 . At the end of supplementation , blood pressure readings were taken , and the prevalence of hypertension was determined . There was a slight reduction in overall mortality in the supplement group ( relative risk ( RR ) = 0.93 , 95 percent confidence interval ( CI ) 0.75 - 1.16 ) , with the decreased relative risk most pronounced for cerebrovascular disease deaths ( RR = 0.63 , 95 percent CI 0.37 - 1.07 ) . This benefit was greater for men ( RR = 0.42 , 95 percent CI 0.19 - 0.93 ) than for women ( RR = 0.93 , 95 percent CI 0.44 - 1.98 ) . Among the survivors , the presence of elevations in both systolic and diastolic blood pressures was less common in those who received the supplement ( RR for men = 0.43 , 95 % CI 0.28 - 0.65 ; RR for women = 0.92 , 95 percent CI 0.68 - 1.24 ) . This study indicates that supplementation with a multivitamin/mineral combination may have reduced mortality from cerebrovascular disease and the prevalence of hypertension in this rural population with a micronutrient-poor diet OBJECTIVE Homocysteinemia may play an etiologic role in the pathogenesis of type 2 diabetes by promoting oxidative stress , systemic inflammation , and endothelial dysfunction . We investigated whether homocysteine-lowering treatment by B vitamin supplementation prevents the risk of type 2 diabetes . RESEARCH DESIGN AND METHODS The Women 's Antioxidant and Folic Acid Cardiovascular Study ( WAFACS ) , a r and omized , double-blind , placebo-controlled trial of 5,442 female health professionals aged ≥40 years with a history of cardiovascular disease ( CVD ) or three or more CVD risk factors , included 4,252 women free of diabetes at baseline . Participants were r and omly assigned to either an active treatment group ( daily intake of a combination pill of 2.5 mg folic acid , 50 mg vitamin B6 , and 1 mg vitamin B12 ) or to the placebo group . RESULTS During a median follow-up of 7.3 years , 504 women had an incident diagnosis of type 2 diabetes . Overall , there was no significant difference between the active treatment group and the placebo group in diabetes risk ( relative risk 0.94 [ 95 % CI 0.79–1.11 ] ; P = 0.46 ) , despite significant lowering of homocysteine levels . Also , there was no evidence for effect modifications by baseline intakes of dietary folate , vitamin B6 , and vitamin B12 . In a sensitivity analysis , the null result remained for women compliant with their study pills ( 0.92 [ 0.76–1.10 ] ; P = 0.36 ) . CONCLUSIONS Lowering homocysteine levels by daily supplementation with folic acid and vitamins B6 and B12 did not reduce the risk of developing type 2 diabetes among women at high risk for CVD BACKGROUND Epidemiological studies suggest that raised plasma concentrations of total homocysteine might be a risk factor for major vascular events . Whether lowering total homocysteine with B vitamins prevents major vascular events in patients with previous stroke or transient ischaemic attack is unknown . We aim ed to assess whether the addition of once-daily supplements of B vitamins to usual medical care would lower total homocysteine and reduce the combined incidence of non-fatal stroke , non-fatal myocardial infa rct ion , and death attributable to vascular causes in patients with recent stroke or transient ischaemic attack of the brain or eye . METHODS In this r and omised , double-blind , parallel , placebo-controlled trial , we assigned patients with recent stroke or transient ischaemic attack ( within the past 7 months ) from 123 medical centres in 20 countries to receive one tablet daily of placebo or B vitamins ( 2 mg folic acid , 25 mg vitamin B6 , and 0.5 mg vitamin B12 ) . Patients were r and omly allocated by means of a central 24-h telephone service or an interactive website , and allocation was by use of r and om permuted blocks stratified by hospital . Participants , clinicians , carers , and investigators who assessed outcomes were masked to the assigned intervention . The primary endpoint was the composite of stroke , myocardial infa rct ion , or vascular death . All patients r and omly allocated to a group were included in the analysis of the primary endpoint . This trial is registered with Clinical Trials.gov , NCT00097669 , and Current Controlled Trials , IS RCT N74743444 . FINDINGS Between Nov 19 , 1998 , and Dec 31 , 2008 , 8164 patients were r and omly assigned to receive B vitamins ( n=4089 ) or placebo ( n=4075 ) . Patients were followed up for a median duration of 3.4 years ( IQR 2.0 - 5.5 ) . 616 ( 15 % ) patients assigned to B vitamins and 678 ( 17 % ) assigned to placebo reached the primary endpoint ( risk ratio [ RR ] 0.91 , 95 % CI 0.82 to 1.00 , p=0.05 ; absolute risk reduction 1.56 % , -0.01 to 3.16 ) . There were no unexpected serious adverse reactions and no significant differences in common adverse effects between the treatment groups . INTERPRETATION Daily administration of folic acid , vitamin B6 , and vitamin B12 to patients with recent stroke or transient ischaemic attack was safe but did not seem to be more effective than placebo in reducing the incidence of major vascular events . These results do not support the use of B vitamins to prevent recurrent stroke . The results of ongoing trials and an individual patient data meta- analysis will add statistical power and precision to present estimates of the effect of B vitamins . FUNDING Australia National Health and Medical Research Council , UK Medical Research Council , Singapore Biomedical Research Council , Singapore National Medical Research Council , Australia National Heart Foundation , Royal Perth Hospital Medical Research Foundation , and Health Department of Western Australia Objective To investigate whether dietary supplementation with B vitamins or omega 3 fatty acids , or both , could prevent major cardiovascular events in patients with a history of ischaemic heart disease or stroke . Design Double blind , r and omised , placebo controlled trial ; factorial design . Setting Recruitment throughout France via a network of 417 cardiologists , neurologists , and other physicians . Participants 2501 patients with a history of myocardial infa rct ion , unstable angina , or ischaemic stroke . Intervention Daily dietary supplement containing 5-methyltetrahydrofolate ( 560 μg ) , vitamin B-6 ( 3 mg ) , and vitamin B-12 ( 20 μg ) or placebo ; and containing omega 3 fatty acids ( 600 mg of eicosapentanoic acid and docosahexaenoic acid at a ratio of 2:1 ) or placebo . Median duration of supplementation was 4.7 years . Main outcome measures Major cardiovascular events , defined as a composite of non-fatal myocardial infa rct ion , stroke , or death from cardiovascular disease . Results Allocation to B vitamins lowered plasma homocysteine concentrations by 19 % compared with placebo , but had no significant effects on major vascular events ( 75 v 82 patients , hazard ratio , 0.90 ( 95 % confidence interval 0.66 to 1.23 , P=0.50 ) ) . Allocation to omega 3 fatty acids  increased plasma concentrations of omega 3 fatty acids by 37 % compared with placebo , but also had no significant effect on major vascular events ( 81 v 76 patients , hazard ratio 1.08 ( 0.79 to 1.47 , P=0.64 ) ) . Conclusion This study does not support the routine use of dietary supplements containing B vitamins or omega 3 fatty acids for prevention of cardiovascular disease in people with a history of ischaemic heart disease or ischaemic stroke , at least when supplementation is introduced after the acute phase of the initial event . Trial registration Current Controlled Trials IS RCT N41926726 Background / Objectives : Vitamin B12 ( B12 ) deficiency is common in Indians and a major contributor to hyperhomocysteinemia , which may influence fetal growth , risk of type II diabetes and cardiovascular disease . The purpose of this paper was to study the effect of physiological doses of B12 and folic acid on plasma total homocysteine ( tHcy ) concentration . Subjects/ Methods : A cluster r and omized , placebo-controlled , double-blind , 2 × 3 factorial trial , using the family as the r and omization unit . B12 was given as 2 or 10 μg capsules , with or without 200 μg folic acid , forming six groups ( B0F0 , B2F0 , B10F0 , B0F200 , B2F200 and B10F200 ) . Plasma tHcy concentration was measured before and after 4 and 12 months of supplementation . Results : From 119 families in the Pune Maternal Nutrition Study , 300 individuals were r and omized . There was no interaction between B12 and folic acid ( P=0.14 ) in relation to tHcy concentration change and their effects were analyzed separately : B0 vs. B2 vs. B10 ; and F0 vs. F200 . At 12 months , tHcy concentration reduced by a mean 5.9 ( 95 % CI : −7.8 , −4.1 ) μmol/l in B2 , and by 7.1 ( 95 % CI : −8.9 , −5.4 ) μmol/l in B10 , compared to nonsignificant rise of 1.2 ( 95 % CI : −0.5 , 2.9 ) μmol/l in B0 . B2 and B10 did not differ significantly . In F200 , tHcy concentration decreased by 4.8 ( 95 % CI : −6.3 , −3.3 ) μmol/l compared to 2.8 ( 95 % CI : −4.3 , −1.2 ) μmol/l in F0 . Conclusion : Daily oral supplementation with physiological doses of B12 is an effective community intervention to reduce tHcy .  