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A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E and Beta Carotene for Age-Related Cataract and Vision Loss
AREDS Report No. 9
Age-Related Eye Disease Study Research Group
Arch Ophthalmol. 2001;119:1439-1452.
ABSTRACT
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Background Experimental and observational data suggest that micronutrients with
antioxidant capabilities may retard the development of age-related cataract.
Objective To evaluate the effect of a high-dose antioxidant formulation on the
development and progression of age-related lens opacities and visual acuity
loss.
Design The 11-center Age-Related Eye Disease Study (AREDS) was a double-masked
clinical trial. Participants were randomly assigned to receive daily oral
tablets containing either antioxidants (vitamin C, 500 mg; vitamin E, 400
IU; and beta carotene, 15 mg) or no antioxidants. Participants with more than
a few small drusen were also randomly assigned to receive tablets with or
without zinc (80 mg of zinc as zinc oxide) and copper (2 mg of copper as cupric
oxide) as part of the age-related macular degeneration trial. Baseline and
annual (starting at year 2) lens photographs were graded at a reading center
for the severity of lens opacities using the AREDS cataract grading scale.
Main Outcome Measures Primary outcomes were (1) an increase from baseline in nuclear, cortical,
or posterior subcapsular opacity grades or cataract surgery, and (2) at least
moderate visual acuity loss from baseline ( 15 letters). Primary analyses
used repeated-measures logistic regression with a statistical significance
level of P = .01. Serum level measurements, medical
histories, and mortality rates were used for safety monitoring.
Results Of 4757 participants enrolled, 4629 who were aged from 55 to 80 years
had at least 1 natural lens present and were followed up for an average of
6.3 years. No statistically significant effect of the antioxidant formulation
was seen on the development or progression of age-related lens opacities (odds
ratio = 0.97, P = .55). There was also no statistically
significant effect of treatment in reducing the risk of progression for any
of the 3 lens opacity types or for cataract surgery. For the 1117 participants
with no age-related macular degeneration at baseline, no statistically significant
difference was noted between treatment groups for at least moderate visual
acuity loss. No statistically significant serious adverse effect was associated
with treatment.
Conclusion Use of a high-dose formulation of vitamin C, vitamin E, and beta carotene
in a relatively well-nourished older adult cohort had no apparent effect on
the 7-year risk of development or progression of age-related lens opacities
or visual acuity loss.
INTRODUCTION
THE FACT that oxidative damage of lens proteins is a prominent feature
of cataract development1-2 has
led to speculation that micronutrients with antioxidant capabilities, such
as vitamin C (ascorbic acid), vitamin E, and the carotenoids, may retard cataract
development.3 However, retrospective, cross-sectional,
and prospective epidemiological studies of cataract and intake or blood levels
of antioxidant nutrients have not produced consistent results.4-27
Most studies with published findings have noted protective associations for
various nutrients, but there is no consensus about the specific nutrient(s)
that may be involved or the specific type of cataract(s) that might be affected.
A major concern in interpreting the results of observational epidemiological
studies of micronutrient intake and cataract risk is the possibility of unadjusted
confounding. A high degree of correlation between intake levels of various
nutrients makes it difficult to identify which of many candidate nutrients
might "explain" any observed associations. Confounding could also result if
persons with better nutritional status are different from others in unrecognized
ways that affect the risk of cataract.
Problems caused by confounding and bias are of less concern in randomized
clinical trials, but only limited and inconsistent data are available from
such trials about the effect of nutritional supplements on cataract development.
In 2 cancer prevention trials of nutritional supplements, end-of-study eye
examinations were conducted to assess the effect of the supplements on cataract
prevalence.28-29 One noted no
effect of either vitamin E or beta carotene on cataract prevalence after a
median supplementation time of 6.6 years28;
the other, conducted in a nutritionally deprived population, noted a beneficial
effect for nuclear cataract of multivitamin and mineral supplements and of
niacin and riboflavin after 5 to 6 years of supplementation.29
A large randomized trial of US male physicians noted no effect on cataract
incidence or cataract extraction after 13 years of beta carotene use.30 A smaller population-based randomized trial found
no effect of vitamin E on the 4-year progression of nuclear or cortical lens
opacities or cataract extraction.31 Given the
inherent limitations of observational studies and the scarcity of available
clinical trial data, clinical trials of sufficient size and duration are needed
before recommendations can be made about the effect of nutritional supplements
on the risk of cataract. Recommendations from clinical trials about the use
of high-dose supplements would be especially useful because such supplements
are readily available, increasingly used for many conditions including cataract,
and mostly untested for safety and efficacy.32
The Age-Related Eye Disease Study (AREDS) is an ongoing multicenter
study of the natural history of age-related cataract and macular degeneration
(AMD).33 The study includes a completed randomized
clinical trial to evaluate the effect of the antioxidants vitamin C, vitamin
E, and beta carotene in combination on the development or progression of age-related
lens opacities, and the effect of both the antioxidants and high doses of
zinc on the progression to advanced AMD. The vitamins were tested because
of preliminary data suggesting that micronutrients with antioxidant characteristics
might protect against both cataract and AMD. Zinc was included because of
its hypothesized effect on the progression of AMD, but its inclusion in the
trial also permits an evaluation of its effect on cataract development. This
article reports whether high-dose supplementation with vitamins having antioxidant
characteristics (vitamin C, vitamin E, and beta carotene) affected the development
or progression of age-related lens opacities in AREDS participants.
