Homocysteine-Lowering and Cardiovascular Disease Outcomes in Kidney Transplant Recipients: Primary Results From the Folic Acid for Vascular Outcome Reduction in Transplantation Trial Homocysteine lowering with folic acid and B vitamins in vascular 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. Homocysteine lowering and cardiovascular events after acute myocardial infarction. 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 Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease--results of the renal Hope-2 study. B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage Renal Disease: Results of a Randomized Controlled Trial Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Homocysteine and risk of cardiovascular disease among postmenopausal women. Folic Acid-Based Intervention in Non-ST Elevation Acute Coronary Syndromes Homocysteine-Lowering Therapy and Risk for Venous Thromboembolism Homocysteine-Lowering Therapy and Stroke Risk, Severity, and Disability: Additional Findings From the HOPE 2 Trial B-Vitamin Therapy for Kidney Transplant Recipients Lowers Homocysteine and Improves Selective Cognitive Outcomes in the Randomized FAVORIT Ancillary Cognitive Trial. 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. 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 A prospective cohort study of predictive value of homocysteine in patients with type 2 diabetes and coronary artery disease. Effect of Homocysteine-Lowering Treatment With Folic Acid and B Vitamins on Risk of Type 2 Diabetes in Women Randomized, placebo-controlled trial of intramuscular vitamin B12 for the treatment of hyperhomocysteinaemia in dialysis patients. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. Plasma folate and total homocysteine levels are associated with the risk of myocardial infarction, independently of each other and of renal function. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. Stabilization of homocysteine in unseparated blood over several days: a solution for epidemiological studies. Homocysteine-lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease.
Background — Kidney transplant recipients , like other patients with chronic kidney disease , experience excess risk of cardiovascular disease and elevated total homocysteine concentrations . Observational studies of patients with chronic kidney disease suggest increased homocysteine is a risk factor for cardiovascular disease . The impact of lowering total homocysteine levels in kidney transplant recipients is unknown . Methods and Results — In a double-blind controlled trial , we r and omized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose ( n=2056 ) or low dose ( n=2054 ) of folic acid , vitamin B6 , and vitamin B12 to determine whether decreasing total homocysteine concentrations reduced the rate of the primary composite arteriosclerotic cardiovascular disease outcome ( myocardial infa rct ion , stroke , cardiovascular disease death , resuscitated sudden death , coronary artery or renal artery revascularization , lower-extremity arterial disease , carotid endarterectomy or angioplasty , or abdominal aortic aneurysm repair ) . Mean follow-up was 4.0 years . Treatment with the high-dose multivitamin reduced homocysteine but did not reduce the rates of the primary outcome ( n=547 total events ; hazards ratio [ 95 confidence interval]=0.99 [ 0.84 to 1.17 ] ) , secondary outcomes of all-cause mortality ( n=431 deaths ; 1.04 [ 0.86 to 1.26 ] ) , or dialysis-dependent kidney failure ( n=343 events ; 1.15 [ 0.93 to 1.43 ] ) compared to the low-dose multivitamin . Conclusions — Treatment with a high-dose folic acid , B6 , and B12 multivitamin in kidney transplant recipients did not reduce a composite cardiovascular disease outcome , all-cause mortality , or dialysis-dependent kidney failure despite significant reduction in homocysteine level . Clinical Trial Registration — http://www . clinical trials.gov . Unique identifier : NCT00064753 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 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 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 . ) 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 Elevated plasma homocysteine levels are reported to be associated with higher rates of vascular diseases . Plasma homocysteine increases in chronic kidney disease ( CKD ) and could contribute to the increased cardiovascular risk in CKD . METHODS Participants aged 55 years or older with CKD , defined as estimated GFR<60 ml/min and at high cardiovascular risk , were r and omly assigned to the combination of folic acid , 2.5 mg , vitamin B6 , 50 mg and vitamin B12 , 1 mg ( n = 