Folic acid ( 200 μg per day ) showed no additional benefit , neither had any unfavorable effects BACKGROUND Observational studies have shown that low folate and elevated homocysteine concentrations are risk factors for vascular disease in the general population . R and omized controlled trials in vascular patients have failed to show that folic acid reduces the risk of recurrent vascular disease , whereas such trials are lacking in the general population . OBJECTIVE The objective was to determine whether folic acid supplementation reduces the progression of atherosclerosis as measured by common carotid intima-media thickness (CIMT)-a vali date d marker of atherosclerosis and predictor of vascular disease risk . DESIGN A r and omized , double-blind , placebo-controlled study in 819 men and postmenopausal women aged 50 - 70 y , free-living in the Netherl and s , and with a total homocysteine concentration ≥13 μmol/L at screening was conducted . Participants received either 800 μg folic acid or placebo daily for 3 y. Rate of change in CIMT and arterial distensibility were the primary and secondary outcomes , respectively . RESULTS Compared with placebo , serum folate increased by 577 % and plasma total homocysteine concentrations decreased by 26 % after 3 y of folic acid supplementation . The mean ( ±SE ) rate of change in CIMT was 1.9 ± 0.9 μm/y in the folic acid arm and 1.3 ± 0.8 μm/y in the placebo arm ( mean difference : 0.7 μm/y ; 95 % CI : -1.8 , 3.1 μm/y ; P = 0.59 ) . No difference was observed ( P = 0.23 ) between the rates of change in distensibility in the folic acid arm ( -0.53 ± 0.06 × 10(-3 ) kPa(-1 ) ) and in the placebo arm ( -0.62 ± 0.06 × 10(-3 ) kPa(-1 ) ) . CONCLUSION Despite a considerable increase in folate concentrations and a reduction in total homocysteine concentrations , 3-y folic acid supplementation did not slow down atherosclerotic progression or arterial stiffening . This trial was registered at clinical trials.gov as NCT00110604 Rationale Epidemiological studies suggest that elevated homocysteine is linked to stroke and heart disease . However , the results of lowering homocysteine levels in reducing the risk of stroke recurrence are controversial . Aims The study aims to evaluate whether homocysteine-lowering therapy with folic acid and vitamins B6 and B12 reduces recurrent stroke events and other combined incidence of recurrent vascular events and vascular death in ischemic stroke patients of low folate regions . Design This is a multicenter , r and omized , double-blinded , placebo-controlled trial . Patients ( n = 8000 , α = 0·05 , β = 0·10 ) within one-month of ischemic stroke ( large-artery atherosclerosis or small-vessel occlusion ) or hypertensive intracerebral haemorrhage with plasma homocysteine level ⩾15 μmol/l will be enrolled . Eligible patients will be r and omized by a web-based , r and om allocation system to receive multivitamins ( folic acid 0·8 mg , vitamin B610 mg , and vitamin B12 500 μg ) or matching placebo daily with a median follow-up of three-years . Study Outcomes Patients will be evaluated at six monthly intervals . The primary outcome event is the composite event ‘ stroke , myocardial infa rct ion , or death from any vascular cause ’ , whichever occurs first . Secondary outcome measures include nonvascular death , transient ischemic attack , depression , dementia , unstable angina , revascularization procedures of the coronary , and cerebral and peripheral circulations . Discussion This is the first multicenter r and omized trial of secondary prevention for ischemic stroke in a Chinese population with a higher homocysteine level but without folate food fortification BACKGROUND To advance knowledge about the cancer-chemopreventive potential of individual nutrients , we investigated the effects of B vitamin and /or ω-3 fatty acid supplements on cancer outcomes among survivors of cardiovascular disease . METHODS This was an ancillary study of the Supplementation With Folate , Vitamins B(6 ) and B(12 ) and /or Omega-3 Fatty Acids ( SU.FOL.OM3 ) secondary prevention trial ( 2003 - 2009 ) . In all , 2501 individuals aged 45 to 80 years were r and omized in a 2 × 2 factorial design to one of the following 4 daily supplementation groups : ( 1 ) 5-methyltetrahydrofolate ( 0.56 mg ) , pyridoxine hydrochloride ( vitamin B(6 ) ; 3 mg ) and cyanocobalamin ( vitamin B(12 ) ; 0.02 mg ) ; ( 2 ) eicosapentaenoic and docosahexaenoic acid ( 600 mg ) in a 2:1 ratio ; ( 3 ) B vitamins and ω-3 fatty acids ; or ( 4 ) placebo .  Overall and sex-specific hazard ratios ( HRs ) and 95 % CIs regarding the cancer outcomes were estimated with Cox proportional hazards models . RESULTS After 5 years of supplementation , incident cancer was vali date d in 7.0 % of the sample ( 145 events in men and 29 in women ) , and death from cancer occurred in 2.3 % of the sample . There was no association between cancer outcomes and supplementation with B vitamins ( HR , 1.15 [ 95 % CI , 0.85 - 1.55 ] ) and /or ω-3 fatty acids ( HR , 1.17 [ 95 % CI , 0.87 - 1.58 ] ) . There was a statistically significant interaction of treatment by sex , with no effect of treatment on cancer risk among men and increased cancer risk among women for ω-3 fatty acid supplementation ( HR , 3.02 [ 95 % CI , 1.33 - 6.89 ] ) . CONCLUSION We found no beneficial effects of supplementation with relatively low doses of B vitamins and /or ω-3 fatty acids on cancer outcomes in individuals with prior cardiovascular disease . Trial Registration is rct n.org Identifier : IS RCT N41926726 BACKGROUND In observational studies , lower homocysteine levels are associated with lower rates of coronary heart disease and stroke . Folic acid and vitamins B6 and B12 lower homocysteine levels . We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease . METHODS We r and omly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 or with placebo for an average of five years . The primary outcome was a composite of death from cardiovascular causes , myocardial infa rct ion , and stroke . RESULTS Mean plasma homocysteine levels decreased by 2.4 micromol per liter ( 0.3 mg per liter ) in the active-treatment group and increased by 0.8 micromol per liter ( 0.1 mg per liter ) in the placebo group . Primary outcome events occurred in 519 patients ( 18.8 percent ) assigned to active therapy and 547 ( 19.8 percent ) assigned to placebo ( relative risk , 0.95 ; 95 percent confidence interval , 0.84 to 1.07 ; P=0.41 ) . As compared with placebo , active treatment did not significantly decrease the risk of death from cardiovascular causes ( relative risk , 0.96 ; 95 percent confidence interval , 0.81 to 1.13 ) , myocardial infa rct ion ( relative risk , 0.98 ; 95 percent confidence interval , 0.85 to 1.14 ) , or any of the secondary outcomes . Fewer patients assigned to active treatment than to placebo had a stroke ( relative risk , 0.75 ; 95 percent confidence interval , 0.59 to 0.97 ) . More patients in the active-treatment group were hospitalized for unstable angina ( relative risk , 1.24 ; 95 percent confidence interval , 1.04 to 1.49 ) . CONCLUSIONS Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease . ( Clinical Trials.gov number , NCT00106886 ; Current Controlled Trials number , IS RCT N14017017 . ) BACKGROUND Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction , whether or not they have heart failure . We assessed the role of an angiotensin-converting-enzyme inhibitor , ramipril , in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure . METHODS A total of 9297 high-risk patients ( 55 years of age or older ) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were r and omly assigned to receive ramipril ( 10 mg once per day orally ) or matching placebo for a mean of five years . The primary outcome was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper . RESULTS A total of 651 patients who were assigned to receive  ramipril ( 14.0 percent ) reached the primary end point , as compared with 826 patients who were assigned to receive placebo ( 17.8 percent ) ( relative risk , 0.78 ; 95 percent confidence interval , 0.70 to 0.86 ; P<0.001 ) . Treatment with ramipril reduced the rates of death from cardiovascular causes ( 6.1 percent , as compared with 8.1 percent in the placebo group ; relative risk , 0.74 ; P<0.001 ) , myocardial infa rct ion ( 9.9 percent vs. 12.3 percent ; relative risk , 0.80 ; P<0.001 ) , stroke ( 3.4 percent vs. 4.9 percent ; relative risk , 0.68 ; P<0.001 ) , death from any cause ( 10.4 percent vs. 12.2 percent ; relative risk , 0.84 ; P=0.005 ) , revascularization procedures ( 16.3 percent vs. 18.8 percent ; relative risk , 0.85 ; P<0.001 ) , cardiac arrest ( 0.8 percent vs. 1.3 percent ; relative risk , 0.62 ; P=0.02 ) , [ corrected ] heart failure ( 9.1 percent vs. 11.6 percent ; relative risk , 0.77 ; P<0.001 ) , and complications related to diabetes ( 6.4 percent vs. 7.6 percent ; relative risk , 0.84 ; P=0.03 ) . CONCLUSIONS Ramipril significantly reduces the rates of death , myocardial infa rct ion , and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure Importance The efficacy of folic acid therapy on renal outcomes has not been previously investigated in population s without folic acid fortification . Objective 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 . Design , Setting , and Participants In this sub study 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 . Interventions Participants were r and omized 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 ) . Main Outcomes and Measures 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 . Results 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 result ed 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 . Conclusions and Relevance Enalapril-folic acid therapy , compared with enalapril alone , can significantly delay the progression of CKD among patients with mild-to-moderate CKD . Trial Registration clinical trials.gov Identifier : NCT00794885 Abstract Purpose We investigated whether daily supplementation with low-dose B vitamins in the healthy elderly population improves the Framingham risk score ( FRS ) , a predictor of cardiovascular disease risk . Methods Between 2007 and 2012 , a double-blind r and omized controlled trial was conducted in a rural area of North China . In all , 390 healthy participants aged 60–74 were r and omly allocated to receive daily vitamin C ( 50 mg ; control group ) or vitamin C plus B vitamins ( 400 µg folic acid , 2 mg B6 , and 10 µg B12 ; treatment group ) for 12 months . FRSs were calculated for all 390 subjects . Results Folate and vitamin B12 plasma concentrations in the treatment group increased by 253 and 80 % , respectively , after 6 months , stopped increasing with continued supplementation after 12 months and returned to baseline levels 6 months after supplementation