PARTICIPANTS AND METHODS
STUDY POPULATION
Details of the study design and methods presented elsewhere33 are briefly summarized herein. Eleven retinal specialty
clinics enrolled 4757 participants aged 55 to 80 years from November 13, 1992,
through January 15, 1998, and followed them up in the clinical trial until
April 16, 2001. Potential participants were identified from the following
sources: medical records of patients being seen at AREDS clinics, referring
physicians, patient lists from hospitals and health maintenance organizations,
public advertisements, friends and family of study participants and clinical
center staff, and screenings at malls, health fairs, senior citizens centers,
and other gathering places.
The ocular eligibility criteria were largely determined by requirements
for the study of AMD. Except for the requirement that the media be sufficiently
clear in a study eye to obtain quality stereoscopic fundus photographs of
the macula, lens opacity status itself was not considered in selecting participants.
All participants had a best-corrected visual acuity of 20/32 or better (visual
acuity score of 74 letters on the ETDRS logMAR chart) in at least 1 eye.
Persons were enrolled in 1 of 4 AMD categories determined by the size and
extent of drusen and retinal pigment abnormalities in each eye, the presence
of manifestations of advanced AMD (determined from photograph grades at a
reading center), and visual acuity as described previously.33
Macular status ranged from essentially no macular abnormality in either eye
(AMD Category 1), to mild or borderline AMD features (AMD Category 2: many
small or few intermediate drusen, or pigment abnormalities), to at least 1
large druse, extensive intermediate drusen, or noncentral geographic atrophy
(AMD Category 3), to advanced AMD or lesions of AMD with visual acuity less
than 20/32 in only 1 eye (AMD Category 4). Persons aged 55 to 59 years were
enrolled only if eligible for AMD Categories 3 and 4.
At least 1 eye of each participant was free from eye disease that could
complicate assessment of AMD, lens opacity progression, or visual acuity (eg,
optic atrophy or acute uveitis), and that eye could not have had previous
ocular surgery (other than cataract surgery). Persons who underwent cataract
surgery were eligible for the study to facilitate recruitment in the AMD component
of the trial and because their inclusion had little effect on the power of
the cataract component of the study to detect differences between the treatment
groups. Potential participants were excluded for illness or disorders (eg,
history of cancer with a poor 7-year prognosis, major cardiovascular or cerebrovascular
event within the last year, or hemachromatosis) that would make long-term
follow-up or compliance with the study protocol unlikely or difficult. Persons
bilaterally aphakic or pseudophakic were ineligible for AMD Category 1.
Of the 4757 study participants, all but 3 met the study eligibility
and exclusion criteria. The 3 exceptions, all in AMD Category 1, were found
after randomization to be technically ineligible because 2 were 58 years old
at randomization and 1 exceeded by 2 weeks the 4-month allowable time between
qualification and randomization visits. All 3 participants remained in the
trial and in their assigned treatment group.
Prior to study initiation, the protocol was approved by an independent
data and safety monitoring committee and by the institutional review board
for each clinical center. Written informed consent was obtained from all participants
before enrollment.
STUDY DESIGN
Interventions
The clinical trial component of AREDS consists of 2 trials—AMD
and cataract—generally sharing 1 pool of participants (Figure 1). The 4 treatment interventions were double masked and
given as an oral total daily supplementation of antioxidants (500 mg of vitamin
C, 400 IU of vitamin E, and 15 mg of beta carotene) or zinc (80 mg of zinc
as zinc oxide, 2 mg of copper as cupric oxide to prevent potential anemia),
or the combination of antioxidants and zinc, or placebo.
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Figure 1. Age-Related Eye Disease Study
(AREDS) randomization schema. AMD indicates age-related macular degeneration;
asterisks, includes participants in AMD Category 1 (580 placebo-treated subjects
and 537 antioxidant-treated subjects).