307 ) or placebo ( n = 312 ) daily for 5 years . The primary outcome was a composite of death from cardiovascular causes , myocardial infa rct ion and stroke . RESULTS Mean baseline plasma homocysteine was 15.9 + /- 7.3 micromol/l in the active treatment group and 15.7 + /- 5.7 micromol/l in placebo group and decreased to 11.9 + /- 3.3 micromol/l ( P < 0.001 ) on active treatment ( 15.5 + /- 4.5 on placebo ) . Primary outcome events occurred in 90 participants ( 29.3 % ) on active therapy and in 80 ( 25.6 % ) on placebo ( relative risk , 1.19 ; 95 % confidence interval , 0.88 - 1.61 ; P = 0.25 ) . There were no significant treatment benefits on death from cardiovascular causes ( 1.24 ; 0.84 - 1.83 ) , myocardial infa rct ion ( 1.10 ; 0.76 - 1.61 ) and stroke ( 1.00 ; 0.54 - 1.85 ) . More participants in the active treatment group were hospitalized for heart failure ( 1.98 ; 1.21 - 3.26 ; P = 0.007 ) and for unstable angina ( 1.70 ; 1.02 - 2.83 ; P = 0.04 ) . Incidence of primary outcome increased with decreasing GFR . CONCLUSIONS Active treatment with B vitamins lowered homocysteine levels  in participants with CKD but did not reduce cardiovascular risk Background — In observational studies , hyperhomocysteinemia has been found to be a risk factor for total mortality and cardiovascular events in patients with end-stage renal disease . These patients have grossly elevated homocysteine levels that can be lowered by supplementation with folic acid and vitamin B12 . We conducted a r and omized clinical trial with B vitamins to reduce homocysteine levels and therefore cardiovascular events and total mortality . Methods and Results — This r and omized , double-blind multicenter study was conducted in 33 dialysis centers in north and east Germany between July 2002 and July 2008 . We r and omly assigned 650 patients with end-stage renal disease who were undergoing hemodialysis to 2 postdialysis treatments : 5 mg folic acid , 50 & mgr;g vitamin B12 , and 20 mg vitamin B6 ( active treatment ) or 0.2 mg folic acid , 4 & mgr;g vitamin B12 , and 1.0 mg vitamin B6 ( placebo ) given 3 times per week for an average of 2 years . The primary outcome was total mortality ; the secondary outcome was fatal and nonfatal cardiovascular events . The primary outcome occurred in 102 patients ( 31 % ) receiving the active treatment and in 92 ( 28 % ) receiving placebo ( hazard ratio , 1.13 ; 95 % confidence interval , 0.85 to 1.50 ; P=0.51 ) . The secondary outcome occurred in 83 patients ( 25 % ) receiving the active treatment and in 98 ( 30 % ) receiving placebo ( hazard ratio , 0.80 ; 95 % confidence interval , 0.60 to 1.07 ; P=0.13 ) . Conclusions — Increased intake of folic acid , vitamin B12 , and vitamin B6 did not reduce total mortality and had no significant effect on the risk of cardiovascular events in patients with end-stage renal disease . Clinical Trial Registration — URL : www.anzctr.org.au . Unique identifier : ACTRN12609000911291 . URL : www.cochrane-renal.org . Unique identifier : CRG010600027 BACKGROUND Cardiovascular disease is the most important cause of morbidity and mortality in hemodialysis patients . These patients frequently have hyperhomocysteinemia , a putative risk factor for cardiovascular disease . Treatment with folate , B6 and B12 partially reduces hyperhomocysteinemia . We conducted a long-term study to evaluate whether 15 mg is more effective than 5 mg oral folic acid as a daily dosage to decrease hyperhomocysteinemia , and to assess whether homocysteine-lowering treatment reduces the risk of cardiovascular disease in hemodialysis patients . MATERIAL / METHODS In a 1-year prospect i ve r and omised trial , 81 chronic hemodialysis patients , matched for age , gender and dialytic age , were divided into three groups : 30 untreated patients , 26 patients receiving 5 mg per day , and 25 patients receiving 15 mg per day . RESULTS There was a significant reduction in hyperhomocysteinemia over time in treated patients as compared to untreated , but there were no significant differences between the two treated groups . Only 12 % of the treated patients reached normal total homocysteine plasma levels . We observed a trend towards a significant difference in survival rate in cardiovascular morbidity between treated and untreated patients . Furthermore , hemodialysis patients with new vascular events showed higher homocysteine levels than patients without events . CONCLUSIONS High-dose folic acid treatment did not improve outcome in hyperhomocysteinemia , and 88 % of treated patients maintained higher than normal homocysteine levels . There was a trend towards a decreased rate of cardiovascular events