EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of the study was to test whether beta carotene supplementation affects age-related maculopathy (ARM) using data from a large scale randomized controlled trial.

Inclusion Criteria:

Inclusion in the Physicians' Health Study I (PHS I)
- Physician
- Male
- Healthy, based on information collected at baseline including height, weight, history of cigarette smoking, alcohol use, blood pressure, cholesterol, history of diabetes mellitus, physical activity and multivitamin use.

Exclusion Criteria:

Not enrolled in the Physicians' Health Study I
Inability to be followed for the first seven years of the study and complete the 84-month questionnaire (i.e., death).

Description of Study Protocol:

Recruitment

Subjects in the PHS I were evaluated

Design

Randomized placebo-controlled trial

The PHS I included a randomized, double-masked, placebo-controlled trial of beta-carotene (50mg supplement every other day) for 12 years
Health information was collected at baseline
Information on diagnosis of ARM made during the first seven years was asked on the 84-month questionnaire
Each following annual questionnaire asked for information on ARM diagnosis for the prior year
If ARM diagnosis, medical records were obtained and ophthalmologists and optometrists were asked to provide further medical information on:
- Date of initial ARM diagnosis
- Best-corrected visual acuity at the time of diagnosis
- Date when best-corrected visual acuity reached 20/30 or worse
- Dates of signs of ARM (even without diagnosis)
- Date when exudative neovascular disease was first noted
- Other ocular abnormalities that could be contributing
Research endpoints:
- Primary:
  - Visually significant ARM defined as a self-report confirmed by medical record evidence of an initial diagnosis before year end 1995, with best-corrected vision loss to 20/30 or worse attributable to ARM
- Secondary:
  - ARM without vision loss
  - Advanced ARM, visually significant with pathological findings

Participants completed annual follow-up questionnaires with information about compliance and occurrence of relevant events
- 78% of the study group was compliment with beta carotene supplements
- 6% of the placebo group reported taking supplemental beta carotene or vitamin A.

Blinding used

Double-masked

Intervention

Beta-carotene (50mg supplement every other day) for duration of the study period

Statistical Analysis

Cox proportional-hazards model to estimate relative risk of ARM among those assigned to beta carotene compared to placebo after age adjustment
Tests of trend of the affect on age on any association between beta carotene and ARM by including a term in the proportional hazards model
For each relative risk, 95 percent confidence intervals and two-sided P value were calculated
Subgroup data was analyzed according to baseline categories to evaluate the statistical significance of any effect.

Data Collection Summary:

Timing of Measurements

Baseline measurements at start of PHS I
Questionnaire at seven years from start of the PHS I
Yearly questionnaires thereafter until close of the PHS I study.

Dependent Variables

Primary endpoint: Visually-significant ARM
- Self-reported and confirmed with medical record prior to end of year 1995
- Best corrected vision loss to 20/30 or worse attributable to ARM
Secondary endpoint: ARM without vision loss
- All incident cases
Secondary endpoint: Advanced ARM
- Visually significant ARM with pathological findings of geographic atrophy, RPE detachment, subretinal neovascular membrane or disciform scar.

Independent Variables

Supplementation with beta carotene
- 325mg every other day.

Control Variables

Description of Actual Data Sample:

Initial N: 22,071 males
Attrition (final N): 21,142 males
- Beta carotene group: 10,585
- Placebo group: 10,557
- Eliminates subjects who died prior to seven years from baseline of study and therefore did not respond to the 84 month questionnaire
Age: 40 to 84 years of age in 1982 at baseline assessment into PHS I

Age Groups Beta Carotene Placebo

Mean Age 52.8 52.8

40-49 42.3% 42.2%

50-59 34.2% 34.2%

60-69 17.9% 17.9%

70-84 5.5% 5.7%
Ethnicity: Not noted
Other relevant demographics:
Anthropometrics: As expected in a large study, baseline medical history and health habits did not differ significantly between the study and placebo groups. Subjects reported:
- Medical history
  - Hypertension
  - High cholesterol level
  - Diabetes mellitus
  - Body mass index
  - Parental history of myocardial infarction
- Health habits
  - Cigarette smoking
  - Alcohol use
  - Physical activity
  - Multivitamin use.
Location: Sample taken from subjects throughout the United States.

Summary of Results:

Statistically, there was no significant benefit or harm of beta carotene supplementation on any ARM endpoint

There were also no significant effects of beta carotene on any of the ARM endpoints after excluding cases diagnosed during the first two years or five years

Endpoint	Beta Carotene	Placebo	RR	CI (95%)
Visually significant ARM	162	170	0.96	0.78-1.20
ARM with or without vision loss	275	274	1.01	0.86-1.20
Advanced ARM	63	66	0.97	0.69-1.37

When looking at beta carotene and placebo as modified by other risk factors measured at baseline, there no significant interactions. These included:
- Medical history
  - Hypertension
  - High cholesterol level
  - Diabetes mellitus
  - Body mass index
  - Parental history of myocardial infarction
Health habits
- Cigarette smoking
- Alcohol use
- Physical activity
- Multivitamin use.

Other Findings

Of the baseline characteristics noted, they were equally distributed between groups.

Author Conclusion:

Data from a large study of healthy males ages 40-84 suggests that beta carotene supplementation with 12 years of treatment has no statistically significant beneficial or harmful effect on the incidence of ARM.

Funding Source:

Government:

National Institue of Health grants

Reviewer Comments:

The PHS I also included as part of its study protocol low-dose aspirin (325mg every other day) from 1982 to 1988
There is no discussion to ensure a representative sample of the US male population ages 40 to 84, although it might be assumed with the nature of the large, randomized study
Attrition from initial n was not detailed other than "death" of subjects not allowing them to fill out the seven-year questionnaire.

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?	???
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?		???
	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%.)	No
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	???
	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?	Yes
	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?	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

Age Groups	Beta Carotene	Placebo
Mean Age	52.8	52.8
40-49	42.3%	42.2%
50-59	34.2%	34.2%
60-69	17.9%	17.9%
70-84	5.5%	5.7%