EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To examine the effects of the combined use of antioxidant vitamin supplements and non-steroidal anti-inflammatory drugs (NSAIDs) on cognitive decline.

Inclusion Criteria:

Those over 65 residing in Cache County, Utah
Those with complete data on medication use
Those who completed three Modified Mini-Mental State Exams
Those without dementia at baseline.

Exclusion Criteria:

Those with dementia at baseline
Those without three Modified Mini-Mental State exams
Those with incomplete data on medication use.

Description of Study Protocol:

Recruitment

All residents of Cache County, Utah were invited to participate. No further information was provided on techniques for recruiting participants.

Design

Prospective cohort study

Participants completed an exam of cognitive function at baseline and at two other points during the study. At each exam the Modified Mini-Mental State exam (3MS) was administered and participants were evaluated for dementia with a multistage assessment.

Buccal DNA samples were obtained at baseline and APOE genotypes were determined by restriction enzyme analysis. Participants were asked to identify all supplements, prescription drugs, and OTC medicines they used and were classified as users of vitamin E supplements, vitamin C supplements, or NSAIDs if they reported taking one or more of these agents four times or more a week for a month or longer or if they used a multivitamin that contained at least 400IU of vitamin D or 500 milligrams of vitamin C.

Users were stratified into five groups:

Non-users of vitamin E, vitamin C, and NSAIDs (non-users)
Users of NSAIDs but not vitamin E or C (NSAIDs alone)
Users of vitamin E and C but not NSAIDs (vit E and C alone)
Users of vitamin E or C (but not both) with or without NSAIDs (vit E or C±NSAIDs)
Users of vitamin E and C and NSAIDs (combined users: Vit E and vit C+NSAIDs).

Changes on 3 MS exams over time were compared between the five groups.

Blinding used

Not used

Intervention

Not applicable

Statistical Analysis

Random effects models were used to estimated changes in 3MS scores over time while controlling for potential confounders such as age, sex, years of education, and history of diabetes or stroke
To assess whether these relationships differed by APOE genotype, the sample was stratified by the presence or absence of one of more ε4 alleles
Mean baseline three MS scores and mean change scores for each user group were compared against the reference group of non-users with T-tests in the full sample and in the subgroups formed by the presence or absence of the APOE ε4 allele.

Data Collection Summary:

Timing of Measurements

Data was collected in three waves. Baseline (Wave 1) was collected in 1995-1996. Wave II took place in 1998-1999 and Wave III in 2003-2004.

Dependent Variables

Cognitive function as measured by the Modified Mini-Mental State Exam

Independent Variables

Intake of vitamin C, vitamin E, and NSAIDs as measured by self-reported intake

Control Variables

Age
Sex
Years of education
History of diabetes or stroke.

Description of Actual Data Sample:

Initial N: 3,376 participants met inclusion criteria
Attrition (final N): Of the 3,376 participants included in the analysis:
- 3,375 provided 3 MS scores at baseline
- 2,140 provided 3 MS scores at all three waves
- 1,236 provided MS scores at two of the three waves
Age: The mean age of all five groups was similar.
- Non-users were 74.3 (SD 6.6)
- NSAIDs users alone were 73.9 (SC 6.3)
- Vit E and C alone were 73.6 (SD 5.5)
- Vit E or C±NSAIDs were 73.4 (SD 6.1)
- Vit E and C+NSAIDs users were 72.9 (SD 6.1)
Ethnicity: Not specified
Other relevant demographics: Participants had similar education levels (mean of 13.2-13.8 years)
Anthropometrics: No data obtained.
Location: Cache County, Utah.

Summary of Results:

Key Findings

Over the eight years of follow-up, combined users (vit E and vit C+NSAIDs) showed less decline on the 3MS scores at baseline and change scores between baseline and Wave III for the five specific user groups
Among the ε4-carriers, combined users maintained their level of performance while non-users declined by -3.77 points. Other groups declined at rates similar to non-users regardless of APOE ε4 status.
Users of vitamin E and C alone performed an average 1.09 points better on the 3MS at baseline, while users of NSAIDs alone performed an average 0.49 points better, compared to non-users of NSAIDs
Over time, only the combined users appeared to perform better than the users
When analysis was stratified by APOE status, the favorable performance over time among combined users was only evident in ε4-carriers. Among APOE ε4 non-carriers, users of vitamin E and C alone performed better than non-users of these compounds.