in treated participants as compared to untreated ones CONTEXT Individuals with elevated levels of homocysteine tend to have higher prevalence of cardiovascular disease . However , prospect i ve studies of homocysteine are inconsistent and data among women are limited . OBJECTIVE To determine whether elevated homocysteine levels in healthy postmenopausal women predict risk of developing cardiovascular disease . DESIGN Prospect i ve , nested case-control study with a mean 3-year follow-up . SETTING The Women 's Health Study , an ongoing US primary prevention trial initiated in 1993 . PARTICIPANTS From a total cohort of 28,263 postmenopausal women with no history of cardiovascular disease or cancer at baseline , 122 women who subsequently experienced cardiovascular events were defined as cases , and 244 age- and smoking status-matched women who remained free of disease during follow-up were defined as controls . MAIN OUTCOME MEASURES Incidence of death due to cardiovascular disease , nonfatal myocardial infa rct ion ( MI ) , stroke , percutaneous transluminal coronary angioplasty , or coronary artery bypass graft by baseline homocysteine level . RESULTS Of the 122 cases , there were 85 events of MI or stroke and 37 coronary revascularizations . Case subjects had significantly higher baseline homocysteine levels than controls ( 14.1 vs 12.4 micromol/L ; P = .02 ) . Subjects with homocysteine levels in the highest quartile had a 2-fold increase in risk of any cardiovascular event ( relative risk [ RR ] , 2.0 ; 95 % confidence interval [ CI ] , 1.1 - 3.8 ) . This effect was largely due to an excess of cases with high levels of homocysteine ; the RR for those with homocysteine levels at or higher than the 95th percentile ( 20.7 micromol/L ) was 2.6 ( 95 % CI , 1.1 - 5.7 ) . Risk estimates were independent of traditional risk factors and were greatest for the end points of MI and stroke ( RR for those with baseline homocysteine levels in the top quartile , 2.2 ; 95 % CI , 1.1 - 4.6 ) . Self-reported multivitamin supplement use at study entry was associated with significantly reduced levels of homocysteine ( P<.001 ) . However , the association between increasing quartile of homocysteine level and risk of MI or stroke remained significant in analyses controlling for baseline multivitamin supplement use ( P = .003 for trend ) , and subgroup analyses limited to women who were ( P = .02 for trend ) or were not ( P = .04 for trend ) taking multivitamin supplements . CONCLUSIONS Among healthy postmenopausal US women , elevated levels of homocysteine moderately increased the risk of future cardiovascular disease . Whether lowering the homocysteine level reduces risk of cardiovascular events requires testing in r and omized controlled trials 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 Context In observational studies , elevated plasma homocysteine levels were associated with venous thromboembolism . A multicenter trial of folic acid and B vitamins to reduce cardiovascular events investigated the effect of homocysteine lowering on venous thromboembolism . Contribution In this trial , 5522 adults were r and omly assigned to receive placebo , or folic acid and vitamins B6 and B12 daily for 5 years . Vitamin therapy decreased homocysteine levels , but the incidence of venous thromboembolism was the same in both groups , even in participants with the highest levels of homocysteine . Caution Venous thromboembolism events were not central ly adjudicated . Implication Decreasing homocysteine levels with supplements containing folic acid and vitamins B6 and B12 does not reduce the incidence of venous thromboembolism . The Editors Observational studies have found an association between elevated total plasma homocysteine levels and venous thromboembolism ( 14 ) . Homocysteine is thought to promote thrombosis through enhanced platelet activation , increased thrombin generation , and impaired fibrinolysis and by causing endothelial dysfunction ( 5 ) . Although homocysteine levels can be decreased by 25 % by using a supplement of folic acid and vitamins B6 and B12 ( 6 ) , whether the risk for venous thromboembolism is reduced as a result is not known . The Heart Outcomes Prevention Evaluation 2 ( HOPE-2 ) evaluated the effect of homocysteine-lowering therapy on the risk for major vascular arterial disease ( 7 ) . In conjunction with the trial , we collected data prospect ively to determine whether decreasing homocysteine levels would reduce the occurrence of symptomatic venous thromboembolism . Methods Design The design of HOPE-2 , a large r and omized , placebo-controlled clinical trial , is described elsewhere ( 7 , 8) . Soon after HOPE-2 began , a decision was made to include venous thromboembolism as a study outcome . A diagnosis of venous thromboembolism was based on prespecified , accepted criteria ( 7 ) . An independent data and safety monitoring board evaluated the safety of the participants and the overall quality and scientific integrity of HOPE-2 . The research ethics review board of each participating center approved the trial , and all participants provided written informed consent . Participants The HOPE-2 included 5522 participants 55 years of age or older who had a history of coronary , cerebrovascular , or peripheral vascular disease ; diabetes mellitus ; and at least 1 additional risk factor for cardiovascular disease , regardless of baseline homocysteine level ( 7 , 8) . Persons taking daily vitamin supplementation that contained more than 0.2 mg of folic acid were excluded . A history of venous thromboembolism or the presence or absence of risk factors for venous thromboembolism did not affect eligibility . A complete list of inclusion and exclusion criteria appears elsewhere ( 7 , 8) . Data on all persons who were enrolled in HOPE-2 are included in the current report . Centers Individuals were recruited from 145 centers in 13 countries , including Canada ( n= 3568 ) , the United States ( n= 414 ) , Brazil ( n= 265 ) , western European countries ( n= 426 ) , and Slovakia ( n= 849 ) . Intervention and R and omization Between January 2000 and December 2000 , participants were r and omly assigned to receive a once-daily supplement containing 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 , or matching placebo . R and omization was computer generated , with a block size of 4 ; was stratified by clinical center ; and was performed by having clinical centers call an automated central ized system . Information about block size and whether it was r and om or fixed was kept confidential for all study investigators . The r and omization sequence was concealed , and all study personnel and study participants were masked to treatment allocation . The vitamin and placebo pill formulations were indistinguishable by size , color , weight , taste , or dissolution in water . Changes in blood levels of folate , vitamins B6 and B12 , and homocysteine , which are affected by the study intervention , are not commonly measured in clinical practice , and the results of any such measurements that were performed as part of the study were kept confidential . No request was made to unmask treatment allocation for a participant . Baseline Measurements and Follow-up Baseline demographic data ; medical history ; and medication use , including current anticoagulant therapy , were recorded for all participants at study entry . History of venous thromboembolism was not documented . Baseline homocysteine levels were obtained in 3306 r and omly selected participants ( 60 % of total ) who had fasted overnight . Stratified r and om sampling was used to achieve proportional representation of a subset of participants in countries with folic acid food fortification ( Canada and the United States ) and countries without this st and ard ( all other countries with participating centers ) . Homocysteine was measured by using a fluorescence polarization immunoassay ( Abbott IMx , Abbott Laboratories , Abbott Park , Illinois ) . The distribution of homocysteine was statistically significantly skewed ; thus , these measures were log-transformed and inverse transformations were used to generate geometric mean values . The first evaluation for venous thromboembolism occurred 18 months after r and omization ; at this visit , all participants were assessed for any venous thromboembolism event arising between trial entry and the 18-month visit . Thereafter , venous thromboembolism was assessed routinely every 6 months , to an average follow-up of 5 years . The trial used simple case report forms , which were faxed toll-free to the study coordinating office and were entered into a data base by using optical character recognition ( Data Fax , Clinical Data Fax Systems , Hamilton , Ontario , Canada ) . The data base was fit for quality control assessment s and statistical analyses . At each 6-month interval , participants were assessed in the study clinics . These assessment s were directed primarily to ascertain study end points . Side effects were also evaluated , and adherence to treatment was assessed by interview and pill count . When in-person visits were not possible , participants were contacted by telephone . Outcomes The primary outcome in our study was symptomatic venous thromboembolism , which included deep venous thrombosis or