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Original Contribution |

Effects of Homocysteine-Lowering With Folic Acid Plus Vitamin B12 vs Placebo on Mortality and Major Morbidity in Myocardial Infarction Survivors:  A Randomized Trial FREE

Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group*
[+] Author Affiliations

*Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group Authors/Writing Committee:Jane M. Armitage, FRCP; Louise Bowman, MRCP; Robert J. Clarke, FRCP; Karl Wallendszus, BA, MSc; Richard Bulbulia, FRCS; Kazem Rahimi, MRCP; Richard Haynes, MRCP; and Sarah Parish, PhD, Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom; Peter Sleight, FRCP, Department of Cardiovascular Medicine, University of Oxford; and Richard Peto, FRS, and Rory Collins, FRCP, Clinical Trial Service Unit, University of Oxford.


JAMA. 2010;303(24):2486-2494. doi:10.1001/jama.2010.840.
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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 B12 on vascular and nonvascular outcomes.

Design, Setting, and Patients Double-blind randomized controlled trial of 12 064 survivors of myocardial infarction in secondary care hospitals in the United Kingdom between 1998 and 2008.

Interventions 2 mg folic acid plus 1 mg vitamin B12 daily vs matching placebo.

Main Outcome Measures First major vascular event, defined as major coronary event (coronary death, myocardial infarction, or coronary revascularization), fatal or nonfatal stroke, or noncoronary revascularization.

Results Allocation to the study vitamins reduced homocysteine by a mean of 3.8 μmol/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 B12 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 B12 supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence.

Trial Registration isrctn.org Identifier: ISRCTN74348595

Figures in this Article

Observational studies have consistently indicated that patients with occlusive vascular disease have higher blood levels of homocysteine than do controls, and these differences precede the onset of disease and are independent of other risk factors.13 A meta-analysis of prospective studies indicated that, after adjustment for known risk factors, a 25% lower usual homocysteine concentration was associated with 11% lower risk of coronary heart disease and 19% lower risk of stroke.3 Daily supplementation with folic acid typically lowers homocysteine levels by about 25%, and the addition of vitamin B12 lowers it by a further 7%.4,5 Folic acid is inexpensive, so there is considerable interest in the possibility of reducing the incidence of occlusive vascular disease with folic acid supplementation.

Seven large-scale randomized trials have previously reported on the effects on occlusive vascular disease of lowering homocysteine with folic acid–based vitamin supplements, but none of those trials has shown definite protective effects.612 It has been unclear whether these generally unpromising results are due to insufficient numbers of particular cardiovascular events, too short a duration of treatment, attenuation of any effects by population-wide folic acid fortification, or lack of real benefit.13,14 A subgroup analysis of the HOPE-2 trial9,15 and a meta-analysis of a subset of these trials suggested protective effects on stroke.16 The SEARCH trial assessed the effects of lowering homocysteine levels with folic acid plus vitamin B12 for almost 7 years in 12 064 survivors of myocardial infarction.17 The large size and long duration of treatment in a high-risk population without background mandatory folate fortification allows SEARCH to provide a reliable assessment of the potential benefits and potential hazards of lowering homocysteine substantially with folic acid and vitamin B12 supplementation.

The study objectives, design, and methods have been reported previously17 (protocol appears at http://www.searchinfo.org). As well as assessing folate-based homocysteine-lowering therapy, a 2 × 2 factorial design allowed the separate assessment of different doses of simvastatin.

Eligibility

Men and women aged 18 to 80 years with a history of myocardial infarction were eligible provided they had no clear indication for folic acid and had blood cholesterol levels of at least 135 mg/dL if already taking a statin medication or 174 mg/dL if not (to convert cholesterol to mmol/L, multiply by 0.0259). Exclusion criteria are reported elsewhere17 and included chronic liver, renal, or muscle disease; history of any cancer (except nonmelanoma skin cancer); and use of potentially interacting medications.

Recruitment

Medical collaborators from 88 UK hospitals appointed senior nurses to run special study clinics (see eAppendix). Approval was obtained from the South East Thames multicenter research ethics committee, and local committees provided site-specific approval. Computerized hospital discharge records were used to identify patients with a diagnosis of myocardial infarction, who, with the agreement of their general practitioners, were invited to attend the local study clinic. At the initial screening visit, a nonfasting blood sample was obtained and guidance given about modification of diet and other vascular disease risk factors. Eligible individuals were given detailed information about the study and those agreeing provided written consent to participate.

Potentially eligible participants entered a prerandomization run-in phase, which was intended chiefly to limit subsequent randomization to those likely to take the randomly allocated study treatment for several years.18 Run-in treatment involved placebo vitamin tablets (and 20 mg simvastatin daily, which allowed baseline lipid levels to be assessed after all participants had received the same statin therapy). Individuals who adhered to this treatment, did not have a major vascular event or other serious problem during the run-in, and agreed to participate for several years were randomly allocated to receive 1 tablet daily containing either 2 mg folic acid plus 1 mg vitamin B12 or matching placebo in specially prepared calendar packs (and, separately, using a 2 × 2 factorial design, either 80 mg or 20 mg simvastatin daily). The central telephone randomization system used a minimization algorithm19 to balance the treatment groups with respect to major prognostic factors.17

Follow-up

Following randomization between September 1998 and October 2001, participants were to be seen for routine follow-up checks and blood safety monitoring at 2, 4, 8, and 12 months and then every 6 months until final follow-up visits between October 2007 and June 2008. Those who did not attend were to be contacted by telephone at the time of their scheduled follow-up (or alternatively, followed up via their family physician) and could be mailed their allocated study vitamins or placebo tablets (but not their study simvastatin because central blood safety monitoring could not be continued). Adherence was assessed by reviewing the calendar-packed tablets remaining, and for those who had stopped study treatment, the reasons for doing so were sought.