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As in all vitamin products, some ingredients degrade somewhat during
the life of the product (ie, prior to an expiration date). The manufacturer
formulated each product with slightly different amounts of ingredients than
listed above in an effort to achieve appropriate potency at an expiration
date. Tablets used in the active treatment arms of these trials were manufactured
to have the following minimum contents throughout the shelf life of the product:
7160 IU of vitamin A (beta carotene), 113 mg of vitamin C (ascorbic acid),
100 IU of vitamin E (dl-alpha tocopheryl acetate),
17.4 mg of zinc (zinc oxide), and 0.4 mg of copper (cupric oxide).
Two study medication tablets were to be taken each morning and 2 each
evening, to meet the total daily dose requirement. Tablets were to be taken
with food to avoid potential irritation of an empty stomach by zinc.
Randomization
Simple randomization, stratified by clinical center and AMD category,
was used to assign treatment (Figure 1).
Participants in AMD Categories 2 through 4 were assigned with a probability
of one quarter to placebo, antioxidants, zinc, or antioxidants and zinc. Participants
in AMD Category 1 were assigned with a probability of one half to placebo
or antioxidants. Persons with little or no AMD abnormality (AMD Category 1)
were not randomized to zinc treatment (only to antioxidants or placebo) because
of no likely effect on lens opacities, no likely benefit to their low risk
of developing AMD, and potential toxic effects. Multiple unique bottle codes
were randomly assigned to each of the 4 treatments for AMD Categories 2 through
4, and also to each of the 2 treatments for participants in AMD Category 1.
A bottle code corresponding to the assigned treatment was randomly selected
for each participant.
Masking
Study medication tablets for the 4 treatment groups were identical in
external appearance and similar in internal appearance and taste. The coordinating
center was custodian of the treatment code. Information documenting unmasking
was collected during the study.
PROCEDURES
General physical and ophthalmic examinations at baseline and at annual
intervals included standardized measurement of the participant's height, weight,
blood pressure, manifest refraction, best-corrected visual acuity, and intraocular
pressure. Slitlamp biomicroscopy and ophthalmoscopy were performed at each
examination. Lens photographs were taken at baseline and annually starting
with the second annual visit by a specially modified slitlamp (model SL-6E;
Topcon Corp, Tokyo, Japan) and retroillumination cameras (Neitz Instruments
Co Ltd, Tokyo). The presence and severity of nuclear, cortical, and posterior
subcapsular lens opacities were graded at a reading center using standardized
grading procedures.34 Demographic information,
history of smoking and sunlight exposure, medical history, history of specific
prescription drug and nonprescription medication use, and history of vitamin
and mineral use were obtained at baseline.
Following determination of participant eligibility by the coordinating
center and the reading center and by the successful participation in a 1-month
placebo run-in to demonstrate compliance with the treatment regimen (at least
75% of the run-in medication taken, according to pill count), participants
were randomly assigned to 1 of the treatment groups and then evaluated every
6 months. Participants supplementing with any of the study medication ingredients
prior to randomization must have agreed to permanently stop using supplements
during the run-in period and were offered Centrum (Whitehall-Robins Healthcare,
Madison, NJ), a multivitamin and mineral supplement with recommended daily
allowance (RDA)–level dosages, as a replacement for the duration of
the study. Fifty-five percent of the study participants were supplementing
their diets with some antioxidant vitamins or zinc prior to joining the study.
Almost all of this group chose to take Centrum. In addition, although not
encouraged, an additional 13% who were not using supplements prior to the
study chose to take Centrum, which the study provided.
At each visit, participants returned their used study medication bottles
and any unused tablets and received new tablets. They received an ophthalmic
examination every 6 months. In addition to the lens photography that was taken
at baseline and at annual visits starting with the second, photographs were
also taken when a decrease in visual acuity score of 10 or more letters was
first observed at a nonannual visit or at the first annual visit. If any submitted
photographs were inadequate to assess lens status, requests were made for
those photographs to be retaken. Best-corrected visual acuity was measured
according to the ETDRS protocol (AREDS Manual of Operations; The EMMES Corp, Rockville, Md) at every annual visit and whenever
a decrease from baseline of 10 or more letters was observed at a nonannual
visit using the participant's previous refraction. Special questionnaires
were administered to all or a subset of participants at various times throughout
the follow-up period: National Eye Institute Visual Function Questionnaire35; a modified Block Food Frequency Questionnaire, a
24-hour dietary recall questionnaire, and cognitive function tasks (AREDS Manual of Operations); and an ocular sunlight-exposure
questionnaire derived from the Melbourne study.36
Four clinical centers (The Johns Hopkins Medical Institutions [Baltimore,
Md], Devers Eye Institute [Portland, Ore], National Eye Institute Clinical
Center [Bethesda, Md], and the Associated Retinal Consultants, PC [Royal Oak,
Mich]) collected blood samples at baseline, which were analyzed at the central
laboratory (Centers for Disease Control and Prevention, Atlanta, Ga) for the
levels of total cholesterol; high-density lipoprotein cholesterol; triglycerides;
vitamins A, C, and E;  -carotene; zinc; copper;  -carotene; lutein
and zeaxanthin; -cryptoxanthin; and lycopene. The first 3 centers also
collected blood samples annually during follow-up visits for estimation of
adherence to the study medication regimen and to assess the effect of the
study medications on serum levels of the parameters measured at baseline.