cessation . Compared with the control group , there was no significant effect of B vitamin  supplementation on FRSs after 6 months ( mean difference −0.38 ; 95 % CI −1.06 , 0.31 ; p = 0.279 ) , whereas a significant effect of supplementation was evident after 12 months ( reduced magnitude 7.6 % ; −0.77 ; 95 % CI −1.47 , −0.06 ; p = 0.033 ) . However , this reduction disappeared 6 months after supplementation stopped ( −0.07 ; 95 % CI −0.80 , 0.66 ; p = 0.855 ) . The reduction in FRS 12 months after supplementation was more pronounced in individuals with a folate deficiency ( 10.4 % ; −1.30 ; 95 % CI −2.54 , −0.07 ; p = 0.039 ) than in those without ( 4.1 % ; −0.38 ; 95 % CI −1.12 , 0.36 ; p =  0.313 ) . B vitamins  increased high-density lipoprotein cholesterol by 3.4 % after 6 months ( 0.04 ; 95 % CI −0.02 , 0.10 ; p = 0.155 ) and by 9.2 % after 12 months ( 0.11 ; 95 % CI 0.04 , 0.18 ; p = 0.003 ) . Compared with the control group , this change in magnitude decreased to 3.3 % ( 0.04 ; 95 % CI −0.02 , 0.10 ; p = 0.194 ) 6 months after supplementation cessation . Conclusions Daily supplementation with a low-dose of B vitamins for 12 months reduced FRS , particularly in healthy elderly subjects with a folate deficiency . These reduced effects declined after supplementation cessation , indicating a need for persistent supplementation to maintain the associated benefits BACKGROUND The lowest dose of folic acid required to achieve effective reductions in homocysteine is controversial but important for food fortification policy given recent concerns about the potential adverse effects of overexposure to this vitamin . OBJECTIVE We compared the effectiveness of 0.2 mg folic acid/d with that of 0.4 and 0.8 mg/d at lowering homocysteine concentrations over a 6-mo period . DESIGN A r and omized dose-finding trial with folic acid was conducted . Of 203 participants screened , 101 patients with ischemic heart disease and 71 healthy volunteers completed the study . Participants were r and omly assigned to receive placebo or folic acid at doses of 0.2 , 0.4 , or 0.8 mg/d for 26 wk ; sub sample s of patients with ischemic heart disease were also examined at 6 or 12 wk . RESULTS Participants with higher baseline homocysteine concentrations had the greatest reductions in homocysteine in response to folic acid doses of 0.2 mg ( -20.6 % ) , 0.4 mg ( -20.7 % ) , and 0.8 mg ( -27.8 % ) ; in those with lower baseline homocysteine concentrations , the responses were -8.2 % , -8.9 % , and -8.3 % , respectively . No significant differences in homocysteine responses to the different doses were observed . In the patient group sample d at intervals during the intervention , the maximal homocysteine response appeared to be achieved by 6 wk in the 0.8-mg/d group and by 12 wk in the 0.4-mg/d group . However , the homocysteine response was suboptimal in the 0.2-mg/d group at both 6 and 12 wk compared with that at 26 wk . CONCLUSIONS A folic acid dose as low as 0.2 mg/d can , if administered for 6 mo , effectively lower homocysteine concentrations . Higher doses may not be necessary because they result in no further significant lowering , whereas doses even lower than 0.2 mg/d may be effective in the longer term . Previous trials probably overestimated the folic acid dose required because of a treatment duration that was too short . This trial was registered at clinical trials.gov as IS RCT N45296887 Abstract Objectives : Homocysteine , folate , and some group B vitamins have been proposed as a cause of Cerebro-Vascular Accidents ( CVA ) . We conducted a case-control study to compare the plasma levels of folate , vitamin B12 and homocysteine in Iranian subjects with and without cerebro-vascular accident . Methods : We recruited 82 patients with ischemic stroke as cases and 60 subjects as controls ( using simple nonr and om sampling ) . Homocysteine was measured by fluorimetric high-performance liquid chromatography .  Plasma folate and vitamin B12 levels were measured by an ion-capture method . Results : Mean plasma level of vitamin B12 in cases and controls were 358.4±290.3 Pg/ml and 369.8±110.4 Pg/ml , respectively which did not show any significant difference . Mean plasma level of folate in cases was significantly lower than the controls ( 6.8±4.5 ng/ml vs. 12.2±3.0 ng/ml , p=0.001 ) . It was also shown that mean plasma level of total homocysteine in cases was significantly higher than the controls ( 21.1±9.8 μM/L vs. 13.5±3.2 μM/L , P=0.001 ) . Homocysteine and folate but not plasma B12 had linear relation with age . Male cases had significantly lower Folate and B12 in contrast to women . In addition , male cases had significantly higher Homocysteine level in contrast to women . Conclusions : Our data shows that the level of homocysteine was higher and the level of folate was significantly lower in patients with ischemic stroke in contrast to controls . Effectiveness of supplementary folate and B 12 in such patients needs further well-structured prospect i ve placebo controlled studies BACKGROUND Folic acid is assumed to have favourable effects on vascular endothelium , directly as well as indirectly through its effect on homocysteine metabolism . However , the clinical value of folic acid in secondary prevention after acute myocardial infa rct ion ( MI ) has never been tested . Thus , a r and omised , open-label , multicentre trial was performed in order to study the effect of folic acid 5 mg o.d . when added to statin therapy on the incidence of recurrent major clinical events up to 1 year post-MI . METHODS A total of 283 patients with a total cholesterol > 6.5 mmol/l ( 251 mg/dl ) ( mean 7.3 mmol/l ) were included . All patients received 40 fluvastatin .  In 140 of the 283 patients , folic acid ( 5 mg o.d . ) was instituted at discharge , and the remaining 143 patients served as controls . Other secondary prevention measures for both groups were advocated . The primary endpoint was a composite consisting of all vascular events , including death , recurrent MI , strokes , and unplanned invasive coronary interventions . RESULTS At baseline , the two groups were well-matched for all clinical and demographic parameters . After 1 year of treatment , no difference was noticed in the primary endpoint between the two groups . These endpoints occurred in 43 patients ( 31 % ) in the folic acid group , as opposed to 45 patients ( 31 % ) in the control group . All separate cardiovascular events were also equally distributed between both groups . Total cholesterol levels decreased to a similar extent in the two groups ( to 5.5 and 5.7 mmol/l , in folic acid and control groups , respectively ) . CONCLUSIONS In this medium-size pilot study , folic acid did not demonstrate any beneficial additive effects on cardiovascular mortality or morbidity in post-MI patients with hypercholesterolemia who were treated with statin therapy .  Larger trials , possibly targeting at selected population s , must be awaited before definitive conclusions regarding the potentially favourable effects of folic acid supplementation in secondary prevention can be drawn CONTEXT Folate , vitamin B(6 ) , and vitamin B(12 ) are thought to play an important role in cancer prevention . OBJECTIVE To evaluate the effect of combined folic acid , vitamin B(6 ) , and vitamin B(12 ) treatment on cancer risk in women at high risk for cardiovascular disease . DESIGN , SETTING , AND PARTICIPANTS In the Women 's Antioxidant and Folic Acid Cardiovascular Study , 5442 US female health professionals aged 42 years or older , with preexisting cardiovascular disease or 3 or more coronary risk factors , were r and omly assigned to receive either a daily combination of folic acid , vitamin B(6 ) , and vitamin B(12 ) or a matching placebo . They were treated for 7.3 years from April 1998 through July 31 , 2005 . INTERVENTION Daily supplementation of a combination of 2.5 mg of folic acid , 50 mg of vitamin B(6 ) , and 1 mg of vitamin B(12 ) ( n = 2721 ) or placebo ( n = 2721 ) . MAIN OUTCOME MEASURES Confirmed newly diagnosed total invasive cancer or breast cancer . RESULTS A total of 379 women developed invasive cancer  ( 187 in the active treatment group and 192 in the placebo group ) . Compared with placebo , women receiving the active treatment had similar risk of developing total invasive cancer ( 101.1/10,000 person-years for the active treatment group vs 104.3/10,000 person-years for placebo group ; hazard ratio [ HR ] , 0.97 ; 95 % confidence interval [ CI ] , 0.79 - 1.18 ; P = .75 ) , breast cancer ( 37.8/10,000 person-years vs 45.6/10,000 person-years , respectively ; HR , 0.83 ; 95 % CI , 0.60 - 1.14 ; P = .24 ) , or any cancer death ( 24.6/10,000 person-years vs 30.1/10,000 person-years , respectively ; HR , 0.82 ; 95 % CI , 0.56 - 1.21 ; P = .32 ) . CONCLUSION Combined folic acid , vitamin B(6 ) , and vitamin B(12 ) treatment had no significant effect on overall risk of total invasive cancer or breast cancer among women during the folic acid fortification era . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000541 CONTEXT Recently , concern has been raised about the safety of folic acid , particularly in relation to cancer risk . OBJECTIVE To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 r and omized controlled trials . DESIGN , SETTING , AND PARTICIPANTS Combined analysis and extended follow-up of participants from 2 r and omized , double-blind , placebo-controlled clinical trials ( Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial ) . A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005 , and were followed up through December 31 , 2007 . INTERVENTIONS Oral treatment with folic acid ( 0.8 mg/d ) plus vitamin B(12 ) ( 0.4 mg/d ) and vitamin B(6 ) ( 40 mg/d ) ( n = 1708 ) ; folic acid ( 0.8 mg/d ) plus vitamin B(12 ) ( 0.4 mg/d ) ( n = 1703 ) ; vitamin B(6 ) alone ( 40 mg/d ) ( n = 1705 ) ; or placebo ( n = 1721 ) . MAIN OUTCOME MEASURES Cancer incidence , cancer mortality , and all-cause mortality . RESULTS During study treatment , median serum folate concentration increased more than 6-fold among participants given folic acid . After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up , 341 participants ( 10.0 % ) who received folic acid plus vitamin B(12 ) vs 288 participants ( 8.4 % ) who did not receive such treatment were diagnosed with cancer ( hazard ratio [ HR ] , 1.21 ; 95 % confidence interval [ CI ] , 1.03 - 1.41 ; P = .02 ) . A total of 136 ( 4.0 % ) who received folic acid plus vitamin B(12 ) vs 100 ( 2.9 % ) who did not receive such treatment died from cancer ( HR , 1.38 ; 95 % CI , 1.07 - 1.79 ; P = .01 ) . A total of 548 patients ( 16.1 % ) who received folic acid plus vitamin B(12 ) vs 473 ( 13.8 % ) who did not receive such treatment died from any cause ( HR , 1.18 ; 95 % CI , 1.04 - 1.33 ; P = .01 ) . Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B(12 ) . Vitamin B(6 ) treatment was not associated with any significant effects . CONCLUSION Treatment with folic acid plus vitamin B(12 ) was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway , where there is no folic acid fortification of foods . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00671346 Elevated plasma total homocysteine ( tHcy ) is a risk factor for vascular disease but lowering tHcy with B-vitamins , including folate , has generally not reduced vascular events in secondary prevention trials . Elevated plasma S-adenosylhomocysteine ( AdoHcy ) concentration may be a more sensitive indicator of vascular disease than plasma tHcy . However , unlike tHcy , plasma AdoHcy did not correlate with folate concentration in one study indicating that folate supplementation may not lower AdoHcy . Our aim was to determine whether providing B-vitamin supplements to healthy older people with elevated tHcy ( > 13 micromol/l ) affects plasma AdoHcy and S-adenosylmethionine ( AdoMet ) concentrations .  Healthy older participants ( n 276 ; > or = 65 years ) were r and omised to receive a daily supplement containing folate ( 1 mg ) , vitamin B12 ( 500 microg ) and vitamin B6 ( 10 mg ) , or placebo , for 2 years . Of these participants , we selected the first fifty participants in each treatment group and measured plasma AdoHcy and AdoMet . Plasma tHcy was 4.4 ( 95 % CI 3.2 , 5.6 ; P < 0.001 ) micromol/l lower at 2 years in the vitamins group compared with the placebo group . At 2 years , there were no significant differences in plasma AdoMet ( + 4 % ( 95 % CI - 2 , 11 ) ; P = 0.19 ) , AdoHcy ( - 1 % ( 95 % CI - 10 , 8) ; P = 0.61 ) or the AdoMet : AdoHcy ratio ( 0.22 ( 95 % CI - 0.04 , 0.49 ) ; P = 0.10 ) between the two groups . In conclusion , B-vitamin supplementation of older people lowered plasma tHcy but had no effect on plasma AdoMet or AdoHcy concentration . If elevated plasma AdoHcy is detrimental , this may explain why B-vitamins have generally failed to reduce vascular events in clinical trials CONTEXT Recent r and omized trials among patients with preexisting cardiovascular disease ( CVD ) have failed to support benefits of B-vitamin supplementation on cardiovascular risk . Observational data suggest benefits may be greater among women , yet women have been underrepresented in published r and omized trials . OBJECTIVE To test whether a combination of folic acid , vitamin B6 , and vitamin B12 lowers risk of CVD among high-risk women with and without CVD . DESIGN , SETTING , AND PARTICIPANTS Within an ongoing r and omized trial of antioxidant vitamins , 5442 women who were US health professionals aged 42 years or older , with either a history of CVD or 3 or more coronary risk factors , were enrolled in a r and omized , double-blind , placebo-controlled trial to receive a combination pill containing folic acid , vitamin B6 , and vitamin B12 or a matching placebo , and were treated for 7.3 years from April 1998 through July 2005 . INTERVENTION Daily intake of a combination pill of 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 . MAIN OUTCOME MEASURES A composite outcome of myocardial infa rct ion , stroke , coronary revascularization , or CVD mortality . RESULTS Compared with placebo , a total of 796 women experienced a confirmed CVD event ( 406 in the active group and 390 in the placebo group ) . Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point ( 226.9/10,000 person-years vs 219.2/10,000 person-years for the active vs placebo group ; relative risk [ RR ] , 1.03 ; 95 % confidence interval [ CI ] , 0.90 - 1.19 ; P = .65 ) , as well as for the secondary outcomes including myocardial infa rct ion ( 34.5/10,000 person-years vs 39.5/10,000 person-years ; RR , 0.87 ; 95 % CI , 0.63 - 1.22 ; P = .42 ) , stroke ( 41.9/10,000 person-years vs 36.8/10,000 person-years ; RR , 1.14 ; 95 % CI , 0.82 - 1.57 ; P = .44 ) , and CVD mortality ( 50.3/10,000 person-years vs 49.6/10,000 person-years ; RR , 1.01 ; 95 % CI , 0.76 - 1.35 ; P = .93 ) . In a blood sub study , geometric mean plasma homocysteine level was decreased by 18.5 % ( 95 % CI , 12.5%-24.1 % ; P < .001 ) in the active group ( n = 150 ) over that observed in the placebo group ( n = 150 ) , for a difference of 2.27 micromol/L ( 95 % CI , 1.54 - 2.96 micromol/L ) . CONCLUSION After 7.3 years of treatment and follow-up , a combination pill of folic acid , vitamin B6 , and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women , despite significant homocysteine lowering . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000541 Introduction : Hyperhomocysteinemia is an important cardiovascular risk indicator in the oldest old , and is associated with elevated arterial stiffness in this age group . Since several intervention trials reported a lack of benefit of B-vitamin supplementation on cardiovascular outcomes , we aim ed to investigate the effect of B-vitamin supplementation on arterial stiffness and atherosclerosis in hyperhomocysteinemic elderly patients . Methods : The B-PROOF study is a double-blind , r and omized controlled trial , including 2919 elderly aged at least 65 years , with hyperhomocysteinemia ( 12–50 & mgr;mol/l ) , treated with B-vitamins ( 500 & mgr;g vitamin B12 and 400 & mgr;g folic acid ) or placebo for 2 years . In a subgroup ( n = 569 ) , the effect of B-vitamins on pulse wave velocity ( PWV ) was investigated as a measurement of arterial stiffness . To measure atherosclerosis , carotid intima – media thickness ( IMT ) measures had been used . Incidents of cardiovascular and cerebrovascular events were determined via structured question naires , and blood pressure was also measured . Results : Compared to placebo , B-vitamin supplementation  lowered serum homocysteine by 3.6 & mgr;mol/l ( P < 0.001 ) . Analysis of covariance showed no effect of supplementation on PWV levels , and this was not different for patients without increased arterial stiffness at baseline . Furthermore , no effect on carotid IMT was observed . Discussion : Vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly patients have no effect on PWV or carotid IMT . Further research will still be necessary to unravel the effects and pathways of homocysteine-lowering treatment on cardiovascular outcomes Background Epidemiological studies suggest that raised plasma concentrations of total homocysteine ( tHcy ) may be a common , causal and treatable risk factor for atherothromboembolic ischaemic stroke , dementia and depression . Although tHcy can be lowered effectively with small doses of folic acid , vitamin B12 and vitamin B6 , it is not known whether lowering tHcy , by means of B vitamin therapy , can prevent stroke and other major atherothromboembolic vascular events . Aim To determine whether the addition of B-vitamin supplements ( folic acid 2 mg , B6 25 mg , B12 500 μg ) to best medical and surgical management will reduce the combined incidence of stroke , myocardial infa rct ion ( MI ) and vascular death in patients with recent stroke or transient ischaemic attack ( TIA ) of the brain or eye . Design A prospect i ve , international , multicentre , r and omised , double blind , placebo-controlled clinical trial . Setting One hundred and four medical centres in 20 countries on five continents . Subjects Eight thous and ( 6600 recruited as of 5 January , 2006 ) patients with recent ( 7 months ) stroke ( ischaemic or haemorrhagic ) or TIA ( brain or eye ) . R and omisation R and omisation and data collection are performed by means of a central telephone service or secure internet site . Intervention One tablet daily of either placebo or B vitamins ( folic acid 2 mg , B6 25 mg , B12 500 μg ) . Primary outcome The composite of stroke , MI or death from any vascular cause , whichever occurs first . Outcome and serious adverse events are adjudicated blinded to treatment allocation . Secondary outcomes TIA , unstable angina , revascularisation procedures , dementia , depression . Statistical power With 8000 patients followed up for a median of 2 years and an annual incidence of the primary outcome of 8 % among patients assigned placebo , the study will have at least 80 % power to detect a relative reduction of 15 % in the incidence of the primary outcome among patients assigned B vitamins ( to 6·8%/year ) , applying a two-tailed level of significance of 5 % . Conclusion VITATOPS aims to recruit and follow-up 8000 patients between 1998 and 2008 , and provide a reliable estimate of the safety and effectiveness of folic acid , vitamin B12 , and vitamin B6 supplementation in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke throughout the world Elevated plasma total homocysteine is independently associated with atherosclerosis . Recent r and omized trials show that vitamins lower total homocysteine but do not prevent cardiovascular events , suggesting the need for nonvitamin therapies to evaluate whether a causative relationship exists . Mesna ( sodium 2-mercaptoethanesulfonate ) is a thiol-containing drug capable of liberating homocysteine bound by disulfide bonds to proteins , facilitating its excretion . The effect of oral mesna on total homocysteine has not been evaluated and was the objective of this study . Eleven healthy volunteers received vehicle or 10 mg/kg mesna in r and om order , after which serial blood and urine sample s were collected over 4 hours . Plasma total homocysteine decreased by 24.2 % ( P < .0001 ) following mesna .  