FNOA: Antioxidants (2011-2012)

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

To examine the effect of a short course of high-dose retinol (preformed vitamin A) on dark adaptation in older adults with normal retinal health or early age related maculopathy (ARM).

Inclusion Criteria:
  • At least 50 years of age
  • Best corrected distance visual acuity as listed in the medical record of 20/80 or better in at least one eye
  • Eye to be tested psychophysically had to have funduscopic grading steps 1 and 9 as determined by the Age-Related Eye Disease Study (AREDS) Grading System.
Exclusion Criteria:

Participants were excluded if:

  • The AREDS grading system indicated that they had advanced disease, either central geographic atrophy or exudative disease in the eye to be tested psychophysically
  • The medical record or a general health interview indicated that they had any of the following: Glaucoma, optic neuropathy or any ocular conditions other than ARM, refractive error with an absolute value of more than 6 D, neurologic diseases such as Alzheimer's disease, Parkinson's disease, history of stroke, diabetes, serious frailty or medical conditions expected to lead to death or disability with 12 months
  • They had a vitamin A deficiency defined as ≤30μg/dL in serum determined by a high-pressure liquid chromatography (HPLC) procedure
  • They had hypercalcemia or abnormal liver function which can be exacerbated by high dose vitamin A
  • They could not perform the psychophysical task used to measure dark adaptation.
Description of Study Protocol:

Recruitment

Participants were recruited from the comprehensive ophthalmology and retina services of the Department of Ophthalmology, University of Alabama at Birmingham based on clinical patients seen over a 14-month period.

Design

Double-masked, placebo-controlled randomized trial.

Blinding used

  • Participants were not informed of their group assignment
  • All study personnel including all investigators and staff involved in testing and interacting with participants were masked with respected to participant group assignment. 

Intervention

Participants were randomly assigned to a 30 day course of a daily tablet containing 50,000 IU vitamin A or a perceptually identical placebo.

Statistical Analysis

  • The t and x2 tests were used to compare the study groups at baseline with respect to continuous and categorical variables including demographics, visual function and health characteristics
  • Baseline dark adaptation parameters and night vision low luminance questionnaire (LLQ) scores were also compared by using t-tests
  • Paired t-tests were used to compare serum vitamin A levels within each study group at each of the study visits
  • For the 30-day measurements of these outcome variables, a linear regression model was used
  • Correlation coefficients (Pearson r) were calculated for the association between changes in variables between baseline and day 30
  • P≤0.05 (two-tailed) was considered statistically significant.
Data Collection Summary:

Timing of Measurements

Baseline and after 30 days

Dependent Variables

Individual dark-adaptation parameter or LLQ score as measured at the follow-up visit

Independent Variables

Random assignment to a 30-day course of a daily tablet containing 50,000IU vitamin A or a perceptually identical placebo.

Control Variables

  • Baseline demographics
  • Visual function
  • Medical characteristics.
Description of Actual Data Sample:
  • Initial N141
  • Attrition (final N): 104
    • Vitamin A group (n=52)
    • Placebo group (n=52)
  • Age: 
    • Mean Vitamin A group: 71.8
    • Mean Placebo Group 71.7
  • Ethnicity:
    • Vitamin A group:  94.2% White, 5.8% Black
    • Placebo group 98.1% White, 1.9% Black
  • Other relevant demographics: General Health, mean: Co-morbid medical conditions: 
    • Vitamin A Group: 4.2
    • Placebo Group:  3.5

Smoking Percentage:

  Vitamin A Group Placebo Group
Never 44.2% 48.1%
Previous 46.2% 42.3%
Current 7.7% 9.6%
Unknown 1.9% 0.0%
  • Anthropometrics: 
  Vitamin A Group Tested Eye Vitamin A Group Follow Eye Placebo Group Tested Eye Placebo Group Fellow Eye
Visual acuity, mean log MAR  0.14 0.38   0.15 0.38 
Contrast sensitivity, mean  1.37 1.24  1.41  1.25 

 AREDS fundus grade percentage:

  Vitamin A Group Placebo Group
1 (normal retinal aging) 42.3% 36.5%
2-6 (early ARM) 48.1% 38.5%
7-9 (intermediate ARM) 9.6% 25%
  • LocationBirmingham, Alabama.
Summary of Results:

Other Results

  • The vitamin A group had significantly larger rod slopes, indicating a faster sensitivity recovery, than did the placebo group (P<0.0419) 
  • After adjusting for baseline demographics, visual function and medical characteristics, the vitamin A group had larger rod slopes than the placebo group (0.16 vs. 0.14, P=0.08) 
  • The magnitude of the association remained unchanged suggesting a lack of confounding by the characteristics baseline demographics, visual function and medical characteristics
  • An interaction term for ARM status was introduced into the model. The interaction term was not statistically significant in any of the models (all P>0.5) suggesting that any observed differences between treatment groups were similar in those with and without ARM. Visual acuity and contrast sensitivity in the tested eye were not different in the two groups at 30 days (P=0.949 and P=0.621).
  • With the LLQ, the vitamin A group had a higher score by five points on the mobility subscale compared with the placebo group (P<0.0141) 
  • This five-point difference between the vitamin A and placebo group (88.4 vs. 83.6) and the statistical significance (P=0.0224) remained after adjustment for the characteristics baseline demographics, visual function and medical characteristics  
  • Change from baseline to day 30 in the mobility subscale score on the LLQ was significantly associated with changes in the rod slope (Pearson r=0.24, P=0.014) 
  • Adjustments for the characteristics baseline demographics, visual function and medical characteristics had little influence on this association (Pearson r=0.22, P=0.0333)
  • Serum vitamin A significantly increased over the 30-day period in the vitamin A group from a mean at baseline of 62.47± 20.10 to 68.47±19.18µg/dL (SD) at 30 days (P=0.0106)  
  • There was no change in the placebo group 
  • In the vitamin A group, the change in serum vitamin A over the 30-day period was not associated with the change in rod slope (P=0.3764) 
  • There was a borderline association between change in serum vitamin A and change in the scores on the mobility subscale of the LLQ (P=0.0873).

 

 

Author Conclusion:
  • A short-term, high-dose course of retinol increased the rate of rod-mediated dark adaptation in older adults who were in the early phases of ARM or were exhibiting normal retinal aging
  • These results are consistent with the hypothesis that depositions and other structural changes in the retinal pigment epithelium and Bruch's membrane in aging and early ARM cause a localized retinoid deficiency
  • Previous research indicates that a scarcity of retinol causes rod photoreceptor dysfunction and death and thus the present data highlight the possibility that retinoid deficiency may contribute to the pathogenesis of early ARM which is a possibility worthy of further study.
Funding Source:
Government: National Institute on Aging Grant and National Eye Institute Grant
Not-for-profit
Research to Prevent Blindness and the EyeSight Foundation of Alabama
Other non-profit:
Reviewer Comments:

The authors note the following limitations:

  • Younger adults were not enrolled, however, many studies have demonstrated that dark adaptation cannot be improved by retinol supplementation in healthy young and middle-aged adults when serum vitamin A levels are within the normal ranges
  • The sample size precluded subgroup analyses on different AREDS grades, however, future research can explore this question.
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? 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
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
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
  3.2. 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? 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
  5.3. 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? No
  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? 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
  7.3. 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
  7.5. 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? 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)? 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