Mean Baseline 3MS and change scores over three waves of observation the full sample and stratified by APOE ε4 status.*

Group

Baseline 3MS
Mean (95%CI)

Change in 3MS¹
Mean (95%CI)

Full Sample

Non-users

NSAIDs alone

Vit E and C alone

Vit E and C +NSAIDs

Vit E or C±NSAIDs

2,006

794

153

337

90.93 (90.68-91.17)

91.68 (91.33-92.03)

92.16 (91.41-92.90)

91.80(91.22-92.37)

90.93(89.80-92.06)

-2.95(-3.40 to -2.49)

-3.13(-3.83 to -2.43)

-3.52(-5.00 to -2.04)

-3.54(-4.58 to -2.50)

-1.37 (-2.66 to -0.08)

0 APOE ε 4 alleles

Non-users

NSAIDs alone

Vit E and C alone

Vit E and C +NSAIDs

Vit E or C±NSAIDs

1,389

554

228

91.05(90.76-91.34)

91.63(91.20-92.07)

92.90(92.02-93.79)

91.72(90.99-92.45)

90.48(88.98-91.98)

-2.58(-3.14 to -2.03)

-3.07(-3.92 to -2.23)

-2.76 (-4.13 to -1.39)

-3.19 (-4.41 to -1.98)

-2.67(-4.56 to -0.78)

1+ APOE ε 4 alleles

Non-users

NSAIDs alone

Vit E and C alone

Vit E and C +NSAIDs

Vit E or C ±NSAIDs

601

236

107

90.63(90.16-91.10)

91.82(91.20-92.43)

91.00(89.70-92.30)

92.02(91.11-92.93)

91.79(90.08-93.50)

-3.77(-4.53 to -3.01)

-3.00(-4.17 to -1.83)

-4.85(-8.21 to -1.49)

-4.12 (-6.12 to -2.12)

0.65(-0.58 to 1.89)²

*Of the 3,376 participants, 3,375 provided 3 MS scores at baseline, 2,140 provided 3MS scores at all three waves and 1,236 provided 3MS scores at two of the three waves.

¹Mean change was calculated by taking the mean of changes in 3MS scores from Wave III minus Wave 1 for those participants who had scores at both waves.

²Mean baseline 3MS scores and mean change scores for each user group were compared against the reference group of non-users with T-tests in the full sample and in the sub-groups formed by the presence or absence of the APOE ε4 allele. Comparison of Vit E and C+NSAIDs group with non-users was significant at P<0.01.

Author Conclusion:

The authors found an association between using a combination of antioxidant vitamins E and C supplements plus NSAIDs and less cognitive decline among elderly APOE ε4 carriers.

Funding Source:

Government:	National Institutes of Health, National Institute of Mental Health, National Institute on Aging
University/Hospital:	Duke University, Johns Hopkins University, Utah State University, University of Washington

Reviewer Comments:

Little detail on recruitment of participants was provided, making this reviewer concerned that the sample is biased
It is unclear to this reviewer if any (or how many) of the participants had a history of or active diabetes or heart disease, which could affect circulatory status and possibly cognitive status
Information on supplement usage was self-reported, making it subject to reporting error
There was limited discussion on the study limitations and study biases
It was reported that not all participants completed all three waves of 3 MS exams and that "loss of follow up" may have biased the results. The numbers that were reported did not appear to reflect those losses. This reviewer is unclear on whether the authors accounted for those losses in their reporting.

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)	N/A
	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
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	N/A

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		No
	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?	???
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	No
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
3.	Were study groups comparable?		???
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	N/A
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	???
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	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?	???
	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.)	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
	4.1.	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
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	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?		No
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	No
	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.)	No
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	No
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	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
	6.1.	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
	6.3.	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
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	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?		???
	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
	7.3.	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?	???
	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
	7.7.	Were the measurements conducted consistently across groups?	N/A
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
	8.2.	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
	8.4.	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)?	N/A
	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
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes