FNOA: Antioxidants (2011-2012)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To evaluate short-term and long-term beta carotene supplementation and cognitive performance among healthy, older men.

Inclusion Criteria:
  • Male
  • Physician
  • Participant in Physician's Health Study (PHS) or recruited into Physicians Health Study II (PHS II)
  • Aged 55 years or older at baseline (PHS) or 65 years or older at baseline (PHS II).
Exclusion Criteria:
  • Those PHS participants who were no longer active in the study.
  • History of cancer, active liver disease, current renal disease, peptic ulcer or gout.
Description of Study Protocol:

Recruitment

No information was provided on recruitment into PHS. Those who originally participated in the Physicians Health Study were invited to enroll in PHS II. In addition, physicians 55 years of  age and older were recruited to PHS II but recruitment methods were not provided. 

Design

Randomized controlled trial

Participants were randomized into two groups: Beta carotene supplement users (50mg on alternate days) and placebo users. Every 12 months men were sent questionnaires on compliance and health factors. In the original PHS compliance was measured during unannounced visits to obtain plasma samples from participants. In PHS II compliance was measured via mailed questionnaire. If participants continued from PHS to PHS II, treatment assignment (beta carotene or placebo) was retained.

Cognitive tests were administered using a validated telephone interview. Tests included: 1) Telephone interview of cognitive status using a telephone version of the Mini-Mental State Examination 2) immediate and 3) delayed recall measures of the East Boston Memory Test (EBMT) to assess verbal memory, 4) delayed recall of a 10-word list to test verbal memory and 5) category fluency, naming animals in one minute. The primary prespecified outcome was a global score combining results of all cognitive tests. A key added secondary outcome was a verbal memory score calculated by averaging the z scores from the immediate and delayed recall assessments of the EBMT and 10-word list.

Participants in the original PHS has longer assignment to treatment or placebo (mean time was 18 years, range 15-20 years) vs. new recruits (mean one year, range two months to three years).

Blinding used 

Participants were blinded as to beta carotene assignment.

Intervention

50mg beta carotene every other day or a placebo.

Statistical Analysis

A prespecified analysis plan included separate analysis within each group (new recruits vs. original PHS recruits). All analyses were based on the intention-to-treat principle. Unpaired T tests were used to assess mean differences in cognitive performance, measured at a single point near the trial's close.

 

Data Collection Summary:

Timing of Measurements

Patients were enrolled in the original PHS beginning in 1982. The beta carotene arm of this study continued until 1995. Invitations to enroll in PHS II were sent and patients began enrolling in August 1997. (There was an 18-month interval between studies when patients may have stopped taking beta carotene). For the original group, cognitive testing began in 1998 and second cognitive assessments were begun in 2002.

New recruits into PHS II were enrolled in the study between 1998 and 2001.

Dependent Variables

Cognition as measured by 1)Telephone interview of cognitive status using a telephone version of the Mini-Mental State Examination, 2) immediate and 3) delayed recall measures of the East Boston Memory Test (EBMT) to assess verbal memory, 4) delayed recall of a 10-word list to test verbal memory and 5) category fluency, naming animals in one minute.

Independent Variables

Beta carotene intake as measured by plasma samples (those who participated in the original PHS) and mailed questionnaire (new enrollees and PHS II).

 

 

Description of Actual Data Sample:
  • Initial N: 4,052 participants from the original PHS and 1,904 new recruits for a total of 5,956 participants
  • Attrition (final N): No attrition; all participants in this study were accounted for
  • Age:
    • New recruits: Mean age was 72.9 for the beta carotene group and 72.8 for the placebo group
    • Participants in the original PHS: Mean age at baseline was 55.9 for beta carotene group and 56 for the placebo group
    • Age at entry into the PHS II was 70.9 (beta carotene group) and 71 (placebo group)
  • Ethnicity: No information provided
  • Other relevant demographics: All participants were physicians, having a similar amount of education
  • Anthropometrics: The percentage of smokers in the original PHS (9% beta-carotene, 9.4% placebo) was much higher than new enrollees (2.5 for beta carotene group and 2.8 for placebo) and those from PHS who were carried into PHS II (1.3 for beta carotene group and 3.5% for placebo). BMI was similar for all groups. Alcohol intake and prevalence of diabetes was much different between those who originally enrolled in PHS, those who entered into PHS II, and new enrollees, but were similar between placebo and beta-carotene groups within each category.
  • Location: United States.
Summary of Results:

Key Findings

  • Slightly better cognition was noted for those assigned to the beta carotene than to placebo groups
  • In analysis that specifically examined the newly-recruited PHS II participants, there was no evidence of cognitive benefits with short-term beta carotene supplements
  • In participants continuing from the PHS with long-term treatment, those assigned to the beta carotene group performed significantly better than the placebo group
  • Performance on the majority of cognitive measures was better with long-term beta carotene supplementation than with placebo
  • The effect of long-term supplementation with beta carotene was comparable to delaying cognitive aging by one to 1.5 years. 