Blood samples were obtained at each follow-up visit for central laboratory assays of alanine aminotransferase and creatine kinase to monitor possible liver- and muscle-related adverse effects of statin therapy. To assess the effects of the vitamin allocation on blood vitamin and homocysteine levels, assays were performed in nonfasting blood collected from a sample of approximately 1000 participants due for follow-up at about the same time each year, from all participants scheduled for follow-up between February 2003 and November 2003 (at median follow-up of 2.5 years) and at all final visits in October 2007 to June 2008. Differences in blood levels between the treatment groups were based on comparisons between all participants allocated vitamins vs all allocated placebo tablets, irrespective of adherence (with any missing data imputed from the baseline values prior to starting any study vitamin treatment).

Information was recorded at each follow-up about any suspected myocardial infarction, stroke, vascular procedure, pulmonary embolus, cancer, or other serious adverse experience, and about the main reasons for all other hospital admissions (including day cases). In addition, reports were systematically sought of muscle pain or weakness and of any serious or nonserious adverse events considered to be probably due to study treatment. Further details were sought from participants' general practitioners (plus, if considered necessary for coding, from any relevant hospital records) about reports that might relate to major vascular events or deaths, and from the Medical Research Information Service for England and Wales and the General Register Office for Scotland about the sites of any registered cancers and the certified causes of any deaths.

All such information was reviewed by coordinating center clinicians who were unaware of the study treatment allocation and events coded according to prespecified criteria.17 Analyses were based on confirmed plus unrefuted reports, with definite confirmation for 93% of the nonfatal myocardial infarctions, 92% of the nonfatal strokes, and 96% of the revascularizations that were included.

At the final follow-up, cognitive function was assessed using a modified Telephone Interview for Cognitive Status (TICS-m)20 and verbal fluency test,21 and hearing thresholds were measured in both ears at 1 KHz and 4 KHz.22

Statistical Analysis

The data analysis plan was prespecified either in the original protocol or in amendments made before any analyses of the effects of the study treatment on clinical outcomes were available to the steering committee.17 Comparisons involved log-rank analyses of the first occurrence of particular events during the scheduled treatment period after randomization among all participants allocated active vitamins vs all those allocated placebo (ie, intention-to-treat analyses).23,24 The primary comparison was of the effect on the incidence of first major vascular event, defined as nonfatal myocardial infarction or death from coronary heart disease, fatal or nonfatal stroke, or any arterial revascularization.

Secondary comparisons were of the effects on major vascular events in the first year after randomization (when little difference was anticipated) and, separately, in the later years of the treatment period; major vascular events among participants subdivided into 3 similar-sized groups with respect to blood homocysteine levels at the end of the prerandomization run-in period (before any study vitamin treatment had been taken); major vascular events in the presence of one or other of the allocated study simvastatin regimens; major coronary events, defined as nonfatal myocardial infarction, death from coronary disease, or coronary revascularization; and any type of stroke (excluding transient ischemic attacks).

Tertiary comparisons included the effects on total and cause-specific mortality (considering vascular and nonvascular causes separately), vascular mortality excluding the first year after randomization, coronary and noncoronary revascularization separately, confirmed hemorrhagic and other strokes separately, pulmonary embolus, total and site-specific cancers, hospitalizations for various other causes, and possible adverse effects of treatment. Tests for heterogeneity, or, if more appropriate, trend, were to be used to help determine whether the proportional effects in specific subcategories differed clearly from the overall effects after due allowance for multiple comparisons.25,26

It had been anticipated that allocation to 2 mg folic acid and 1 mg vitamin B12 daily would produce about a 3- to 4-μmol/L difference in blood homocysteine levels.5 (To convert homocysteine to mg/dL, divide by 7.397.) A meta-analysis of observational studies conducted in the early 1990s indicated that a 3 μmol/L–lower usual homocysteine level was associated with a 20% to 25% lower risk of cardiovascular events.2 Based on previous studies among myocardial infarction survivors,27,28 it was estimated that approximately 1900 major coronary events would occur during median follow-up of approximately 4 years, which would provide 90% power at 2-sided P < .01 to detect a 15% reduction in risk.

It was prespecified in the protocol that the steering committee could modify the study plans while still blinded to the event rates in each treatment group. Following completion of recruitment, an updated meta-analysis of observational studies reported that a 3 μmol/L–lower usual homocysteine level was associated with only an 11% lower risk of CHD and a 19% lower risk of stroke.3 After median follow-up of 3 to 4 years, both the reduction in risk that might realistically be expected with the homocysteine-lowering therapy (and with the statin comparison27,28) and the overall major coronary event rate were smaller than had been anticipated. Consequently in 2004, blind to interim results for clinical outcomes, the steering committee decided to change the primary outcome from major coronary events to major vascular events and to continue until at least 2800 patients had had a confirmed major vascular event in order to have 90% power at P < .05 to detect a 10% reduction in risk.17,27,28

Postal invitations were sent to 83 237 potentially eligible survivors of myocardial infarction and 34 780 attended the initial screening clinic visit, of whom 19 190 remained potentially eligible and entered the prerandomization run-in phase of the study (Figure 1). Participants were given a run-in pack containing placebo vitamin tablets (and 20 mg simvastatin daily), and their family physicians were informed of their provisional entry into the trial.

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Figure 1. Flow Diagram for Participants in the SEARCH Trial
Graphic Jump Location

Numbers lost to follow-up relate to those without information to the end of the scheduled treatment period on mortality (as well as morbidity) and on morbidity alone. For the reasons given for stopping study tablets, nonstudy statin was started in 92% of the participants who were advised to stop for medical reasons. “Personal reasons” excludes discontinuations attributed to medical reasons. More than 1 reason could be reported.