Hematocrit was measured at all centers on all participants at baseline and
annually thereafter to monitor for the development of anemia. Safety outcomes
included serum levels, adverse events, hospitalizations, and mortality. Participants
were also asked at each annual visit if they had experienced any of 19 conditions
since the last follow-up visit. These included anemia, gastrointestinal conditions,
kidney stones, fatigue, skin conditions, cardiovascular conditions, and thyroid
abnormalities. Although individuals could have multiple occurrences of a condition
or safety outcome, analyses compared the frequency of those who ever had the
event with those who never had the event. Safety outcomes were monitored annually
by the data and safety monitoring committee. A network of collaborating physicians
from non-AREDS clinics was formed to assist in obtaining visual acuity measurements
and fundus photographs and to perform ophthalmic examinations for participants
who could not return to an AREDS clinic.
SAMPLE SIZE AND POWER
A total sample size of 4600 was planned. For the cataract trial with
an estimated 4500 participants enrolled, power was calculated assuming 7 years
of follow-up, during which time 20% were projected to drop out (discontinue
study medication) and assume the placebo event rate, 30% would drop in (begin
a nonstudy supplement containing study medication ingredients) and assume
the full treatment (antioxidants) event rate, and 15% would be lost to follow-up
before experiencing an event. For 2-sided = .05, a projected sample
size of 4500 would provide at least 90% power to detect treatment effects
of 15%, 25%, and 30% and for placebo event rates of 50%, 30%, and 20%, respectively.33
OUTCOMES
Slitlamp photographs were used to grade nuclear opacities on a decimal
scale by comparing photographs of participants with standard stereophotographs
of lenses with increasingly severe nuclear opacities; retroillumination photographs
were used to estimate the area of involvement for cortical and posterior subcapsular
(PSC) opacities.34
Cataract
The protocol defines the lens event outcome in a participant as the
occurrence in at least 1 eye (having a natural lens) of cataract surgery or
of any of the following changes from baseline in photographic grade: nuclear
opacity (a 1.5-U increase on a scale from 0.9-6.1 U); cortical opacity (10%
absolute increase in the area of opacity within a standard central 5-mm circle);
and PSC (5% absolute increase in the area of opacity within a standard central
5-mm circle). Examples of these changes are shown in Figure 2.
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Figure 2. Examples of lens opacity progression
in Age-Related Eye Disease Study (AREDS) participants. Nuclear opacity graded
from slitlamp photographs (model SL-6E; Topcon Corp, Tokyo, Japan) increased
from 2.0 U (equal to AREDS standard photograph 3) at baseline (A) to 3.9 U
(approaching standard photograph 5) at the 5-year visit (B). Cortical opacity
within 5 mm of the lens center (ie, within the second innermost circle of
the grid) graded from retroillumination photographs (Neitz Instruments Co,
Ltd, Tokyo) increased from 6% at baseline (C) to 45% at the 6-year visit (D).
Posterior subcapsular opacity within 5 mm of the lens center increased from
6% at baseline (E) to 22% at the 5-year visit (F).
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Visual Acuity Loss
The primary visual acuity outcome was a decrease of best-corrected visual
acuity score from baseline of 15 or more letters in a study eye (equivalent
to a doubling or more of the initial visual angle, eg, 20/20 to  20/40
or 20/50 to 20/100). Visual acuity was measured every 6 months.
Secondary Outcomes
Secondary outcomes defined during the design phase of the study included
worsening of each opacity type and cataract surgery. In addition, at the time
of analysis, a severe lens event was defined as follows: an increase in nuclear
opacity of at least 2.5 U, an absolute increase in the area of cortical or
PSC opacity of at least 20%, or cataract surgery.
STATISTICAL ANALYSES
All comparisons were made on an intention-to-treat basis. Photographic
lens events were determined from photographs taken at annual visits, beginning
at year 2. Events of cataract surgery from clinical reports at nonannual visits
were attributed to the next annual visit. The primary comparison for lens
event and visual acuity event was the overall (main) effect of antioxidants
(1 + 3) vs no antioxidants (2 + 4) among all participants (Table 1). Analyses of possible zinc effect involving the factorial
design (1 + 2 vs 3 + 4) were of persons in AMD Categories 2 through 4. Because
persons are the units of analysis, no adjustment for correlation between paired
eyes is needed.