Urinary homocysteine excretion was significantly greater with mesna ( 3.9 + /- 2.4 mumol ) compared to vehicle ( 0.4 + /- 0.1 mumol ) , P < .01 . Oral mesna decreases plasma total homocysteine and is a potential nonvitamin treatment for assessing the homocysteine theory of atherosclerosis OBJECTIVES Vitamin B-12 and n-3 polyunsaturated fatty acids ( PUFA ) decrease blood homocysteine ( Hcy ) concentrations . However , the combined effect of these nutrients on Hcy and ferritin , and C-reactive protein is limited and inconclusive . The objective was to examine the synergistic effect of vitamin B-12 in combination of n-3 PUFA on plasma Hcy , ferritin , and other biochemical markers . METHODS In a r and omized controlled trial , thirty eligible subjects were r and omly divided into three groups , and assigned to receive 1000 μg of vitamin B-12 , 2 g fish oil , or 1000 μg vitamin B-12 and 2 g fish oil , respectively , for 8 weeks . Plasma phospholipids ( PL ) fatty acids and biochemical markers were determined . This study was registered under Clinical Trials.gov Identifier : NCT01762072 . RESULTS Plasma PL 20:5n-3 , 22:6n-3 and n-3 PUFA was increased after 4 and 8 week supplementation of fish oil , and vitamin B-12+fish oil . Plasma concentrations of triacylglycerol , uric acid , C-reactive protein , and ferritin were significantly decreased after 4 and 8 week supplementation of fish oil , and vitamin B-12+fish oil . In all groups , significant changes in plasma Hcy were observed during the study period . Vitamin B-12 , fish oil , and vitamin B-12+fish oil supplementation lowered plasma Hcy concentrations by 22 % , 19 % , and 39 % , respectively . CONCLUSIONS The combination of vitamin B-12 and fish oil has a synergistic effect on lowering plasma concentrations of Hcy BACKGROUND Mechanisms involved in coronary stenosis evolution are different than those involved in clinical events . Because of differential vascular effects , N-3 polyunsatured fatty acids ( PUFA ) and B vitamins could have differential effects on different types of cardiovascular clinical events in high-risk patients . METHODS We analyzed the effects of n-3 PUFA and of B vitamins on both coronary revascularization and on hard coronary events risks in a subgroup of the SU.FOL.OM3 trial , a r and omized , double-blind , placebo-controlled secondary prevention trial . Data were analyzed according to the intention-to-treat principle , with the use of Cox proportional-hazards models . RESULTS After a mean follow-up of 4.2 ± 1.0 years among the 1,863 participants with coronary heart disease , 163 coronary revascularizations were performed , and 95 patients experienced a hard coronary event . Neither treatment with n-3 PUFA , nor treatment with B vitamins was associated with any significant effect on the occurrence of hard coronary events . Allocation to n-3 PUFA was not associated with any significant effect on coronary revascularization . However , treatment with B vitamins was associated with a statistically significant 52 % increase in the risk of coronary revascularization ( multivariate HR : 1.52 ; 95 % CI : [ 1.11 - 2.10 ] ; p=0.01 ) . CONCLUSIONS Neither n-3 PUFA , nor B vitamins  reduced the rates of hard coronary events and of coronary revascularization .  Furthermore , B vitamins  significantly increased the rate of coronary revascularization . Consistent with the findings of previous trials , our results do not support the routine use of dietary supplements containing n-3 PUFA and argue against using dietary supplements containing B-vitamins in coronary patients in secondary cardiovascular prevention Homocysteine is a risk factor for atherosclerosis in the general population , and serum homocysteine levels are almost universally elevated in chronic renal failure patients . When such patients are treated with dialysis , cardiovascular disease accounts for more than 50 % of their mortality , which , in some proportion , may be pathophysiologically related to the elevated serum homocysteine levels . From April 2003 to March 2005 , we conducted a 2-year , double-blind , r and omized , placebo-controlled trial of 186 patients with end-stage kidney disease due to any cause , who were older than 18 years and stable on hemodialysis . Patients were assigned to receive either oral folic acid 10 mg 3 times a week immediately after every dialysis session under nurse supervision or an identical-appearing placebo for the entire study . On admission , plasma total homocysteine ( tHcy ) levels were above 13.9 micromol/L in 96.7 % of patients ( median 25.0 micromol/L , range 9.3 - 104.0 micromol/L ) . In the placebo group , tHcy levels remained elevated at 6 , 12 , and 24 months , while oral folate significantly decreased tHcy to a median value of 10.5 ( 2.8 - 20.3 ) micromol/L , ( p<0.01 ) . During the study , 38 patients ( folic acid group 17 vs. placebo group 21 ; p=0.47 ) died from cardiovascular disease . Kaplan-Meier life table analysis dealing with the incidence of cardiovascular events , both fatal and nonfatal ( myocardial infa rct ion , arrhythmias , angina , heart failure , cerebrovascular accident ) , showed that 2 years of folic acid treatment and the lowering of the homocysteine blood levels had no effect on cardiovascular events ( p=0.41 ; hazard ratio 1.24 , 95 % CI 0.74 - 2.10 ) . However , the carotid artery intima-media wall thickness measured in a blinded fashion decreased from 1.94 + /- 0.59 mm to 1.67 + /- 0.38 mm ( p<0.01 ) after 2 years of folate therapy . In this short-term study of uremic patients , 2 years of folic acid supplementation normalized the tHcy blood levels in 92.3 % of patients but did not change the incidence of cardiovascular events compared with the control group . However , ultrasonography of the common carotid arteries performed at entry and 24 months later showed a significant decrease in intima-media thickness with folate supplementation . This suggests that early folate supplementation may benefit patients with chronic renal failure by preventing cardiovascular deterioration OBJECTIVES We sought to conduct a r and omized trial with folic acid 0.5 mg/day in a patient population with stable coronary artery disease ( CAD ) . BACKGROUND Folic acid has favorable effects on vascular endothelium and lowers plasma homocysteine levels . In addition , homocysteine appears to be an independent risk factor for atherosclerotic disease . However , the value of folic acid in secondary prevention had seldom been tested . METHODS In this open-label study , 593 patients were included ; 300 were r and omized to folic acid and 293 served as controls .  Mean follow-up time was 24 months . At baseline all patients had been on statin therapy for a mean of 3.2 years . RESULTS In patients treated with folic acid , plasma homocysteine levels decreased by 18 % , from 12.0 + /- 4.8 to 9.4 + /- 3.5 micromol/l , whereas these levels remained unaffected in the control group ( p < 0.001 between groups ) . The primary end point ( all-cause mortality and a composite of vascular events ) was encountered in 31 ( 10.3 % ) patients in the folic acid group and in 28 ( 9.6 % ) patients in the control group ( relative risk 1.05 ; 95 % confidence interval : 0.63 to 1.75 ) . In a multifactorial survival model with adjustments for clinical factors , the most predictive laboratory parameters were , in order of significance , levels of creatinine clearance , plasma fibrinogen , and homocysteine . CONCLUSIONS Within two years , folic acid does not seem to reduce clinical end points in patients with stable coronary artery disease ( CAD ) while on statin treatment . Homocysteine might therefore merely be a modifiable marker of disease . Thus , low-dose folic acid supplementation should be treated with reservation , until more trial outcomes become available OBJECTIVES A high level of total homocysteine ( tHcy ) is a risk marker for cardiovascular disease ( CVD ) , and is related to inflammation . We wanted to test the effect of homocysteine-lowering B-vitamin therapy , as used in the Western Norway B-vitamin Intervention Trial ( WENBIT ) , on inflammatory markers associated with atherosclerosis . DESIGN Single centre , prospect i ve double-blind clinical interventional study , r and omised in a 2 x 2 factorial design . SUBJECTS AND METHODS Ninety patients ( 21 female ) with suspected coronary artery disease ( CAD ) , aged 38 - 80 years , were blindly r and omised into one of four groups of daily oral treatment with ( A ) folic acid ( 0.8 mg)/vitamin B12 ( 0.4 mg)/vitamin B6 ( 40 mg ) , ( B ) folic acid/vitamin B12 , ( C ) vitamin B6 alone or ( D ) placebo . Blood sample s were collected before and after 6 months of treatment . RESULTS Before intervention , median levels of the analytes were : tHcy 11.0 micromol L(-1 ) , neopterin 8.1 nmol L(-1 ) , soluble CD40 lig and ( sCD40L ) 3.9 ng mL(-1 ) , interleukin (IL)-6 1.9 pg mL(-1 ) , C-reactive protein ( CRP ) 1.9 mg L(-1 ) and low-density lipoprotein ( LDL ) cholesterol 3.3 mmol L(-1 ) . tHcy was significantly associated with neopterin ( r = 0.49 , P < 0.001 ) and with IL-6 ( r = 0.29 , P = 0.01 ) , but not with CRP or sCD40L . Neither treatment with folic acid/B12 nor with B6 induced significant changes in any of these inflammatory biomarkers ( P > or= 0.14 ) . In patients receiving folic acid/B12 ( groups A and B ) , tHcy was reduced with 33 % ( P < 0.001 ) . CONCLUSIONS In patients with stable CAD , homocysteine-lowering therapy with B-vitamins does not affect levels of inflammatory markers associated with atherogenesis . Failure to reverse inflammatory processes , may partly explain the negative results in clinical secondary B-vitamin intervention trials BACKGROUND Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular ( CV ) disease . Simple , inexpensive and nontoxic therapy with folic acid and vitamins B6 and B12 reduces plasma homocysteine levels by approximately 25 % to 30 % and may reduce CV events . Therefore , a large , r and omized clinical trial -- the Heart Outcomes Prevention Evaluation (HOPE)-2 study --is being conducted to evaluate this therapy in patients at high risk for CV events . OBJECTIVES To evaluate whether long-term therapy with folic acid and vitamins B6 and B12 reduces the risk of major CV events in a high-risk population . The primary study outcome is the composite of death from CV causes , myocardial infa rct ion and stroke . METHODS A total of 5522 patients aged 55 years or older with pre-existing CV disease or with diabetes and additional risk factor(s ) at 145 centres in 13 countries were r and omly assigned to daily therapy with combined folic acid 2.5 mg , vitamin B6 50 mg and vitamin B12 1 mg , or to placebo . Follow-up will average five years , to be completed by the end of 2005 . RESULTS The patients ' baseline characteristics confirmed their high-risk status . Baseline homocysteine levels varied between countries and regions . HOPE-2 is one of the largest trials of folate and vitamins B6 and B12 and is expected to significantly contribute to the evaluation of the role of homocysteine lowering in CV prevention CONTEXT Plasma homocysteine level has been recognized as an important cardiovascular risk factor that predicts adverse cardiac events in patients with established coronary atherosclerosis and influences restenosis rate after percutaneous coronary intervention . OBJECTIVE To evaluate the effect of homocysteine-lowering therapy on clinical outcome after percutaneous coronary intervention . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind placebo-controlled trial involving 553 patients referred to the University Hospital in Bern , Switzerl and , from May 1998 to April 1999 and enrolled after successful angioplasty of at least 1 significant coronary stenosis ( > or = 50 % ) . INTERVENTION Participants were r and omly assigned to receive a combination of folic acid ( 1 mg/d ) , vitamin B12 ( cyanocobalamin , 400 micro g/d ) , and vitamin B6 ( pyridoxine hydrochloride , 10 mg/d ) ( n = 272 ) or placebo ( n = 281 ) for 6 months . MAIN OUTCOME MEASURE Composite end point of major adverse events defined as death , nonfatal myocardial infa rct ion , and need for repeat revascularization , evaluated at 6 months and 1 year . RESULTS After a mean ( SD ) follow-up of 11 ( 3 ) months , the composite end point was significantly lower at 1 year in patients treated with homocysteine-lowering therapy ( 15.4 % vs 22.8 % ; relative risk [ RR ] , 0.68 ; 95 % confidence interval [ CI ] , 0.48 - 0.96 ; P = .03 ) , primarily due to a reduced rate of target lesion revascularization ( 9.9 % vs 16.0 % ; RR , 0.62 ; 95 % CI , 0.40 - 0.97 ; P = .03 ) . A nonsignificant trend was seen toward fewer deaths ( 1.5 % vs 2.8 % ; RR , 0.54 ; 95 % CI , 0.16 - 1.70 ; P = .27 ) and nonfatal myocardial infa rct ions ( 2.6 % vs 4.3 % ; RR , 0.60 ; 95 % CI , 0.24 - 1.51 ; P = .27 ) with homocysteine-lowering therapy . These findings remained unchanged after adjustment for potential confounders . CONCLUSION Homocysteine-lowering therapy with folic acid , vitamin B12 , and vitamin B6 significantly decreases the incidence of major adverse events after percutaneous coronary intervention CONTEXT Observational studies have found lower rates of coronary heart disease ( CHD ) in postmenopausal women who take estrogen than in women who do not , but this potential benefit has not been confirmed in clinical trials . OBJECTIVE To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease . DESIGN R and omized , blinded , placebo-controlled secondary prevention trial . SETTING Outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 women with coronary disease , younger than 80 years , and postmenopausal with an intact uterus . Mean age was 66.7 years . INTERVENTION Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . Follow-up averaged 4.1 years ; 82 % of those assigned to hormone treatment were taking it at the end of 1 year , and 75 % at the end of 3 years . MAIN OUTCOME MEASURES The primary outcome was the occurrence of nonfatal myocardial infa rct ion ( MI ) or CHD death . Secondary cardiovascular outcomes included coronary revascularization , unstable angina , congestive heart failure , resuscitated cardiac arrest , stroke or transient ischemic attack , and peripheral arterial disease . All-cause mortality was also considered . RESULTS Overall , there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes : 172 women in the hormone group and 176 women in the placebo group had MI or CHD death ( relative hazard [ RH ] , 0.99 ; 95 % confidence interval [ CI ] , 0.80 - 1.22 ) . The lack of an overall effect occurred despite a net 11 % lower low-density lipoprotein cholesterol level and 10 % higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group ( each P<.001 ) . Within the overall null effect , there was a statistically significant time trend , with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5 . More women in the hormone group than in the placebo group experienced venous thromboembolic events ( 34 vs 12 ; RH , 2.89 ; 95 % CI , 1.50 - 5.58 ) and gallbladder disease ( 84 vs 62 ; RH , 1.38 ; 95 % CI , 1.00 - 1.92 ) . There were no significant differences in several other end points for which power was limited , including fracture , cancer , and total mortality ( 131 vs 123 deaths ; RH , 1.08 ; 95 % CI , 0.84 - 1.38 ) . CONCLUSIONS During an average follow-up of 4.1 years , treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease . The treatment did increase the rate of thromboembolic events and gallbladder disease . Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events , we do not recommend starting this treatment for the purpose of secondary prevention of CHD . However , given the favorable pattern of CHD events after several years of therapy , it could be appropriate for women already receiving this treatment to continue BACKGROUND Cholesterol lowering with statins reduces the risk of vascular disease , but uncertainty remains as to whether more intensive statin therapy produces worthwhile benefits safely . Blood homocysteine level is an independent marker of vascular risk , but it is unknown whether this association is causal . METHODS AND RESULTS 12,064 myocardial infa rct ion survivors have been r and omized to more versus less intensive cholesterol-lowering treatment using simvastatin 80 mg versus 20 mg daily . Allocation to more intensive treatment has yielded average further low-density lipoprotein cholesterol reductions of 0.5 mmol/L at 2 months and 0.4 mmol/L at 5 years . In addition , using a factorial design , these patients have been r and omized to homocysteine lowering with folic acid 2 mg plus vitamin B12 1 mg daily versus matching placebo , yielding an average 3 to 4 mumol/L reduction in  homocysteine . After 6 years of median follow-up , the annual overall rate of major vascular events is approximately 3 % . Follow-up is scheduled to continue for a median of 7 years . CONCLUSION SEARCH should provide reliable evidence about the efficacy and safety of prolonged use of more intensive cholesterol-lowering therapy and , separately , of folate-based homocysteine-lowering therapy in a high-risk population BACKGROUND Dietary supplements are widely used in industrialized countries . OBJECTIVE The objective was to examine the association between multivitamin use and myocardial infa rct ion ( MI ) in a prospect i ve , population -based cohort of women . DESIGN The study included 31,671 women with no history of cardiovascular disease ( CVD ) and 2262 women with a history of CVD aged 49 - 83 y from Sweden . Women completed a self-administered question naire in 1997 regarding dietary supplement use , diet , and lifestyle factors . Multivitamins were estimated to contain nutrients close to recommended daily allowances : vitamin A ( 0.9 mg ) , vitamin C ( 60 mg ) , vitamin D ( 5 μg ) , vitamin E ( 9 mg ) , thiamine ( 1.2 mg ) , riboflavin ( 1.4 mg ) , vitamin B-6 ( 1.8 mg ) , vitamin B-12 ( 3 μg ) , and folic acid ( 400 μg ) . RESULTS During an average of 10.2 y of follow-up , 932 MI cases were identified in the CVD-free group and 269 cases in the CVD group . In the CVD-free group , use of multivitamins only , compared with no use of supplements , was associated with a multivariable-adjusted hazard ratio ( HR ) of 0.73 ( 95 % CI : 0.57 , 0.93 ) . The HR  for multivitamin use together with other supplements was 0.70 ( 95 % CI : 0.57 , 0.87 ) . The HR for use of supplements other than multivitamins was 0.93 ( 95 % CI : 0.81 , 1.08 ) . The use of multivitamins for ≥5 y was associated with an HR of 0.59 ( 95 % CI : 0.44 , 0.80 ) . In the CVD group , use of multivitamins alone or together with other supplements was not associated with MI . CONCLUSIONS The use of multivitamins was inversely associated with MI , especially long-term use among women with no CVD . Further prospect i ve studies with detailed information on the content of preparations and the duration of use are needed to confirm or refute our findings 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 r and omized 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 CONTEXT High plasma homocysteine levels are a risk factor for mortality and vascular disease in observational studies of patients with chronic kidney disease .  