A prospective cohort study of predictive value of homocysteine in patients with type 2 diabetes and coronary artery disease. 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. Homocysteine-Lowering and Cardiovascular Disease Outcomes in Kidney Transplant Recipients: Primary Results From the Folic Acid for Vascular Outcome Reduction in Transplantation Trial Homocysteine and risk of cardiovascular disease among postmenopausal women. Homocysteine and coronary heart disease in the Caerphilly cohort: a 10 year follow up 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 Plasma total homocysteine levels and prognosis in patients with previous premature myocardial infarction: a 10-year follow-up study. Homocysteine-Lowering Therapy and Stroke Risk, Severity, and Disability: Additional Findings From the HOPE 2 Trial Plasma homocysteine levels and mortality in patients with coronary artery disease. 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. Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease--results of the renal Hope-2 study. Hyperhomocysteinemia in Japanese patients with convalescent stage ischemic stroke: Effect of combined therapy with folic acid and mecobalamine Serum Homocysteine and Long-Term Risk of Myocardial Infarction and Sudden Death in Patients with Coronary Heart Disease Homocysteine and major coronary events: a prospective population study amongst women. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial.
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 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 . ) 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 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 OBJECTIVE Prospect i ve assessment of the risk of coronary heart disease associated with total serum homocyst(e)ine ( homocysteine ) concentration . DESIGN Nested case-control study . SETTING Caerphilly and surrounding villages in south Wales , UK . PARTICIPANTS 2290 men who participated in phase II of the study in 1984 . After a mean follow up of 10 years , 312 men developed coronary heart disease and were compared with 1248 r and omly selected , age frequency matched controls . MAIN OUTCOME MEASURE Acute myocardial infa rct ion or death from coronary heart disease . RESULTS The geometric mean serum homocysteine concentration was higher in cases ( 12.2 μmol/l , 95 % confidence interval ( CI ) 11.8 to 12.6 μmol/l ) than in controls ( 11.8 μmol/l , 95 % CI 11.3 to 12.5 μmol/l ) ( p = 0.09 ) . There was a grade d increase in the odds ratio of coronary heart disease across quintiles of the homocysteine concentration distribution compared with the first ( p = 0.04 ) , which was attenuated when adjusted for confounding variables ( p = 0.4 ) . There was a small but non-significant increase in the adjusted odds ratio of coronary heart disease per st and ard deviation change in the log distribution of homocysteine concentration ( OR = 1.07 ( 95 % CI .93 to 1.24 ) , p = 0.34 ) . Comparing the top quintile of the homocysteine concentration with the remaining 80 % , the adjusted odds ratio of coronary heart disease was 1.03 ( 95 % CI 0.73 to 1.45 ) ( p = 0.8 ) and comparing the top 5 % with the remaining 95 % it was 1.05 ( 95 % CI 0.56 to 1.95 ) ( p = 0.9 ) . CONCLUSIONS These findings do not support the hypothesis that a raised homocysteine concentration is a strong independent risk factor for coronary heart disease . R and omised controlled trials of homocysteine lowering treatment such as folic acid are needed before generalising the early positive results of observational studies 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 OBJECTIVES To explore plasma total homocysteine ( tHcy ) as a predictor of long-term prognosis after premature myocardial infa rct ion ( MI ) . DESIGN Prospect i ve cohort study . SETTING S Akershus University Hospital . SUBJECTS A total of 247 patients ( 193 men and 54 women ) in stable clinical phase after premature MI ( males : first MI at age < or = 55 ; females < or = 60 ) . MAIN OUTCOME MEASURES The primary end-point was total mortality and the secondary end-point was cardiac death . The third end-point was major cardiac events : a combination of cardiac death , MI and cardiac arrest . RESULTS After 10 years , 44 patients had died , 36 from cardiac causes . Major cardiac event occurred in 70 patients . The relative risk for death of all causes increased 1.43 ( 95 % CI , 1.08 - 1.88 ) per tHcy quartile ( P for trend = 0.01 ) , and was only modestly reduced after adjustment for age , ejection fraction , total cholesterol , C-reactive protein , fibrinogen , smoking and hypertension to 1.37 ( 95 % CI , 1.04 - 1.80 ) ( P for trend = 0.03 ) . Similar results were observed when cardiac death was used as the end-point , but we observed no association between tHcy and the end-point major cardiac event . CONCLUSIONS Total homocysteine was an independent predictor of total and cardiac mortality in stable patients following premature MI . tHcy had no effect on major cardiac event in contrast to most other risk factors in this study . Thus , the mechanism(s ) underlying the effects of homocysteine on coronary heart disease may differ from other risk factors 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 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 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 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 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 We have prospect ively evaluated the risk of incident coronary events in association with serum total homocysteine in patients with preexisting chronic coronary heart disease . A nested case-control design was used . Total homocysteine concentration was measured in baseline fasting serum sample s from patients with chronic coronary heart disease enrolled in the Bezafibrate Infa rct ion Prevention Study ( n = 3,090 ) who developed coronary events during 6.2 years of follow-up ( n = 69 ) . They were matched for age and gender with controls without subsequent cardiovascular events . Elevated homocysteine levels were associated with 2.5 times higher risk of subsequent coronary events and each 5 µmol/l increment was associated with a 25 % higher risk OBJECTIVES To study serum homocysteine concentration for its prediction of major coronary heart disease events amongst women . DESIGN A case-control study nested within a follow-up study . Subjects . A total of 74 and 75 major coronary events ( coronary deaths or nonfatal myocardial infa rct ion ) which occurred in women with and without known heart disease , respectively , during a 13-year follow-up and two individually matched controls per case . Main outcome measure . Major coronary event . RESULTS Amongst women with baseline heart disease , the relative risk ( 95 % CI ) of such events , adjusted for age , smoking , hypertension , diabetes , serum cholesterol and body mass index , was 3.32 ( 1.05 - 10.5 ) in the highest homocysteine quintile compared with the lowest quintile . Amongst women free of heart disease at baseline , the corresponding relative risk value was 0.77 ( 0.24 - 2.45 ) . CONCLUSIONS This prospect i ve study support the hypothesis that homocysteine is a risk factor for coronary events in women with heart disease 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
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 .