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Table 1. Treatment Design
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Primary analysis of treatment effect was by repeated-measures logistic
regression, hereinafter referred to as "repeated measures," using the SAS
procedure GENMOD (SAS Institute, Cary, NC), a generalized estimating equations
method that allows for determining events at each visit. In repeated-measures
logistic regression we model the effect of explanatory variables on the occurrence
of an event, considering the correlation of observations at follow-up visits
within a patient and the time at which visits occurred. Cox proportional hazards
survival analyses for the lens outcomes and repeated-measures analysis of
variance of mean change in visual acuity and lens opacity scores were used
for comparison with the logistic regression findings. Cox proportional hazards
survival analysis, an extension of life-table analysis, is a regression model
of the effect of explanatory variables on time to first occurrence of an event.
This method is given secondary importance in the primary analyses because
it is more appropriate for irreversible and error-free events such as cataract
surgery and death, where subsequent observations are not relevant. Analyses
were unadjusted and also adjusted for the following baseline covariates: age
(55-64, 65-69, and 70-80 years), sex, race, smoking status, and AMD category.
STATISTICAL MONITORING
A data and safety monitoring committee monitored 5 end points from the
2 trials (AMD and cataract) simultaneously for both safety and efficacy.33 Sequential monitoring of end points assumed no interaction
between antioxidants and zinc, so that only main effects were analyzed. An -spending
function group–sequential method37 was
extended to address multiple time-to-event outcome variables by a Bonferroni
adjustment distributing the type I error among the multiple end points. Log
rank tests were used to compare the response distributions of the 2 treatment
groups with an O'Brien-Fleming boundary.38
A separate monitoring of mortality used a Pocock-type boundary.39
Comparisons were made, with spending of , when requested by the data
and safety monitoring committee. At the end of the trial, treatment effects
significant at P = .01 can be considered statistically
significant at = .05 after adjustment for multiple outcomes and interim
analyses.
CHANGE IN TREATMENT
In 1994 and 1996, AREDS participants were informed of the results of
the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study40
and the Beta-Carotene and Retinol Efficacy Trial41
suggesting potential harmful effects of beta carotene among smokers. Participants
who were current cigarette smokers at baseline were contacted in 1996 and
offered the option of continuing or discontinuing their masked AREDS study
medication. Participants in AMD Categories 2 through 4 who were current or
former smokers at baseline were additionally given the opportunity to be reassigned
to a masked study medication that excluded any antioxidant component. As a
result, 117 (2.5% of all participants and 24% of the current smokers) of the
participants stopped taking medications (38 participants or 2.6% in the placebo
arm), and 84 participants (1.8%) were reassigned from a study medication containing
beta carotene to one without beta carotene. The original treatment group assignments
were retained for intention-to-treat analyses.
RESULTS
ENROLLMENT AND PARTICIPANT CHARACTERISTICS
Thirty-three of the 4629 participants enrolled in the clinical trial
of cataract had no annual photographic or visual acuity follow-up after randomization
in an AREDS clinic. There is a good balance of characteristics between treatment
groups (Table 2). Fifty-six percent
of the participants were female, 96% were white, and the median age was 68
years. At baseline 8% were current cigarette smokers and 66% chose to take
Centrum. After accounting for age, sex, and race, participants in AREDS had
higher or similar dietary intake of vitamins A, C, and E and zinc than the
general population sample from the Third National Health and Nutrition Examination
Survey (data not shown).42 Baseline dietary
intake of the study nutrients was balanced by treatment.
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Table 2. Baseline Characteristics by Treatment Group*
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DATA QUALITY
About 2.3% of participants were lost to follow-up (missed at least their
last 2 consecutive visits). The rate of participant withdrawal from study
medication was 14% by 60 months and 15% by the end of the trial. These rates
include participants lost to follow-up and current smokers, 24% of whom withdrew
from study medication after the results from the clinical trials of beta carotene
and lung cancer were announced.40-41 Figure 3 shows the number of participants
with follow-up and adherence to the study medication regimen by year of follow-up.
Overall, adherence was estimated to be 75% or greater (ie, participants took 75%
of their study tablets) for 70% of the participants at 5 years. At 60 months,
20% of the participants (20% both for current smokers and former or nonsmokers)
reported taking some multivitamin supplement containing at least 1 of the
study medication ingredients in addition to their assigned study medication
and Centrum. Less than 0.1% of the participants were reported to have been
unmasked during the trial. About 1 (15%) of 7 participants did not have a
set of photographs taken in the last year of the trial, and only 1 of every
11 opportunities for annual photographs (starting at the second annual visit)
did not yield any photographs. Of more than 62 000 possible follow-up
visits, 9% were missed. Mean follow-up time (6.3 years) did not differ by
treatment. Most participants (90%) had at least 5 years of follow-up.