pulmonary embolism ( or both ) . In the original HOPE-2 report ( 8) , venous thromboembolism was included under other outcomes . Diagnosis of deep venous thrombosis required confirmation with duplex leg ultrasonography or venography . Diagnosis of pulmonary embolism required confirmation with ventilationperfusion lung scanning , computed tomographic pulmonary angiography , or conventional pulmonary angiography . When diagnostic testing had indeterminate results or was not done , which rarely occurred , we required oral anticoagulant therapy to be initiated at the same time that new-onset venous thromboembolism was recorded on the case report form . A maximum of 1 episode of venous thromboembolism per participant was counted during follow-up . We subcategorized episodes as unprovoked venous thromboembolism if they occurred in participants who did not have cancer at baseline and occurred 90 days or more after a lower limb fracture or 30 days or more after a hospitalization . We ascertained all events with concealment to r and omization for study participants and assessors . Statistical Analysis Our primary analysis was a comparison of the incidence of venous thromboembolism in the 2 study groups . We prespecified secondary analyses and included comparisons between the groups of rates of venous thromboembolism ( including unprovoked events ) according to subgroups and strata ( Figure 1 ) . Figure 1 . Risk for venous thromboembolism ( VTE ) in prespecified subgroups . We used an intention-to-treat analysis to compare the effect of homocysteine-lowering therapy with that of placebo on the subsequent development of venous thromboembolism . We conducted the time-to-event analysis by using a Cox proportional hazards regression model and expressed unadjusted risk as hazard ratios and 95 % CIs . We examined the proportional hazards assumption by fitting the models with the interaction terms between time and treatment . We estimated a survival curve according to the KaplanMeier procedure and compared treatment groups by using a log-rank test . At each interval clinic visit , follow-up was greater than 99 % . In the rare circumstance that an individual could not be assessed at a clinic visit and could not be contacted by telephone , we considered the individual to be free of venous thromboembolism at that point . Individuals who were lost to follow-up were censored at the time of last contact . The original HOPE-2 was design ed to recruit 5000 participants , with a mean of 5 years of follow-up , to detect a relative risk reduction of 17 % to 20 % and a statistical power of 80 % and 90 % in the primary composite outcome of cardiovascular death , myocardial infa rct ion , and stroke , given an annual event rate of 4 % in the placebo group and a 2-sided P value of 0.05 . We did not estimate a formal sample size . A 2-sided P value less than 0.05 was considered significant for all analyses , which we performed by using SAS , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) . Role of the Funding Sources The study was funded by the Canadian Institutes of Health Research and Jamieson Laboratories . The funding sources had no role in the design , conduct , or reporting of the study or in the decision to su bmi t the manuscript for publication . Results Study Participants and Homocysteine Levels Of the 5522 study participants , 2758 were r and omly assigned to receive homocysteine-lowering therapy and 2764 were assigned to receive placebo ( Table 1 ) . A total of 3982 participants ( 72 % ) were from Canada and the United States , where universal food fortification with folic acid was in place before the start of the trial . Adherence to 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 BACKGROUND Objectives : Elevated plasma total homocysteine ( tHcy ) is associated with increased risk of cardiovascular disease , stroke and dementia . Results of clinical trials using B-vitamins to reduce the cognitive risks attributed to tHcy have been inconsistent . The high prevalence of both hyperhomocysteinemia and cognitive impairment among kidney transplant recipients makes them an important population in which to evaluate the effect of lowering homocysteine on cognitive function . We therefore evaluated whether B-vitamin therapy to lower tHcy would prevent cognitive-decline in a cohort of stable kidney transplant recipients . DESIGN The study was a longitudinal ancillary of the FAVORIT trial , a r and omized , placebo-controlled multi-site trial of high-dose B vitamins to reduce cardiovascular and cerebrovascular events in clinical ly stable kidney transplant recipients with elevated tHcy . PARTICIPANTS 584 participants