DLM: Homocysteine, Folate, B6 or B12 (2007-2011)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To see if high doses of folic acid, pyridoxine (vitamin B6), and cobalamin (vitamin B12) given to decrease total Hcyt levels will reduce the risk of recurrent stroke over a 2 year period compared to low doses of these vitamins.
Inclusion Criteria:

--nondisabling ischemic stroke (onset £ 120 days before randomization)

--total Hcyt level ³ 25th percentile for North American stroke population (³ 10.5 mmol/L in Nov 1997, ³ 9.5 mmol/L after 4/8/98, ³ 9.5 mmol/L for men and ³ 8.5 mmol/L for women after 5/5/99)

--age ³ 35 years

Exclusion Criteria:

--potential sources of emboli (a fib within 30 days of stroke, prosthetic cardiac valve, intracardiac thrombosis or neoplasm, or valvular vegetation)

--other major neurologic illness that would obscure evaluation of recurrent stroke

--life expectancy < 2 years

--renal insuff requiring dialysis

--untreated anemia or B12 deficiency

--systolic bp > 185mm Hg or diastolic bp > 105mm Hg

--refractory depression, sever cognitive impairment, or alcoholism or other substance abuse

--use of meds in last 30days that would affect total Hcyt level or bile acid sequestrants that can decrease folate levels

--childbearing potential

--participation in another active intervention trial

--general anesthesia or hospital stay of ³ 3 days, any type of invasive cardiac instrumentation, or endarterectomy, stent placement, thrombectomy, or any other endovascular treatment of carotid artery within 30 days prior to randomization or scheduled to be performed within 30 days of randomization

Description of Study Protocol:

--multi-center double-blind RCT

--performed at 56 centers across the US (n=45), Canada (n=10), and Scotland (n=1)

--all subjects were given low dose vitamin supp for 1 month to determine compliance, assessed by pill counts; those with > 75% compliance were able to continue eligibility for randomization

--randomized to high or low dose vitamin groups within strata defined by clinic, sex, and age (³70 years or < 70 years)

--used permuted block randomization (with block size randomly selected as 4 or 6)

--high dose vitamin includes: 25mg pyridoxine, 0.4 mg cobalamin, 2.5mg folic acid

--low dose vitamin includes: 200mg pyridoxine, 6mg cobalamin, 20m folic acid

--participants were contacted every 3months alternating between phone and in-clinic visits for up to 2 years

Data Collection Summary:

--at baseline: medical history, current medication and vitamin use, physical and neurological exam, dietary inventory, stroke symptoms questionnaire, stroke severity determination, the Mini Mental State Exam, Rose angina questionnaire

--lab values: plasma folate, B12, and creatinine levels

--end points for stroke: death, clinical exam including CT or MRI, and stroke symptoms questionnaire, likely hospital discharges with diagnosis of stroke, cerebral infarction, CVA, or other synonyms

--end points for coronary heart disease: MI requiring hospitalization, coronary revascularization, cardiac resuscitation, fatal coronary disease, hospital discharge diagnosis (MI, unstable angina, coronary athlerosclerosis)

--visits every 6 months for pill counts (94% in each group took ³ 75% pills)

Description of Actual Data Sample:

--3680 randomized:

--1853 randomized to low-dose vitamin group

--1837 randomized to high-dose vitamin group

--at the end of the study, n=2954 (n=1472 in high dose vitamin group, n=1482 in low dose vitamin group)

Summary of Results:

At Baseline:

--low vitamin more likely to smoke than high vitamin (15.5% vs 18.3% respectively; p=0.02)

--low vitamin higher history of diabetes than high vitamin (30.8% vs 27.4% respectively; p=0.02)

--low vitamin higher history of chest pain than high vitamin (34.9% vs 38.1% respectively; p=0.04)

At 1 year follow-up:

--estrogen/progestin use significantly higher in high vitamin group (26.3%) vs low vitamin group (20.3%); p=0.01

--mean HDL-C significantly higher in high vitamin group (49.2 mg/dL ± 16.7) vs low vitamin group (47.8 mg/dL ± 15.0); p=0.02

--both groups at baseline had similar plasma Hcyt (13.4 mmol/L); after taking vitamins, both groups decreased total Hcyt, however high dose vitamin group had a larger decrease (2.4 mmol/L in high group vs 0.3 mmol/L in low group); in one year, high vitamin group decreased to 2.2 mmol/L and decreased by 2.3 mmol/L in 2 years (plateau effect)

--even though vitamin treatment decreased Hcyt, there was no significant effect on vascular outcomes 2 years after follow-up

--unadjusted RR for stroke, CHD event, or death was 1.0 (95% CI: 0.8-1.1) for chance of an event within 2 years 18% in high dose group vs 18.6% in low dose group

--risk of ischemic stroke within 2 years: 9.2% for high dose group vs 8.8% for low dose group (RR=1.0, (95% CI: 0.8-1.3); p=0.8)

 

Author Conclusion:

--found no treatment effect between baseline total Hcyt and CVD in follow-up

--high dose vitamin group had no effect on the outcome measurements of stroke, CHD events, or death

--question if saw no effect because participants Hcyt levels were too low (increased risk associated with hyperhomocysteinemia involves Hcyt levels in the hundreds of mmol/L)

--question if modest decrease in Hcyt is from folate fortification in US grains

--need to wait longer than 2 years follow-up to see an effect?
Funding Source:
University/Hospital: Wake Forest University School of Medicine
Reviewer Comments:
--great discussion section
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
  1. Was the research question clearly stated? Yes
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
  1.3. Were the target population and setting specified? Yes
  2. Was the selection of study subjects/patients free from bias? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  3. Were study groups comparable? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) Yes
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
  4. Was method of handling withdrawals described? Yes
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
  5. Was blinding used to prevent introduction of bias? Yes
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? Yes
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? Yes
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
  6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
  7. Were outcomes clearly defined and the measurements valid and reliable? Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
  8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? Yes
  9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  10. Is bias due to study's funding or sponsorship unlikely? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes
  10.2. Was the study free from apparent conflict of interest? Yes