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Figure 3. Participant follow-up and adherence,
by year in study. A, Number of participants with follow-up visits and percentage
of total enrolled (n = 4629). B, Percentage of participants taking at least
75% of their study tablets.
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The network of collaborating physicians provided data for 50 annual
visits and 11 nonannual visits made by 34 participants. The results reported
do not include these data, although inclusion of this information had no discernible
effect on results.
PHOTOGRAPHIC QUALITY
Slitlamp and retroillumination photographs of the lens taken during
the clinical trial were judged by the reading center to be of gradable quality
98% and 99.3% of the time, respectively, during the entire study period.
PRIMARY OUTCOMES
Progression of Lens Opacity or Cataract Surgery
Figure 4 shows repeated-measures
estimates of the probability of any lens event over time by treatment. The
estimated probability of an event at 5 years is 30% for participants regardless
of treatment. Of the 2286 participants with follow-up assigned to an antioxidant
treatment, 756 (33%) had a primary lens event within 5 years. First events
included 127 nuclear opacity only events, 17 cortical opacity only events,
12 PSC opacity only events, 113 cataract surgical procedures, and 487 events
of mixed type. Of the 2310 participants with follow-up assigned to a nonantioxidant
treatment, 785 (34%) had a lens event by 5 years. First events included 124
nuclear opacity only events, 17 cortical opacity only events, 12 PSC opacity
only events, 147 cataract surgical procedures, and 485 events of mixed type.
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Figure 4. Repeated-measures logistic regression
estimates of the probability of any lens event in at least 1 study eye by
antioxidant-treated group (all participants). Study eye is an eye without
cataract surgery at baseline. Persons with bilateral aphakia are excluded
from this analysis. Events before year 2 reflect only cataract surgery.
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Treatment effects, estimated by repeated-measures logistic regression,
on an increase in lens opacity grade (nuclear, cortical, or PSC opacities)
or cataract surgery are listed in Table
3. Participants taking antioxidant treatments did not differ in
the risk of developing a lens event from participants not taking antioxidant
treatments (odds ratio [OR] = 0.97, P = .55). An
analysis adjusted for age, sex, race, smoking status, and AMD category did
not materially alter the size or direction of these estimates. The results
from the Cox proportional hazards survival model are consistent with the repeated-measures
analysis (data not shown).
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Table 3. Effect of Treatment on Risk of Any Lens Event*
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Analyses of a possible zinc effect were done on persons enrolled in
the AMD trial. In unadjusted and adjusted repeated-measures analyses, participants
taking zinc did not differ in risk of developing a lens event from participants
not taking zinc (data not shown).
Visual Acuity
Figure 5 shows repeated-measures
estimates of the probability of visual acuity loss of 15 letters or more in
at least1 eye over time, by treatment, for the 1117 participants without AMD
(AMD Category 1) at enrollment. Restriction to these participants should avoid
any confounding effect of AMD on visual acuity. Treatment effects are tested
using repeated-measures logistic regression (Table 4). No difference was noted between the groups for loss of
15 or more letters in visual acuity score compared with baseline measurement
(OR = 1.03, P = .89). Results from an analysis of
mean change in visual acuity (data not shown) are consistent with results
from the repeated-measures analysis.
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Figure 5. Repeated-measures logistic regression
estimates of the probability of a loss in visual acuity score of at least
15 letters in at least 1 study eye by antioxidant-treated group (AMD Category
1 participants only).
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Table 4. Effect of Treatment on Risk of Loss of Visual Acuity Score
of 15 Letters or More From Baseline (Participants Without Age-Related Macular
Degeneration Only)*
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SECONDARY OUTCOMES
Nuclear Opacity
Analyses of each type of a lens event—nuclear opacity, cortical
opacity, PSC opacity, and cataract surgery—were performed. Because cataract
surgery ends type-specific follow-up of progression of opacity (informative
censoring), lens events for each opacity type included cataract surgery. The
results are summarized in Table 5.
Participants assigned to antioxidants treatment were as likely to experience
a nuclear opacity event as participants assigned to no antioxidant treatments
(OR = 0.98, P = .71). Participants taking the antioxidants-only
treatment were also as likely to experience a nuclear opacity event as those
taking placebo (OR = 1.00, P = .97). An analysis
of mean change in nuclear opacity score, unadjusted for informative censoring,
finds results consistent with the repeated-measures analysis. The same analysis
was performed for cortical and PSC opacity scores and also found no treatment
differences.