from 18 sites across North America . INTERVENTION The intervention consisted of a daily multivitamin containing high-doses of folate ( 5.0 mg ) , vitamin B12 ( 1.0 mg ) and vitamin B6 ( 50 mg ) . The placebo consisted of a daily multi-vitamin containing no folate and recommended daily allowances of vitamins B12 and B6 ( 0 mg folate ; 2.0 µg vitamin B12 ; 1.4 mg vitamin B6 ) . MEASUREMENTS Annual neuropsychological assessment for up to 5 years ( mean 3.3 years ) using a st and ardized test battery . Efficacy was analyzed on an intention-to-treat basis using end-of-trial data . Subgroup analyses included stratification for baseline plasma B-vitamin and tHcy concentrations . RESULTS At baseline , cognitive impairment was common with 61 % of participants falling more than one st and ard deviation below published norms for at least one cognitive test . Fewer than 1 % of participants had insufficient plasma folate < 5 ng/ml or vitamin B12 < 148 pmol/L. However , 44.6 % had plasma B6 concentrations < 30 nmol/L. At follow-up , processing speed and memory scores were modestly but significantly better in the B-vitamin supplement group than in controls ( p≤0.05 ) . There was no interaction between baseline tHcy , B-vitamin status and treatment on the cognitive outcomes . CONCLUSIONS High-dose B-vitamin supplementation provided modest cognitive benefit for kidney transplant recipients with elevated baseline tHcy . Since nearly all participants were folate and vitamin B12 sufficient at baseline , the potential cognitive benefits of folate and B12 supplementation in individuals with poor B-vitamin status remains to be determined 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 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 BACKGROUND Little evidence exists on the role of homocysteine as a predictor of mortality in patients with type 2 diabetes . The aim of this study was to investigate whether elevated plasma homocysteine levels are independently associated with all-cause or cardiovascular mortality in patients with type 2 diabetes and coronary artery disease . METHODS This is a prospect i ve cohort study that included 507 patients with type 2 diabetes and angiographically proven coronary artery disease . Patients were divided into 2 groups according to homocysteine level above or below median value ( 12.4 micromol/L ) : the high homocysteine group ( 255 patients ) and the low homocysteine group ( 252 patients ) . The primary end-point of the study was all-cause mortality . RESULTS There were 103 deaths during a 4-year follow-up : 62 deaths in the high homocysteine group and 41 deaths in the low homocysteine group ( Kaplan-Meier estimates of mortality 25.6 % and 17.4 % , respectively ( odds ratio [ OR ] 1.53 , 95 % confidence interval [ CI ] 1.03 - 2.27 , P=0.031 ) . Sixty-two of 103 deaths ( 60.2 % ) were of cardiovascular origin : 37 deaths ( 14.5 % ) occurred in the high homocysteine group and 25 deaths ( 9.9 % ) occurred in the low homocysteine group ( P=0.115 ) . Cox proportional hazards model showed that plasma homocysteine was not an independent correlate of all-cause ( adjusted hazard ratio [ HR ] 1.10 , 95 % CI 0.89 - 1.33 ; P=0.397 for 5 micromol/L increase in concentration ) or cardiovascular ( adjusted HR 1.04 , 95 % CI 0.80 - 1.36 , P=0.753 , for 5 micromol/L increase in concentration ) mortality . CONCLUSION In patients with type 2 diabetes and coronary artery disease , elevated level of homocysteine is an associate of increased cardiovascular risk but not an independent predictor of cardiovascular mortality 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 Plasma homocysteine is elevated in patients with end-stage renal disease ( ESRD ) and is a risk factor for cardiovascular disease . Folic acid has been shown to partially reduce homocysteine levels in dialysis patients . It is not known whether vitamin B12 reduces homocysteine independent of folic acid in patients who are not vitamin B12 deficient . AIM To determine whether 1 mg vitamin B12 lowers homocysteine in stable , chronic , haemodialysis patients independent of folic acid . METHODS Twenty-eight haemodialysis patients were r and omized to receive three doses of 1 mg vitamin B12 or 1 mL saline placebo in a double-blind fashion at 1-month intervals . Fasting plasma total homocysteine , folic acid , red-cell folate , vitamin B12 and haemoglobin levels were determined prior to each dose and 4 weeks after the final injection . The study was powered to detect a 30 % reduction in homocysteine over the 3 months . RESULTS Both the two groups were well matched with respect to total homocysteine levels , folic acid , red-cell folate