A total of 12 064 individuals (10 012 men and 2052 women) with a history of myocardial infarction were randomized (Table), with a mean (SD) age of 64.2 (8.9) years. Previous coronary revascularization was reported by 33%, noncoronary revascularization by 2%, cerebrovascular disease (stroke or transient ischemic attack) by 7%, diabetes mellitus by 11%, and treated hypertension by 42%. At the end of the 2-month prerandomization run-in phase taking placebo-vitamin tablets, the subsequently randomized participants had mean (SD) nonfasting blood levels of homocysteine of 13.5 (4.8) μmol/L, folate of 7.4 (4.6) ng/mL, and vitamin B12 of 388 (240) pg/mL. (To convert folate to nmol/L, multiply by 2.266; and vitamin B12 to pmol/L, multiply by 0.7378.) The large size of the trial (and the use of minimized randomization) produced good balance between the treatment groups for the main prerandomization prognostic features that were measured (Table) and should have done likewise for those that were not.

Table Graphic Jump LocationTable. Baseline Characteristics of Randomized Patients
Adherence and Blood Homocysteine

Mean (SD) follow-up duration was 6.7 (1.5) person-years: totals of 40 083 person-years among those allocated vitamins and 40 204 person-years among those allocated placebo. Adherence at each follow-up was defined as at least 80% of the scheduled vitamin or placebo tablets having been taken since the previous follow-up (with only about 2%-3% of participants reporting taking some, but less than 80%, of the treatment). Adherence was similar among those allocated vitamins vs placebo, with 94% in each treatment group adherent after 12 months of follow-up, 89% vs 90% at 48 months, and 84% vs 85% at 84 months.

There were no clear differences between those allocated vitamins or placebo in the proportions reporting different reasons for stopping (Figure 1). Because only a single set of reasons was provided for stopping the study simvastatin, the vitamin tablets, or both, it was not possible to know whether the reason recorded applied to the study vitamin/placebo tablets (but few participants stopped their study vitamins alone). The main reasons given were medical advice and personal wishes, generally because of a perceived need for more intensive low-density lipoprotein–lowering therapy (which is related to the simvastatin comparison).

Compared with placebo, allocation to 2 mg folic acid plus 1 mg vitamin B12 daily reduced blood levels of homocysteine by a mean (SE) of 4.0 (0.3) μmol/L at 12 months, and by 3.3 (0.2) μmol/L at 84 months, yielding a weighted average difference during the study of 3.8 (0.1) μmol/L. Folate levels were increased by a weighted mean of 16.2 (0.5) ng/mL and vitamin B12 levels by 625 (19) pg/mL. (No significant differences in plasma lipid levels were seen between these treatment groups.)

Major Vascular Events

During the scheduled treatment period, major vascular events occurred in 1537 of the 6033 participants (25.5%) allocated folic acid plus vitamin B12 vs 1493 of the 6031 (24.8%) allocated placebo (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.97-1.12; P = .28) (Figure 2). There was no evidence of any benefit beginning to emerge with more prolonged treatment and follow-up (trend P value = .48) (Figure 3). Among participants in the low, middle, and high thirds of baseline homocysteine levels, allocation to the study vitamins produced mean (SE) reductions in homocysteine of 2.54 (0.07) μmol/L, 3.34 (0.07) μmol/L, and 5.58 (0.18) μmol/L, respectively, but no significant reduction in major vascular events even among those in the highest third (Figure 4). Nor were there any significant differences in the effects on major vascular events in any of the other subcategories of participant studied, including among participants subdivided by random allocation to 80 mg vs 20 mg simvastatin daily.

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Figure 2. Effects of Folate Allocation on Major Vascular Events: Major Coronary Events, Strokes, and Noncoronary Revascularizations
Graphic Jump Location

Analyses are of the numbers of participants having a first event of each type during follow-up (with nonfatal and fatal events considered separately), so there is some nonadditivity between different types of event. Risk ratios compare outcome among participants allocated folic acid and vitamin B12 to that among those allocated placebo. Data markers are approximately proportional to the numbers of events in each subdivision. CI indicates confidence interval; MI, myocardial infarction; CHD, coronary heart disease.

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Figure 3. Effects of Folate Allocation on Major Vascular Events by Year of Follow-up
Graphic Jump Location

Analyses are of numbers of participants having a first event during each year of follow-up and of those still at risk of a first event at the start of each year. CI indicates confidence interval.

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Figure 4. Effects of Folate Allocation on First Major Vascular Event in Different Categories of Participant
Graphic Jump Location

P values for χ21 tests are given for heterogeneity between risk ratios within dichotomous categories and for trend within other categories (except for prior disease categories since there is some overlap between them). Cholesterol categories relate to measured values at the randomization visit after all participants had been taking 20 mg simvastatin daily for 2 months during the prerandomization run-in phase. The data analysis plan prespecified that blood homocysteine, vitamin, and cholesterol values would be used to subdivide participants into 3 similar-sized groups. GFR MDRD indicates glomerular filtration rate estimated using the Modification of Diet in Renal Disease equation.29,30 CI indicates confidence interval; MI, myocardial infarction; CHD, coronary heart disease; LDL, low-density lipoprotein.

Compared with placebo, allocation to folic acid plus vitamin B12 was associated with nonsignificant adverse trends for death due to coronary heart disease (RR, 1.10; 95% CI, 0.96-1.25) and for noncoronary revascularization (RR, 1.18; 95% CI, 0.95-1.46), but there were no apparent differences for nonfatal myocardial infarction and for coronary revascularization (Figure 2). In addition, allocation to study vitamins was not associated with a significant effect on any stroke (vitamins, 269 [4.5%], vs placebo, 265 [4.4%]; RR, 1.02; 95% CI, 0.86-1.21). Nor were there significant differences in fatal or nonfatal stroke considered separately, or in the numbers of presumed ischemic strokes (vitamins, 243 [4.0%], vs placebo, 245 [4.1%]; RR, 0.99; 95% CI, 0.83-1.19).

For other vascular outcomes, there were no significant differences between the treatment groups in the numbers of patients who were hospitalized for stable or unstable angina (vitamins, 753 [12.5%], vs placebo, 708 [11.7%]), hospitalized or died due to heart failure (vitamins, 260 [4.3%], vs placebo, 248 [4.1%]), or reported to have had transient cerebral ischemic attacks (vitamins, 136 [2.3%], vs placebo, 169 [2.8%]) or any nonfatal or fatal pulmonary emboli (vitamins, 52 [0.9%], vs placebo, 60 [1.0%]).