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Table 5. Effect of Treatment on Risk of a Lens Event by Type of Event*
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Cortical and PSC Opacities
Participants taking antioxidants were as likely to experience a cortical
event as were those assigned to no antioxidant treatments (OR = 0.99, P = .84). Restricting the analysis to antioxidants only
vs placebo, the risk of cortical opacity decreased for antioxidants relative
to placebo, but not significantly (OR = 0.91, P =
.29).
Participants taking antioxidants showed no significant change in the
risk of a PSC event (OR = 0.94, P = .39). Restricting
the analysis to antioxidants only vs placebo yielded similar results.
Cataract Surgery
No significant difference was noted between persons taking and not taking
antioxidants in the incidence of cataract surgery by Cox proportional hazards
survival analysis (relative risk = 0.94, P = .41).
More Severe Lens Opacity Progression or Cataract Surgery
An analysis of a more severe lens event (2.5-U increase for nuclear, 20%
increase for cortical or PSC opacities, or cataract surgery) is presented
in Table 6. Participants assigned
to antioxidant treatments did not differ significantly in the risk of experiencing
a more severe lens event from participants not assigned to antioxidant treatments
(OR = 0.92, P = .27).
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Table 6. Effect of Treatment on Risk of Any Severe Lens Event*
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Lens Events in Eyes Without Opacities
In the subset of 823 participants with no or minimal opacity in at least
1 eye at baseline (nuclear, <1.5 U; cortical, 5%; and PSC, 5%),
there was no significant effect of treatment on risk of developing lens events
in these eyes (OR = 0.85, 99% confidence interval, 0.55-1.33). Results were
similar in the smaller subset of 338 participants with no or minimal opacity
in both eyes at baseline, OR = 0.66 (99% confidence interval, 0.33-1.33).
(Data not shown.)
ADHERENCE
Serum Levels
Serum levels of micronutrients were measured at 3 AREDS clinics to monitor
adherence to the treatment regimens. Table
7 provides median baseline values and median percentage of change
from baseline at year 1 and year 5 for up to 906 participants (86% of those
alive at 5 years) for each of the study ingredients and also for vitamin A, -carotene, -cryptoxanthin,
lutein and zeaxanthin, and lycopene. Serum levels of each are presented separately
for the antioxidant-treated and no antioxidant-treated groups.
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Table 7. Serum Values at Baseline and Median Percent Change at Follow-up
Years 1 and 5
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Changes in Serum Levels of Antioxidants
Participants assigned to medications containing antioxidants had large
and statistically significant increases in median serum levels from baseline
to year 1: 25% for vitamin C, 83% for vitamin E–cholesterol ratio, and
496% for beta carotene. These increases lessened slightly over the 5-year
period. Participants assigned to study medications not containing antioxidants
(placebo and zinc treatment arms) experienced modest median level changes
over the 5-year period: a decrease of 10% for vitamin C, an increase of 5%
for vitamin E–cholesterol ratio, and no change for beta carotene.
Changes in Other Serum Levels
Only one of the other serum levels had a statistically significant change
during follow-up by treatment arm. Participants assigned to medications containing
antioxidants showed a statistically significant increased median percent change
in serum levels from baseline at year 1 of 40% for -carotene, compared
with no change for participants taking nonantioxidant medications. This increase
was not seen at year 5, but the difference between treatment groups remained.
Serum levels of lutein and zeaxanthin decreased over the 5-year period, with
decreases of 17% in the nonantioxidant arms and 26% in the antioxidant arms;
however, these changes were not significantly different by treatment (P>.20). The effect of Centrum on serum levels of antioxidants
in this population was negligible.
SAFETY OUTCOMES
There were no significant differences from baseline measurement in serum
cholesterol levels or hematocrit over the 5-year period (Table 7). Self-reported use of lipid-lowering medications at 5 years
was more frequent among those in the antioxidant treatment arms than in the
no antioxidant treatment arms (23.5% vs 20.9%, P
= .04, data not shown). Other safety outcomes were examined for all participants,
regardless of cataract status, to describe and contrast the potential adverse
events experienced by the entire exposed population. Table 8 summarizes the statistically significant differences in
safety outcomes (reported cause of hospitalizations, adverse experiences,
and self-reported conditions) of nearly 50 antioxidants vs no antioxidants
comparisons. The analyses were for all participants who had follow-up examinations.