and vitamin B12 levels . Serum vitamin B12 levels were significantly higher in the treatment group compared to placebo ( 217.7 pmol/L ; 95 % confidence interval ( CI ) 103.0 - 332.5 ; P < 0.001 ) at the end of the trial but homocysteine levels were not significantly different ( 3.08 micromol/L ; 95 % CI -4.44 - 10.61 ; P= 0.406 ) . CONCLUSIONS The administration of intramuscular vitamin B12 over a 3-month period does not result in any reduction of plasma homocysteine levels in haemo-dialysis patients independent of folate status , however reductions of < 30 % can not be excluded by the present study . High-dose folic acid remains the treatment of choice in reducing homocysteine , but whether this results in a reduction in cardiovascular events remains to be determined 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 OBJECTIVES To investigate the relationship between plasma folate , vitamin B12 and total homocysteine concentrations ,  dietary intake of folate and vitamins B12 , B6 and B2  , and the  risk of first acute myocardial infa rct ion ( MI ) .  DESIGN Nested case-referent study with up to 13 years of follow-up . SETTING The population -based Northern Sweden Health and Disease Study , with 73 879 participants at the time of case ascertainment . SUBJECTS A total of 571 MI cases ( 406 men ) and 1569 matched referents . Of the cases , 530 had plasma sample s available , and 247 had dietary B-vitamin intake data . RESULTS Plasma concentrations of folate were inversely associated , and total homocysteine positively associated , with the risk of MI , independently of each other and of a number of established and novel cardiovascular risk factors , including renal function [ multivariate odds ratio for highest vs. lowest quintile of folate 0.52 ( 95 % CI 0.31 - 0.84 ) , P for trend = 0.036 , and homocysteine 1.92 ( 95 % CI 1.20 - 3.09 ) , P for trend = 0.006 ] . For plasma vitamin B12 concentrations , and vitamin B12 , B6 and B2 intake , no clear risk relationship was apparent . Though not statistically significant , the results for folate intake were consistent with those for plasma concentrations . CONCLUSIONS In this large prospect i ve study of a population without m and atory folic acid fortification , both folate and homocysteine were strongly associated with the risk of myocardial infa rct ion , independently of each other and of renal function . Although r and omized trials of folic acid supplementation are needed to determine causality , our findings highlight the potential importance of folate , or sources of folate , in incident cardiovascular disease 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 Increased blood homocysteine is a potentially modifiable risk factor for cardiovascular disease . In a recent meta analysis of individual participant data from prospect i ve epidemiologic studies , a 25 % lower homocysteine concentration was associated with an 11 % lower risk for ischemic heart disease and a 19 % lower risk for stroke ( 1 ) . Blood homocysteine is easily lowered by folic acid supplementation , and several large-scale r and omized trials are currently underway to assess the effects of homocysteine-lowering vitamin supplements on the risk of vascular disease . If such trials demonstrate benefit , there will be increasing interest in homocysteine determinations to assess vascular disease risk . In addition , further large-scale epidemiologic studies may be required to investigate the association between homocysteine and cardiovascular disease in a wider range of population s. These would be facilitated by simple and cost-effective methods for blood collection and analysis . One of the chief constraints in homocysteine measurements is the continuing production and release of homocysteine by red blood cells after venipuncture , which causes an artificial increase in plasma concentration of ∼10 % per hour (2)(3 ) . It has been recommended , therefore , that blood sample s for homocysteine measurements be drawn into tubes containing EDTA , chilled , or placed on ice immediately after collection and that the plasma be separated from the red cells within 1 h. Such procedures can be difficult to implement in large-scale epidemiologic studies or other situations in which sample s have to be collected remotely ( e.g. , in multiple clinics or in people ’s homes ) and transported to a central laboratory . Use of NaF or acidic citrate has been advocated for stabilization of homocysteine in whole blood at ambient temperature 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
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 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 .