Mortality

There were no apparent differences in the numbers of deaths attributed to vascular causes (vitamins, 578 [9.6%], vs placebo, 559 [9.3%]; RR, 1.04; 95% CI, 0.92-1.16) or nonvascular causes (vitamins, 405 [6.7%] vs placebo, 392 [6.5%]; RR, 1.04; 95% CI, 0.90-1.19) (Figure 5). Among the vascular deaths, allocation to the study vitamins was associated with slightly more deaths due to acute myocardial infarction and coronary heart disease, but those differences were not significant and were partially offset by nonsignificantly fewer deaths from other vascular causes. No significant benefit was seen after exclusion of vascular deaths that occurred in the first year after starting study treatment (vitamins, 8.8%, vs placebo, 8.5%; RR, 1.03; 95% CI, 0.91-1.16). Among the nonvascular deaths, there were no significant differences in the numbers of deaths attributed to neoplastic, respiratory, or other medical or nonmedical causes.

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Figure 5. Effects of Folate Allocation on Cause-Specific Mortality
Graphic Jump Location

CHD indicates coronary heart disease; CI, confidence interval; MI, myocardial infarction.

Cancer Incidence

New primary cancers (excluding nonmelanoma skin cancer) were diagnosed in 678 (11.2%) of the participants allocated folic acid plus vitamin B12 vs 639 (10.6%) allocated placebo (RR, 1.07; 95% CI, 0.96-1.19) (Figure 6) and caused death in 260 (4.3%) vs 252 (4.2%) of the participants (RR, 1.03; 95% CI, 0.87-1.23) (Figure 5). These differences were not significant, nor were there significant differences between the treatment groups in the incidence of cancers in any particular body system (Figure 6).

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Figure 6. Effect of Folate Allocation on Site-Specific Cancer Incidence
Graphic Jump Location

Analyses are of the numbers of participants developing cancer at each site (excluding recurrences or new cancers at the same site), so there is some nonadditivity between cancers at different sites. “Connective tissue” excludes nonmelanoma skin cancers, which are given separately. CI indicates confidence interval.

Other Outcomes

Blood pressure was measured in all participants attending their final follow-up visit, and no differences were detected between the treatment groups. Full blood counts were performed at the 1- and 4-year follow-up visits for each patient, with no significant effects of vitamin allocation seen on any of the hematological parameters measured. However, some conditions known to be associated with deficiencies of these vitamins were less likely to be reported among the participants allocated folic acid and vitamin B12: peripheral neuropathy (vitamins, 7 [0.1%], vs placebo, 17 [0.3%]) and any hematological condition (vitamins, 130 [2.2%], vs placebo, 182 [3.0%]), which includes nonspecific reports of anemia (vitamins, 80 [1.3%], vs placebo, 102 [1.7%]).

Low folate status and increased homocysteine levels have been associated with osteoporosis and fracture risk,3133 but fracture incidence was similar in the 2 groups, both overall (vitamins, 253 [4.2%], vs placebo, 242 [4.0%]) and when only fractures at the hip, wrist, or spine were considered (vitamins, 85 [1.4%], vs placebo, 69 [1.1%]). Hospitalization rates for all other outcomes did not differ significantly between the treatment groups (even before making allowance for the exploratory nature of such analyses), and there were no confirmed reports of serious adverse reactions to the vitamins.

One small randomized trial had reported that folate supplementation might improve age-related hearing loss.34 As would be expected,35 measured hearing thresholds increased with age at both the lower and higher frequencies (with a greater age-related effect at the higher frequency). But at neither frequency was there any significant effect of allocation to folic acid and vitamin B12 (eTable).

Elevated blood homocysteine levels have also been associated with dementia and cognitive impairment in some, but not all, studies.3640 A TICS-m score below 22 out of 39 was prespecified to be indicative of cognitive impairment and, as would be expected, was more common among older individuals and among those with a previous stroke. But despite this discriminatory ability, no significant differences were observed between the treatment groups in the percentages of participants classified as cognitively impaired, either overall (22% allocated vitamins vs 22% allocated placebo; P < .99) or in various subgroups. Nor was there any significant difference between the groups in mean TICS-m score (24.3 vs 24.3; difference [SE], 0.0 [0.1]) or verbal fluency scores (data not shown). Similar numbers of participants in each treatment group were reported to have developed dementia during follow-up (vitamins, 43 [0.7%], vs placebo, 38 [0.6%]).

The SEARCH trial demonstrates that, despite lowering blood homocysteine levels by 3.8 μmol/L (28%) for up to 7 years in 12 064 high-risk patients, supplementation with 2 mg folic acid and 1 mg vitamin B12 daily had no beneficial effects on major vascular events either overall or in any of the prespecified subgroups studied. Moreover, despite the suggestion that such treatment might preferentially reduce stroke,15,16 SEARCH found no significant effects on either strokes or coronary events. A meta-analysis of individual patient data from 8 homocysteine lowering trials (including SEARCH), which has been submitted for publication and includes data on 37 485 individuals, confirms that folic acid supplementation has no significant effects on major vascular events (RR, 1.01; 95% CI, 0.97-1.05) or any of its separate components.