Folic acid and B vitamins decrease homocysteine levels in this population but whether they lower mortality is unknown . OBJECTIVE To determine whether high doses of folic acid and B vitamins administered daily reduce mortality in patients with chronic kidney disease . DESIGN , SETTING , AND PARTICIPANTS Double-blind r and omized controlled trial ( 2001 - 2006 ) in 36 US Department of Veterans Affairs medical centers . Median follow-up was 3.2 years for 2056 participants aged 21 years or older with advanced chronic kidney disease ( estimated creatinine clearance < or = 30 mL/min ) ( n = 1305 ) or end-stage renal disease ( n = 751 ) and high homocysteine levels ( > or = 15 micromol/L ) . INTERVENTION Participants received a daily capsule containing 40 mg of folic acid , 100 mg of pyridoxine hydrochloride ( vitamin B6 ) , and 2 mg of cyanocobalamin ( vitamin B12 ) or a placebo . MAIN OUTCOME MEASURES The primary outcome was all-cause mortality . Secondary outcomes included myocardial infa rct ion ( MI ) , stroke , amputation of all or part of a lower extremity , a composite of these 3 plus all-cause mortality , time to initiation of dialysis , and time to thrombosis of arteriovenous access in hemodialysis patients . RESULTS Mean baseline homocysteine level was 24.0 micromol/L in the vitamin group and 24.2 micromol/L in the placebo group . It was lowered 6.3 micromol/L ( 25.8 % ; P < .001 ) in the vitamin group and 0.4 micromol/L ( 1.7 % ; P = .14 ) in the placebo group at 3 months , but there was no significant effect on mortality ( 448 vitamin group deaths vs 436 placebo group deaths ) ( hazard ratio [ HR ] , 1.04 ; 95 % CI , 0.91 - 1.18 ) . No significant effects were demonstrated for secondary outcomes or adverse events : there were 129 MIs in the vitamin group vs 150 for placebo ( HR , 0.86 ; 95 % CI , 0.67 - 1.08 ) , 37 strokes in the vitamin group vs 41 for placebo ( HR , 0.90 ; 95 % CI , 0.58 - 1.40 ) , and 60 amputations in the vitamin group vs 53 for placebo ( HR , 1.14 ; 95 % CI , 0.79 - 1.64 ) . In addition , the composite of MI , stroke , and amputations plus mortality ( P = .85 ) , time to dialysis ( P = .38 ) , and time to thrombosis in hemodialysis patients ( P = .97 ) did not differ between the vitamin and placebo groups . CONCLUSION Treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced chronic kidney disease or end-stage renal disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00032435 BACKGROUND Methylenetetrahydrofolate dehydrogenase ( MTHFD1 ) catalyzes three sequential reactions that metabolize derivatives of tetrahydrofolate ( THF ) in folate-dependent one-carbon metabolism . Impaired MTHFD1 flux has been linked to disturbed lipid metabolism and oxidative stress . However , limited information is available on its relation to the development of atherothrombotic cardiovascular disease . METHODS AND RESULTS We explored the association between a MTHFD1 polymorphism ( rs1076991 C > T ) and acute myocardial infa rct ion ( AMI ) , and potential effect modifications by folic acid/B12 and /or vitamin B6 treatment in suspected stable angina pectoris patients ( n = 2381 ) participating in the r and omized Western Norway B Vitamin Intervention Trial ( WENBIT ) . During the median follow-up of 4.9 years 204 participants ( 8.6 % ) suffered an AMI . After adjusting for established CVD risk factors , the MTHFD1 polymorphism was significantly associated with AMI ( HR : 1.49 ; 95 % CI , 1.23 - 1.81 ) . A similar association was observed among patients allocated to treatment with vitamin B6 alone ( HR : 1.53 ; 95 % CI , 1.01 - 2.31 ) , and an even stronger relationship was seen in patients treated with both vitamin B6 and folic acid/B12 ( HR : 2.35 ; 95 % CI , 1.55 - 3.57 ) . However , no risk association between the MTHFD1 polymorphism and AMI was seen in patients treated with placebo ( HR : 1.29 ; 95 % CI , 0.86 - 1.93 ) or folic acid/B12 ( 1.17 ; 95 % CI , 0.83 - 1.65 ) . CONCLUSION A common and functional MTHFD1 polymorphism is associated with increased risk of AMI , although the risk seems to be dependent on specific B vitamin treatment . Further studies are warranted to eluci date the possible mechanisms , also in order to explore potential effect modifications by nutritional factors Abstract Cardiovascular disease ( CVD ) is a major cause of morbidity and mortality in developed countries . However , traditional risk factors can not fully account for this . In the last 20 years , there has been an explosion of interest in plasma total homocysteine ( tHcy ) as a potential modifiable risk factor for CVD . Recent meta-analyses of epidemiological studies support the concept that increased tHcy concentrations are associated with CVD . This has led to the ‘ homocysteine hypothesis ’ , which states that lowering plasma tHcy using folic acid and other B-vitamins will reduce the risk of CVD . In experimental studies , homocysteine has been shown to cause oxidative stress , endothelial cell dysfunction and promote thrombogenesis . However , data from recent large r and omized controlled trials have shown that there is no clinical benefit to lowering plasma tHcy concentrations with folic acid and other B-vitamins . This lack of effect of tHcy lowering strongly suggests that homocysteine is not an instigator but merely an indicator of CVD Background Plasma concentration of total homocysteine is associated with risk of cardiovascular disease in epidemiological studies . We wanted to examine the effects of B-vitamin therapy , which may lower total homocysteine , on coronary flow and vascular function in patients with established coronary artery disease ( CAD ) . Methods Forty patients with stable CAD , mean ( st and ard deviation ) aged 57.8 ( 9.0 ) years , recruited into the Western Norway B-Vitamin Intervention Trial , were r and omly assigned to daily oral treatment with 0.8 mg of folic acid and 0.4 mg of vitamin B12 or placebo , and 40 mg of vitamin B6 or placebo , using a 2 × 2 factorial design . At baseline , and after 9 and 24 months , coronary blood flow was assessed by coronary angiography and Doppler flow-wire measurements during intracoronary infusion of saline ( basal ) , incremental doses of acetylcholine , adenosine , and nitroglycerin . Results We found a significant increase in basal ( P<0.02 ) and adenosine-induced ( P<0.05 ) coronary blood flow in patients who received folic acid/vitamin B12 for 24 months , compared with placebo or vitamin B6 alone . Folic acid/vitamin B12 or vitamin B6 treatment did not change endothelial-dependent response after acetylcholine infusion or flow-dependent proximal dilatation in response to adenosine-induced maximal hyperemia ( P≥0.45 ) . Conclusion Long-term treatment with a combination of folic acid and vitamin B12  increase basal and adenosine-induced maximal coronary blood flow . This may reflect improved microvascular function in patients with stable CAD BACKGROUND Elevated plasma homocysteine levels are a risk factor for coronary heart disease , but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined . METHODS We prospect ively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease . At the time of angiography in 1991 or 1992 , risk factors for coronary disease , including homocysteine levels , were evaluated . The majority of the patients subsequently underwent  coronary-artery bypass grafting  ( 318 patients ) or percutaneous transluminal coronary angioplasty ( 120 patients ) ; the remaining 149 were treated medically . RESULTS After a median follow-up of 4.6 years , 64 patients ( 10.9 percent ) had died . We found a strong , grade d relation between plasma homocysteine levels and overall mortality . After four years , 3.8 percent of patients with homocysteine levels below 9 micromol per liter had died , as compared with 24.7 percent of those with homocysteine levels of 15 micromol per liter or higher . Homocysteine levels were only weakly related to the extent of coronary artery disease but were strongly related to the history with respect to myocardial infa rct ion , the left ventricular ejection fraction , and the serum creatinine level . The relation of homocysteine levels to mortality remained strong after adjustment for these and other potential confounders . In an analysis in which the patients with homocysteine levels below 9 micromol per liter were used as the reference group , the mortality ratios were 1.9 for patients with homocysteine levels of 9.0 to 14.9 micromol per liter , 2.8 for those with levels of 15.0 to 19.9 micromol per liter , and 4.5 for those with levels of 20.0 micromol per liter or higher ( P for trend=0.02 ) . When death due to cardiovascular disease ( which occurred in 50 patients ) was used as the end point in the analysis , the relation between homocysteine levels and mortality was slightly strengthened . CONCLUSIONS Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease BACKGROUND AND AIMS Hypercholesterolemia is one of the predisposing factors of cardiovascular diseases . A positive correlation of homocysteine ( Hcy ) concentration with total cholesterol is described . Lovastatin , one of the most administered agents in hypercholesterolemia , is not effective in lowering the level of serum Hcy and increasing serum total antioxidant capacity ( TAC ) . This study was performed to evaluate the effects of folate supplementation on lowering Hcy level and changes of TAC in asymptomatic hypercholesterolemic adults under lovastatin treatment . METHODS This was a double-blind r and omized controlled clinical trial . Forty asymptomatic newly diagnosed hypercholesterolemic individuals were recruited . Patients were r and omized into two groups : group A--20 patients supplemented for 8 weeks with folate ( 5 mg daily ) and group B--20 patients receiving placebo . Lovastatin was administered to both groups . Laboratory lipid profiles , serum Hcy and folate concentration , and TAC were measured at the beginning and after the 8(th ) week of the study period . RESULTS After folate supplementation in group A subjects , serum Hcy was significantly decreased ( 13.35+/-5.01 micromol/L to 8.43+/-2.52 micromol/L , p=0.001 ) , whereas no significant changes occurred in group B ( p>0.05 ) . A significant increase in TAC was only observed in group A ( 1.54+/-0.24 micromol/L to 1.96+/-0.42 micromol/L , p<0.001 ) . CONCLUSIONS Folate supplementation decreases the serum level