Mean Cognitive Performance with Short-term Treatment Assignment: The PHS II

Cognitive Group

Placebo Group
n=968

Beta Carotene Group
n=936
P value

Global scoreb

   Mean z score(SD)c

   Mean difference

   (95% CI)

 
0.007(0.67)

0(reference)

 
-0.0007(0.67)

-0.014(-0.07-0.05)

 0.65
Verbal memoryb

   Mean z score(SD)c

   Mean difference

   (95% CI)

 
0.008(0.72)

0 (reference)

 
-0.008(0.72)

-0.015(-0.08 to 0.05)

 0.64
TICSb

   Mean points(SD)c

   Mean difference

   (95% CI)

 
34.29

0(reference)

 
34.15 (2.57)

-0.13 (-0.37 to 0.10)

 0.26
Category fluencyb

   Mean Points(SD)c

   Mean difference

   (95% CI)

 
20.09(6.15)

0 (reference)

 
20.02 (6.14)

-.06(-0.62 to 0.49)

 0.82

bThe global score is the primary outcome and combines results of all cognitive tests. Verbal memory is the key secondary outcome and combines results of immediate and delayed recalls of 10-word list and East Boston Memory Test; additional secondary outcomes are the TICS and category fluency.

cFor the global score and the verbal memory score, the outcome is obtained by deriving z scores for each relevant cognitive test and averaging z scores across component tests; the unit for these measures is a standard unit. For TICS and category fluency, the outcome is the number of points scored on that test. On the TICS, scores can range from zero to 41 points, and on category fluency, scores can range form zero to infinity, with one point assigned for each distinct animal named during one minute.

Mean Cognitive Performance with Long-term Treatment Assignment: The PHS II

Cognitive Group Placebo Group
n=2,021
Beta Carotene Group
n=2,031
P value

Global scoreb

 Mean z score(SD)c

 Mean difference(SD)c

 (95% CI)

0.024(0.71)

0(reference)

0.023 (0.69)

0.047(0.00 to 0.09)

0.03

Verbal memoryb

 Mean z score(SD)c

 Mean difference

 (95% CI)

-0.032(0.74)

0 (reference)

0.031(0.73)

0.063(0.02 to 0.11) 

0.007

TICSb

 Mean points(SC)c

 Mean difference

 (95% CI)

34.23(2.80)

0 (reference)

34.41 (2.73)

0.18 (0.01 to 0.35)

0.04

Category fluencyb

 Mean Points (SD)c

 Mean difference

 (95% CI)

20.04(6.04)

0 (reference)

20.03(5.94)

-0.012(-0.38 to 0.35)

0.95

TICS=telephone interview of cognitive status

bThe global score is the primary outcome and combines results of all cognitive tests. Verbal memory is the key secondary outcome and combines results of immediate and delayed recalls of 10-word list and East Boston Memory Test; additional secondary outcomes are the TICS and category fluency.

cFor the global score and the verbal memory score, the outcome is obtained by deriving z scores for each relevant cognitive test and averaging z scores across component tests; the unit for these measures is a standard unit. For TICS and category fluency, the outcome is the number of points scored on that test. On the TICS, scores can range from zero to 41 points, and on category fluency, scores can range form zero to infinity, with one point assigned for each distinct animal named during one minute.

 

Author Conclusion:

The authors did not find an impact of short-term beta carotene supplementation on cognitive performance, but long-term supplementation may provide cognitive benefits. In this generally-healthy population the extent of protection offered by long-term treatment appeared modest.

Funding Source:
Government: National Institutes of Health
Industry:
BASF Corporation, Wyeth, DMS
Pharmaceutical/Dietary Supplement Company:
University/Hospital: Harvard Medical School
In-Kind support reported by Industry: Yes
Reviewer Comments:
  • The investigators did not appear to consider beta carotene intake from diet or multivitamin supplements
  • It was specified that subjects were blinded, but not if investigators/interviewers were blinded
  • Adherence to the intervention (and/or placebo) was self-reported by phone interview and thus subject to reporting error
  • Declines in cognition can be attributed to many unknown factors, making it difficult to draw conclusions about supplement use and changes in cognition over an extended period of time.
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
  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) Yes
 
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? ???
  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? No
  2.2. Were criteria applied equally to all study groups? 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? ???
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) No
  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
  3.4. 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.) 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? Yes
  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? ???
  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.) No
  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? 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? No
  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
  6.8. 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? N/A
  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? No
  7.5. Was the measurement of effect at an appropriate level of precision? ???
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  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
  8.1. 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)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  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