Concerns have been expressed that folic acid may play a role in carcinogenesis, preventing initiation when administered in healthy individuals but potentially promoting tumor growth when administered to individuals with established cancers.41 It has been suggested that the introduction of folic acid fortification in the United States was linked to an increase in colorectal cancer incidence in the late 1990s.42 Previous trials of folic acid supplementation in patients with colorectal polyps have reported conflicting results, with some suggesting possible hazards for those with multiple and advanced colorectal adenomas,43 while others suggested no such effects.44,45 In addition, some trials of folic acid supplementation have reported increased risks of prostate cancer46 and, more recently, of lung cancer.47

By contrast, with more than 1300 incident cancers during up to 7 years of treatment with 2 mg folic acid and 1 mg vitamin B12 daily, SEARCH provides no evidence of adverse effects on cancer at any particular site including colorectal cancer in 86 patients (1.4%) allocated vitamins vs 91 patients (1.5%) allocated placebo (RR, 0.95; 95% CI, 0.71-1.27); prostate cancer in 159 (2.6%) vs 135 (2.2%) (RR, 1.18; 95% CI, 0.94-1.49); and lung cancer in 116 (1.9%) vs 122 (2.0%) (RR, 0.95; 95% CI, 0.74-1.23). A planned collaborative meta-analysis of all of the large folate-based trials should be able to provide even more reliable evidence about any effects on site-specific cancer. SEARCH did not find that any excess of cancer emerged with prolonged treatment, and continued surveillance of the study participants using UK cancer and mortality registries should allow even longer-term safety of folic acid supplementation to be assessed.

SEARCH was conducted in the United Kingdom during a period without mandatory folate fortification of flour (albeit with increasing voluntary fortification). The daily dose of folic acid given during SEARCH was about 20 times higher than would typically be consumed with mandatory fortification (about 100 μg/d). Hence, these findings from SEARCH are relevant to the public health debate about the safety of mandatory folate fortification for protecting against neural tube defects.41,48

Taken together with the previous homocysteine-lowering trials, the results of SEARCH indicate that folic acid supplementation has no significant adverse effects on cancer or other major health outcomes, even if it also produces no beneficial effects on cardiovascular disease. In addition, these results highlight the importance of focusing on drug treatments (eg, aspirin, statins, and antihypertensive therapy) and lifestyle changes (in particular, stopping smoking and avoiding excessive weight gain) that are of proven benefit, rather than lowering homocysteine with folic acid–based vitamin supplements, for the prevention of cardiovascular disease.

Corresponding Author: Jane M. Armitage, FRCP, SEARCH Study, Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, Richard Doll Bldg, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, United Kingdom (search@ctsu.ox.ac.uk).

Author Contributions: Dr Armitage had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Armitage, Parish, Sleight, Peto, Collins.

Acquisition of data: Armitage, Bowman, Wallendszus, Bulbulia, Rahimi, Haynes, Peto, Collins.

Analysis and interpretation of data: Armitage, Bowman, Clarke, Wallendszus, Parish, Peto, Collins.

Drafting of the manuscript: Armitage, Bowman, Peto, Collins.

Critical revision of the manuscript for important intellectual content: Clarke, Wallendszus, Bulbulia, Rahimi, Haynes, Parish, Sleight, Peto, Collins.

Statistical analysis: Wallendszus, Parish, Peto, Collins.

Obtained funding: Peto, Collins.

Administrative, technical, or material support: Armitage, Bowman, Clarke, Wallendszus, Bulbulia, Rahimi, Haynes, Peto, Collins.

Study supervision: Armitage, Parish, Peto, Collins.

Financial Disclosures: The Clinical Trial Service Unit (CTSU) reported having a staff policy of not accepting honoraria or other payments from the pharmaceutical industry, except for the reimbursement of costs to participate in scientific meetings. The CTSU members of the writing committee have, therefore, only had such costs reimbursed. Dr Sleight reported receiving speaker or data safety monitoring board fees from the following companies: Abbott, AstraZeneca, Aventis, Bayer, Boehringer-Ingelheim, Boehringer Mannheim, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Knoll, Medscape, Menarini, Merck, Monarch, MSD, Novartis, Pfizer, Pharmacia, Sanofi, and Servier. The CTSU reported receiving grants from Merck as well as from various other pharmaceutical companies to conduct independent research.

Funding/Support: The study was funded by Merck (manufacturers of simvastatin and suppliers of the vitamins). The CTSU also receives core support from the UK Medical Research Council and the British Heart Foundation.

Role of the Sponsors: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. The University of Oxford acted as the sponsor of the study. Data analysis was performed by an Oxford University senior academic biostatistical programmer (Mr Wallendszus) under the supervision of the senior statistician (Dr Parish) and principal investigators (Dr Collins, Mr Peto, and Dr Armitage).

Additional Contributions: The most important acknowledgment is to the participants in the study and to the doctors, nurses, and administrative staff in hospitals and general practices throughout the United Kingdom who assisted with its conduct. The salary costs of the nurses working on the study were funded from the study grant, but none of the doctors or participants were paid (although travel costs could be reimbursed).

A list of the SEARCH Collaborative Group members appears in the eAppendix.