of Hcy and increases TAC . It seems that a pharmacological dose of folate supplementation could potentially decrease the risk of cardiovascular diseases by reducing serum level of Hcy in adults with hypercholesterolemia Homocysteine ( HCY ) , C-reactive protein ( hsCRP ) , and triglycerides ( TG ) are risk factors for cardiovascular disease ( CVD ) . While multivitamins ( MVit ) may reduce HCY and hsCRP , omega-3 fatty acids ( N3 ) reduce TG ; yet , they are seldom studied simultaneously . We r and omly assigned 100 participants with baseline HCY ( > 8.0 umol/L ) to the daily ingestion of : ( 1 ) placebo , ( 2 ) MVit ( VitC : 200 mg ; VitE : 400 IU ; VitB6 : 25 mg ; Folic Acid : 400 ug ; VitB12 : 400 ug ) + placebo , ( 3 ) N3 ( 2 g N3 , 760 mg EPA , 440 mg DHA)+placebo , or ( 4 ) MVit + N3 for 12 weeks . At follow-up , we observed significant reductions in HCY ( umol/L ) for the MVit ( - 1.43 , 95 % CI , - 2.39 , - 0.47 ) and MVit + N3 groups ( - 1.01 , 95 % CI , - 1.98 , - 0.04 ) groups , both being significant ( p < 0.05 ) vs. placebo ( - 0.57 , 95 % CI , - 1.49 , 0.35 ) and N3 ( 1.11 , 95 % CI , 0.07 , 2.17 ) . hsCRP ( nmol/L ) was significantly reduced in the MVit ( - 6.00 , 95 % CI , - 1.04 , - 0.15 ) and MVit + N3 ( - 0.98 , 95 % CI , - 1.51 , - 0.46 ) groups , but not vs. placebo ( - 0.15 , 95 % CI , - 0.74 , 0.43 ) or N3 ( - 0.53 , 95 % CI , - 1.18 , 0.12 ) . Lastly , we observed significant reductions in TG for the N3 ( - 0.41 , 95 % CI , - 0.69 , - 0.13 ) and MVit + N3 ( - 0.71 , 95 % CI , - 0.93 , - 0.46 ) groups , both significant vs. placebo ( - 0.10 , 95 % CI , - 0.36 , 0.17 ) and MVit groups ( 0.15 , 95 % CI , - 12 , 0.42 ) . The co-ingestion of MVit + N3 provides synergistic affects on HCY , hsCRP , and plasma TG Background : Previous studies support an association between elevated total homocysteine ( tHcy ) levels and increased all-cause mortality . However , few prospect i ve studies have examined this association in hypertensive patients , and /or tested any effect modification by the methylene tetrahydrofolate reductase ( MTHFR ) C677 T genotype . Methods : This was a post hoc analysis of the China Stroke Primary Prevention Trial . Serum tHcy and folate were measured at baseline . Individual MTHFR C677 T genotype ( CC , CT , and TT ) was determined . Evidence for death included death certificates or home visits . Cumulative hazards of all-cause mortality by tHcy quartiles were estimated using the Kaplan – Meier method , and group differences were compared by log-rank tests . Hazard ratios ( HRs ) and 95 % confidence intervals were estimated by Cox proportional-hazard regression models , adjusting for age , sex , baseline folate , vitamin B12 , blood pressure , body mass index , smoking and alcohol drinking status , study center , total cholesterol , triglycerides , high-density lipoprotein cholesterol , fasting glucose , creatinine , and treatment group . Potential effect modification by the MTHFR genotype on the relationship between tHcy and all-cause mortality was tested . Results : The analyses included 20,424 hypertensive patients ( 41 % males ) without a history of myocardial infa rct ion or stroke . Baseline mean age ( SD ) was 60 ± 7.5 years and mean ( SD ) serum tHcy was 14.5 ± 8.4 & mgr;mol/L. After a mean follow-up period of 4.5 years , there were 612 ( 3 % ) all-cause deaths . Kaplan – Meier survival curves revealed a grade d relationship between tHcy quartiles and all-cause mortality . The HRs , using the lowest quartile as the reference , were 1.2 , 1.2 , and 1.5 in Q2 , Q3 , and Q4 , respectively . A linear trend test , using natural log-transformed tHcy , result ed in an HR of 1.5 ( 95 % confidence interval 1.2–1.9 , P < .001 ) after adjustment for lifestyle and health-related variables . Whereas the MTHFR genotype alone had little effect on mortality , it significantly modified the tHcy – mortality association , which was much stronger in the CC/CT genotype than in the TT genotype ( P for interaction < 0.05 ) . Conclusions : Among Chinese hypertensive patients without cardiovascular comorbidities , elevated tHcy was a significant risk marker for death from all causes , and the association was subject to effect modification by MTHFR genotypes . If confirmed that tHcy and MTHFR genotypes may serve as useful biomarkers for mortality risk assessment and targeted intervention Background : Homocysteine may promote atherosclerosis by exacerbating inflammatory processes within the arterial wall . B-vitamin supplements reduce total plasma homocysteine concentrations ( tHcy ) , but it is not known whether the treatment also reduces arterial wall inflammation . We used 18F-fluorodeoxygluose positron emission tomography ( 18F-FDG PET ) to investigate whether long-term homocysteine-lowering treatment alters arterial wall inflammation in patients with a history of ischemic stroke . Methods : 30 stroke patients were r and omly assigned to B-vitamin therapy ( folic acid 2 mg , vitamin B6 25 mg and vitamin B12 0.5 mg ) or placebo in a double-blind clinical trial . After a mean treatment period of 4.0 ± 0.7 years , all subjects had tHcy , carotid intima-medial thickness ( CIMT ) and flow-mediated dilation ( FMD ) of the brachial artery measured and underwent an 18F-FDG PET scan . St and ardised uptake values ( SUV ) were measured at six sites in the carotid , femoral and aortic arteries . Areas of locally increased tracer uptake in the arterial wall ( ‘ hot spots ’ ) were also identified and counted . Results : Long-term B-vitamin treatment significantly reduced tHcy compared with placebo ( 8.4 μmol/l , 95 % confidence interval , CI , 7.2–9.6 vs. 11.6 μmol/l , 95 % CI 10.0–13.4 , p = 0.002 ) . The treatment did not affect mean arterial SUV ( 2.0 ± 0.3 vitamins vs. 2.1 ± 0.3 placebo , p = 0.65 ) or the number of hot spots ( n = 1.1 ± 1.0 vitamins vs. n = 1.2 ± 1.0 placebo , p = 0.65 ) . There was no significant correlation between mean arterial SUV and CIMT or FMD . Conclusions : These results suggest that a long-term Hcy reduction with B vitamins does not affect arterial wall inflammation assessed by 18F-FDG PET The relationship of folic acid supplementation with the risk of cancer remains inconclusive . We aim ed to evaluate the effects of folic acid supplementation on cancer incidence among adults with hypertension without history of stroke or myocardial infa rct ion ( MI ) in the China Stroke Primary Prevention Trial ( CSPPT ) . A total of 20,702 hypertensive adults without history of stroke or MI , stratified by MTHFR C677 T genotypes(CC , CT and TT ) , were r and omly assigned to receive double‐blind daily treatment with a single pill containing 10 mg enalapril and 0.8 mg folic acid(n = 10,348 ) or a pill containing 10 mg enalapril alone(n = 10,354 ) . During a median treatment duration of 4.5 years , cancer occurred in 116 participants ( 1.12 % ) in the enalapril‐folic acid group versus 116 participants ( 1.12 % ) in the enalapril group ( HR , 1.00 ; 95%CI , 0.77–1.29 ) . There was also no significant difference in the HRs for specific types of cancer(esophageal , gastric , breast , lung , colorectal , head and neck , liver and gynecologic cancer or lymphoma ) or cancer mortality(HR , 1.05 ; 95%CI , 0.69–1.58 ) . For participants not receiving folic acid treatment ( enalapril only group ) , MTHFR 677 TT genotype was an independent predictor of total cancer risk compared to CC genotype ( HR , 1.86 ; 95%CI , 1.07–3.22 ) . Consistently , a beneficial effect was observed in participants with MTHFR TT genotype and low folate levels ( < 9.0 ng/mL ; HR , 0.47 ; 95%CI , 0.24–0.94 ) . There is no evidence that 0.8 mg daily folic acid supplementation can increase the risk of cancer incidence among adults with hypertension without history of stroke or MI in China . Our data suggest a protective effect in participants with MTHFR TT genotype and low folate levels CONTEXT Blood homocysteine levels are positively associated with cardiovascular disease , but it is uncertain whether the association is causal . OBJECTIVE To assess the effects of reducing homocysteine levels with folic acid and vitamin B(12 ) on vascular and nonvascular outcomes . DESIGN , SETTING , AND PATIENTS Double-blind r and omized controlled trial of 12,064 survivors of myocardial infa rct ion in secondary care hospitals in the United Kingdom between 1998 and 2008 . INTERVENTIONS 2 mg folic acid plus 1 mg vitamin B(12 ) daily vs matching placebo . MAIN OUTCOME MEASURES First major vascular event , defined as major coronary event ( coronary death , myocardial infa rct ion , or coronary revascularization ) , fatal or nonfatal stroke , or noncoronary revascularization . RESULTS 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 % ] ) . CONCLUSION 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 . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N74348595
target: In this third up date of the Cochrane review , there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6 , B9 or B12 given alone or in combination comparing with placebo on myocardial infa rct ion , death from any cause or adverse events .
background: BACKGROUND Cardiovascular disease , which includes coronary artery disease , stroke and peripheral vascular disease , is a leading cause of death worldwide .
  Homocysteine is an amino acid with biological functions in methionine metabolism .
  A postulated risk factor for cardiovascular disease is an elevated circulating total homocysteine level .
  The impact of homocysteine-lowering interventions , given to patients in the form of vitamins B6 , B9 or B12 supplements , on cardiovascular events has been investigated .
  This is an up date of a review previously published in 2009 , 2013 , and 2015 .
  OBJECTIVES To determine whether homocysteine-lowering interventions , provided to patients with and without pre-existing cardiovascular disease are effective in preventing cardiovascular events , as well as reducing all-cause mortality , and to evaluate their safety .