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Toole JF, Malinow MR, Chambless LE,  et al.  Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.  JAMA. 2004;291(5):565-575
PubMed   |  Link to Article
Bønaa KH, Njolstad I, Ueland PM,  et al; NORVIT Trial Investigators.  Homocysteine lowering and cardiovascular events after acute myocardial infarction.  N Engl J Med. 2006;354(15):1578-1588
PubMed   |  Link to Article
Lonn E, Yusuf S, Arnold MJ,  et al; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators.  Homocysteine lowering with folic acid and B vitamins in vascular disease.  N Engl J Med. 2006;354(15):1567-1577
PubMed   |  Link to Article
Ebbing M, Bleie O, Ueland PM,  et al.  Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial.  JAMA. 2008;300(7):795-804
PubMed   |  Link to Article
Jamison RL, Hartigan P, Kaufman JS,  et al; Veterans Affairs Site Investigators.  Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial.  JAMA. 2007;298(10):1163-1170
PubMed   |  Link to Article
Albert CM, Cook NR, Gaziano JM,  et al.  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.  JAMA. 2008;299(17):2027-2036
PubMed   |  Link to Article
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials.  JAMA. 2006;296(22):2720-2726
PubMed   |  Link to Article
Bazzano LA. Folic acid supplementation and cardiovascular disease: the state of the art.  Am J Med Sci. 2009;338(1):48-49
PubMed   |  Link to Article
Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E.Heart Outcomes Prevention Evaluation 2 Investigators.  Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial.  Stroke. 2009;40(4):1365-1372
PubMed   |  Link to Article
Wang X, Qin X, Demirtas H,  et al.  Efficacy of folic acid supplementation in stroke prevention: a meta-analysis.  Lancet. 2007;369(9576):1876-1882
PubMed   |  Link to Article
Bowman L, Armitage J, Bulbulia R, Parish S, Collins R.SEARCH Study Collaborative Group.  Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors.  Am Heart J. 2007;154(5):815-823
PubMed   |  Link to Article
Lang JM, Buring JE, Rosner B, Cook N, Hennekens CH. Estimating the effect of the run-in on the power of the Physicians' Health Study.  Stat Med. 1991;10(10):1585-1593
PubMed   |  Link to Article
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.  Biometrics. 1975;31(1):103-115
PubMed   |  Link to Article
de Jager CA, Budge MM, Clarke R. Utility of TICS-M for the assessment of cognitive function in older adults.  Int J Geriatr Psychiatry. 2003;18(4):318-324
PubMed   |  Link to Article
Rosen W. Verbal fluency in aging and dementia.  J Clin Exp Neuropsychol. 1980;2(2):135-146
Link to Article
 Recommended procedures for pure-tone audiometry using a manually operated instrument.  Br J Audiol. 1981;15(3):213-216
PubMed   |  Link to Article
Peto R, Pike MC, Armitage P,  et al.  Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II, analysis and examples.  Br J Cancer. 1977;35(1):1-39
PubMed   |  Link to Article
Peto R, Pike MC, Armitage P,  et al.  Design and analysis of randomized clinical trials requiring prolonged observation of each patient: I, introduction and design.  Br J Cancer. 1976;34(6):585-612
PubMed   |  Link to Article
Peto R, Collins R, Gray R. Large-scale randomized evidence: large, simple trials and overviews of trials.  J Clin Epidemiol. 1995;48(1):23-40
PubMed   |  Link to Article
Collins R, MacMahon S. Reliable assessment of the effects of treatment on mortality and major morbidity: I, clinical trials.  Lancet. 2001;357(9253):373-380
PubMed   |  Link to Article
The Scandinavian Simvastatin Survival Study (4S).  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease.  Lancet. 1994;344(8934):1383-1389
PubMed
Sacks FM, Pfeffer MA, Moye LA,  et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators.  N Engl J Med. 1996;335(14):1001-1009
PubMed   |  Link to Article
Levey AS, Greene T, Kusek JW, Beck GJ.MDRD Study Group.  A simplified equation to predict glomerular filtration rate from serum creatinine [abstract].  J Am Soc Nephrol. 2000;11:155A
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D.Modification of Diet in Renal Disease Study Group.  A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation.  Ann Intern Med. 1999;130(6):461-470
PubMed   |  Link to Article
van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM,  et al.  Homocysteine levels and the risk of osteoporotic fracture.  N Engl J Med. 2004;350(20):2033-2041
PubMed   |  Link to Article
McLean RR, Jacques PF, Selhub J,  et al.  Homocysteine as a predictive factor for hip fracture in older persons.  N Engl J Med. 2004;350(20):2042-2049
PubMed   |  Link to Article
McLean RR, Jacques PF, Selhub J,  et al.  Plasma B vitamins, homocysteine, and their relation with bone loss and hip fracture in elderly men and women.  J Clin Endocrinol Metab. 2008;93(6):2206-2212
PubMed   |  Link to Article
Durga J, Verhoef P, Anteunis LJ, Schouten E, Kok FJ. Effects of folic acid supplementation on hearing in older adults: a randomized, controlled trial.  Ann Intern Med. 2007;146(1):1-9
PubMed   |  Link to Article
Gates GA, Mills JH. Presbycusis.  Lancet. 2005;366(9491):1111-1120
PubMed   |  Link to Article
Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.  Arch Neurol. 1998;55(11):1449-1455
PubMed   |  Link to Article
Clarke R, Sherliker P, Hin H,  et al.  Folate and vitamin B12 status in relation to cognitive impairment and anaemia in the setting of voluntary fortification in the UK.  Br J Nutr. 2008;100(5):1054-1059
PubMed   |  Link to Article
Seshadri S, Beiser A, Selhub J,  et al.  Plasma homocysteine as a risk factor for dementia and Alzheimer's disease.  N Engl J Med. 2002;346(7):476-483
PubMed   |  Link to Article
Hin H, Clarke R, Sherliker P,  et al.  Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study.  Age Ageing. 2006;35(4):416-422
PubMed   |  Link to Article
Brady CB, Gaziano JM, Cxypoliski RA,  et al.  Homocysteine lowering and cognition in CKD: the Veterans Affairs homocysteine study.  Am J Kidney Dis. 2009;54(3):440-449
PubMed   |  Link to Article
Smith AD, Kim YI, Refsum H. Is folic acid good for everyone?  Am J Clin Nutr. 2008;87(3):517-533
PubMed
Mason JB, Dickstein A, Jacques PF,  et al.  A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis.  Cancer Epidemiol Biomarkers Prev. 2007;16(7):1325-1329
PubMed   |  Link to Article
Cole BF, Baron JA, Sandler RS,  et al; Polyp Prevention Study Group.  Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.  JAMA. 2007;297(21):2351-2359
PubMed   |  Link to Article
Wu K, Platz EA, Willett WC,  et al.  A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma.  Am J Clin Nutr. 2009;90(6):1623-1631
PubMed   |  Link to Article
Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR.ukCAP Trial Group.  Aspirin and folic acid for the prevention of recurrent colorectal adenomas.  Gastroenterology. 2008;134(1):29-38
PubMed   |  Link to Article
Figueiredo JC, Grau MV, Haile RW,  et al.  Folic acid and risk of prostate cancer: results from a randomized clinical trial.  J Natl Cancer Inst. 2009;101(6):432-435
PubMed   |  Link to Article
Ebbing M, Bønaa KH, Nygard O,  et al.  Cancer incidence and mortality after treatment with folic acid and vitamin B12.  JAMA. 2009;302(19):2119-2126
PubMed   |  Link to Article
MRC Vitamin Study Research Group.  Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.  Lancet. 1991;338(8760):131-137
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Flow Diagram for Participants in the SEARCH Trial
Graphic Jump Location

Numbers lost to follow-up relate to those without information to the end of the scheduled treatment period on mortality (as well as morbidity) and on morbidity alone. For the reasons given for stopping study tablets, nonstudy statin was started in 92% of the participants who were advised to stop for medical reasons. “Personal reasons” excludes discontinuations attributed to medical reasons. More than 1 reason could be reported.

Place holder to copy figure label and caption
Figure 2. Effects of Folate Allocation on Major Vascular Events: Major Coronary Events, Strokes, and Noncoronary Revascularizations
Graphic Jump Location

Analyses are of the numbers of participants having a first event of each type during follow-up (with nonfatal and fatal events considered separately), so there is some nonadditivity between different types of event. Risk ratios compare outcome among participants allocated folic acid and vitamin B12 to that among those allocated placebo. Data markers are approximately proportional to the numbers of events in each subdivision. CI indicates confidence interval; MI, myocardial infarction; CHD, coronary heart disease.

Place holder to copy figure label and caption
Figure 3. Effects of Folate Allocation on Major Vascular Events by Year of Follow-up
Graphic Jump Location

Analyses are of numbers of participants having a first event during each year of follow-up and of those still at risk of a first event at the start of each year. CI indicates confidence interval.

Place holder to copy figure label and caption
Figure 4. Effects of Folate Allocation on First Major Vascular Event in Different Categories of Participant
Graphic Jump Location

P values for χ21 tests are given for heterogeneity between risk ratios within dichotomous categories and for trend within other categories (except for prior disease categories since there is some overlap between them). Cholesterol categories relate to measured values at the randomization visit after all participants had been taking 20 mg simvastatin daily for 2 months during the prerandomization run-in phase. The data analysis plan prespecified that blood homocysteine, vitamin, and cholesterol values would be used to subdivide participants into 3 similar-sized groups. GFR MDRD indicates glomerular filtration rate estimated using the Modification of Diet in Renal Disease equation.29,30 CI indicates confidence interval; MI, myocardial infarction; CHD, coronary heart disease; LDL, low-density lipoprotein.

Place holder to copy figure label and caption
Figure 5. Effects of Folate Allocation on Cause-Specific Mortality
Graphic Jump Location

CHD indicates coronary heart disease; CI, confidence interval; MI, myocardial infarction.

Place holder to copy figure label and caption
Figure 6. Effect of Folate Allocation on Site-Specific Cancer Incidence
Graphic Jump Location

Analyses are of the numbers of participants developing cancer at each site (excluding recurrences or new cancers at the same site), so there is some nonadditivity between cancers at different sites. “Connective tissue” excludes nonmelanoma skin cancers, which are given separately. CI indicates confidence interval.

Tables

Table Graphic Jump LocationTable. Baseline Characteristics of Randomized Patients

References

Clarke R, Daly L, Robinson K,  et al.  Hyperhomocysteinemia: an independent risk factor for vascular disease.  N Engl J Med. 1991;324(17):1149-1155
PubMed   |  Link to Article
Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes.  JAMA. 1995;274(13):1049-1057
PubMed   |  Link to Article
Homocysteine Studies Collaboration.  Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.  JAMA. 2002;288(16):2015-2022
PubMed   |  Link to Article
Homocysteine Lowering Trialists' Collaboration.  Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials.  BMJ. 1998;316(7135):894-898
PubMed   |  Link to Article
Homocysteine Lowering Trialists' Collaboration.  Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials.  Am J Clin Nutr. 2005;82(4):806-812
PubMed
Baker F, Picton D, Blackwood S,  et al.  Blinded comparison of folic acid and placebo in patients with ischaemic heart disease: an outcome trial.  Circulation. 2002;106:(suppl 2)  2-741
Link to Article
Toole JF, Malinow MR, Chambless LE,  et al.  Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.  JAMA. 2004;291(5):565-575
PubMed   |  Link to Article
Bønaa KH, Njolstad I, Ueland PM,  et al; NORVIT Trial Investigators.  Homocysteine lowering and cardiovascular events after acute myocardial infarction.  N Engl J Med. 2006;354(15):1578-1588
PubMed   |  Link to Article
Lonn E, Yusuf S, Arnold MJ,  et al; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators.  Homocysteine lowering with folic acid and B vitamins in vascular disease.  N Engl J Med. 2006;354(15):1567-1577
PubMed   |  Link to Article
Ebbing M, Bleie O, Ueland PM,  et al.  Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial.  JAMA. 2008;300(7):795-804
PubMed   |  Link to Article
Jamison RL, Hartigan P, Kaufman JS,  et al; Veterans Affairs Site Investigators.  Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial.  JAMA. 2007;298(10):1163-1170
PubMed   |  Link to Article
Albert CM, Cook NR, Gaziano JM,  et al.  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.  JAMA. 2008;299(17):2027-2036
PubMed   |  Link to Article
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials.  JAMA. 2006;296(22):2720-2726
PubMed   |  Link to Article
Bazzano LA. Folic acid supplementation and cardiovascular disease: the state of the art.  Am J Med Sci. 2009;338(1):48-49
PubMed   |  Link to Article
Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E.Heart Outcomes Prevention Evaluation 2 Investigators.  Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial.  Stroke. 2009;40(4):1365-1372
PubMed   |  Link to Article
Wang X, Qin X, Demirtas H,  et al.  Efficacy of folic acid supplementation in stroke prevention: a meta-analysis.  Lancet. 2007;369(9576):1876-1882
PubMed   |  Link to Article
Bowman L, Armitage J, Bulbulia R, Parish S, Collins R.SEARCH Study Collaborative Group.  Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors.  Am Heart J. 2007;154(5):815-823
PubMed   |  Link to Article
Lang JM, Buring JE, Rosner B, Cook N, Hennekens CH. Estimating the effect of the run-in on the power of the Physicians' Health Study.  Stat Med. 1991;10(10):1585-1593
PubMed   |  Link to Article
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.  Biometrics. 1975;31(1):103-115
PubMed   |  Link to Article
de Jager CA, Budge MM, Clarke R. Utility of TICS-M for the assessment of cognitive function in older adults.  Int J Geriatr Psychiatry. 2003;18(4):318-324
PubMed   |  Link to Article
Rosen W. Verbal fluency in aging and dementia.  J Clin Exp Neuropsychol. 1980;2(2):135-146
Link to Article
 Recommended procedures for pure-tone audiometry using a manually operated instrument.  Br J Audiol. 1981;15(3):213-216
PubMed   |  Link to Article
Peto R, Pike MC, Armitage P,  et al.  Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II, analysis and examples.  Br J Cancer. 1977;35(1):1-39
PubMed   |  Link to Article
Peto R, Pike MC, Armitage P,  et al.  Design and analysis of randomized clinical trials requiring prolonged observation of each patient: I, introduction and design.  Br J Cancer. 1976;34(6):585-612
PubMed   |  Link to Article
Peto R, Collins R, Gray R. Large-scale randomized evidence: large, simple trials and overviews of trials.  J Clin Epidemiol. 1995;48(1):23-40
PubMed   |  Link to Article
Collins R, MacMahon S. Reliable assessment of the effects of treatment on mortality and major morbidity: I, clinical trials.  Lancet. 2001;357(9253):373-380
PubMed   |  Link to Article
The Scandinavian Simvastatin Survival Study (4S).  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease.  Lancet. 1994;344(8934):1383-1389
PubMed
Sacks FM, Pfeffer MA, Moye LA,  et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators.  N Engl J Med. 1996;335(14):1001-1009
PubMed   |  Link to Article
Levey AS, Greene T, Kusek JW, Beck GJ.MDRD Study Group.  A simplified equation to predict glomerular filtration rate from serum creatinine [abstract].  J Am Soc Nephrol. 2000;11:155A
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D.Modification of Diet in Renal Disease Study Group.  A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation.  Ann Intern Med. 1999;130(6):461-470
PubMed   |  Link to Article
van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM,  et al.  Homocysteine levels and the risk of osteoporotic fracture.  N Engl J Med. 2004;350(20):2033-2041
PubMed   |  Link to Article
McLean RR, Jacques PF, Selhub J,  et al.  Homocysteine as a predictive factor for hip fracture in older persons.  N Engl J Med. 2004;350(20):2042-2049
PubMed   |  Link to Article
McLean RR, Jacques PF, Selhub J,  et al.  Plasma B vitamins, homocysteine, and their relation with bone loss and hip fracture in elderly men and women.  J Clin Endocrinol Metab. 2008;93(6):2206-2212
PubMed   |  Link to Article
Durga J, Verhoef P, Anteunis LJ, Schouten E, Kok FJ. Effects of folic acid supplementation on hearing in older adults: a randomized, controlled trial.  Ann Intern Med. 2007;146(1):1-9
PubMed   |  Link to Article
Gates GA, Mills JH. Presbycusis.  Lancet. 2005;366(9491):1111-1120
PubMed   |  Link to Article
Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.  Arch Neurol. 1998;55(11):1449-1455
PubMed   |  Link to Article
Clarke R, Sherliker P, Hin H,  et al.  Folate and vitamin B12 status in relation to cognitive impairment and anaemia in the setting of voluntary fortification in the UK.  Br J Nutr. 2008;100(5):1054-1059
PubMed   |  Link to Article
Seshadri S, Beiser A, Selhub J,  et al.  Plasma homocysteine as a risk factor for dementia and Alzheimer's disease.  N Engl J Med. 2002;346(7):476-483
PubMed   |  Link to Article
Hin H, Clarke R, Sherliker P,  et al.  Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study.  Age Ageing. 2006;35(4):416-422
PubMed   |  Link to Article
Brady CB, Gaziano JM, Cxypoliski RA,  et al.  Homocysteine lowering and cognition in CKD: the Veterans Affairs homocysteine study.  Am J Kidney Dis. 2009;54(3):440-449
PubMed   |  Link to Article
Smith AD, Kim YI, Refsum H. Is folic acid good for everyone?  Am J Clin Nutr. 2008;87(3):517-533
PubMed
Mason JB, Dickstein A, Jacques PF,  et al.  A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis.  Cancer Epidemiol Biomarkers Prev. 2007;16(7):1325-1329
PubMed   |  Link to Article
Cole BF, Baron JA, Sandler RS,  et al; Polyp Prevention Study Group.  Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.  JAMA. 2007;297(21):2351-2359
PubMed   |  Link to Article
Wu K, Platz EA, Willett WC,  et al.  A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma.  Am J Clin Nutr. 2009;90(6):1623-1631
PubMed   |  Link to Article
Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR.ukCAP Trial Group.  Aspirin and folic acid for the prevention of recurrent colorectal adenomas.  Gastroenterology. 2008;134(1):29-38
PubMed   |  Link to Article
Figueiredo JC, Grau MV, Haile RW,  et al.  Folic acid and risk of prostate cancer: results from a randomized clinical trial.  J Natl Cancer Inst. 2009;101(6):432-435
PubMed   |  Link to Article
Ebbing M, Bønaa KH, Nygard O,  et al.  Cancer incidence and mortality after treatment with folic acid and vitamin B12.  JAMA. 2009;302(19):2119-2126
PubMed   |  Link to Article
MRC Vitamin Study Research Group.  Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.  Lancet. 1991;338(8760):131-137
PubMed   |  Link to Article
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