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Table 8. Participants Reporting at Least One Hospitalization, Adverse
Experience, or Condition During Follow-up by Treatment*
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Potential Adverse Effects
At the time of enrollment, participants were informed of possible adverse
effects from or contraindications to the use of study medications: vitamin
C (kidney stones), vitamin E (fatigue, muscle weakness, decreased thyroid
gland function, and increased hemorrhagic stroke), and beta carotene (yellow
skin). Among participants in the antioxidant treatment arms, there was an
observed excess of self-reports of yellow skin (8.6% vs 6.1%, P = .001). No differences were seen for the other conditions of prestudy
concern. All other statistically significant safety measures found during
the course of this study are summarized in the following sections.
Hospitalizations
Participants in the antioxidant treatment arms were hospitalized less
frequently for reasons in the category "mild/moderate symptoms," eg, chest
pain or discomfort, abdominal pain, vasovagal episode, and fever (7.3% vs
9.3%, P = .01).
Adverse Experiences
Adverse experiences reported by participants were assigned International Classification of Diseases, Ninth Revision codes. Skin
and subcutaneous tissue conditions were more frequent in the antioxidant treatment
arms (2.4% vs 0.9%, P<.001); most participants
with these conditions also self-reported yellow skin.
Conditions Reported at Follow-up
Participants in the antioxidant treatment arms less frequently reported
chest pains (19.8% vs 22.8%, P = .01).
Mortality
Table 9 provides the relative
risk estimates from the Cox proportional hazards survival model for treatment
with antioxidants. Figure 6 shows
the Kaplan-Meier estimates of the probability of death for each treatment.
The antioxidant treatment does not statistically significantly reduce or increase
risk of mortality (P>.50).
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Table 9. Effect of Treatment on Risk of Mortality*
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Figure 6. Kaplan-Meier estimates of the
probability of death by treatment group among all participants enrolled. P = .53, unadjusted comparison across treatments.
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COMMENT
Dietary supplementation with high doses of vitamin C, vitamin E, and
beta carotene for an average duration of 6.3 years had no statistically significant
effect on the development or progression of age-related lens opacities in
AREDS participants. No effect of the antioxidants was noted for the combined
opacity group (nuclear, cortical, PSC, or cataract surgery), for the individual
types of opacity, or for cataract surgery. For participants with no AMD at
baseline no difference was noted between treatment groups for a visual acuity
decrease of 15 or more letters compared with the baseline measurement. The
5-year event rate for the primary opacity outcome was 30%, consistent with
pretrial estimates of at least 90% power to detect a 25% treatment effect.
Several features of the AREDS design need to be considered in interpreting
the null findings for cataract development and progression. First, as is often
the case in prevention studies, the population participating in the this study
may differ from the general population. The AREDS participants were relatively
well nourished compared with the general population, and the effect of this
and other differences on the generalizability of AREDS findings is unknown.
Second, only a select few antioxidants were studied in AREDS. At the time
AREDS was planned, basic science investigations and animal research had suggested
an antioxidant hypothesis, and a very limited amount of epidemiological data
suggested that cataract occurrence might be inversely associated with use
of multivitamins or intake or blood levels of vitamin C, vitamin E, and/or
carotenoids.32 In the absence of any proven
medical treatment for cataract and the absence of any therapy for most patients
with AMD combined with the perception that toxic effects from vitamin usage
were low, the use of supplements was being increasingly promoted for both
conditions, even in the absence of any convincing efficacy data. During the
AREDS planning period a panel of expert nutritionists, ophthalmologists, and
biochemists reviewed the basic science and epidemiological data and recommended
the AREDS formulation. Two carotenoids, lutein and zeaxanthin, were strong
candidates for inclusion in the formulation mainly because they are concentrated
in the central retina43 and it was thought
that supplementation with these carotenoids might be of benefit in preventing
the development of AMD. At the time there were no reports of associations
between lutein and zeaxanthin and cataract; there were no commercial preparations
available of lutein and zeaxanthin. Beta carotene, another carotenoid with
antioxidant properties, was chosen for use in the study because the manufacturers
of ophthalmic nutritional supplements were then promoting its effectiveness
because of its antioxidant properties, because clinical trials of heart disease
and cancer were studying it, and because it was commercially available.33
Since the start of AREDS many observational epidemiological studies
have reported associations between the intake or blood levels of various nutrients
and cataract.4-27
While almost all retrospective and cross-sectional studies have reported a
lower prevalence of cataract in persons who choose to take various supplements
or have a higher intake of selected nutrients, the results have been inconsistent
in identifying a specific nutrient or cataract type that is affected.
Clinical trials and prospective epidemiological studies have provided
little support for a beneficial effect on cataract development of the antioxidant
nutrients included in the AREDS formulation. A large randomized trial of US
male physicians reported no effect on incident cataract or cataract extraction
after 13 years of beta carotene use.3 In 2
cancer prevention trials, treatment with beta carotene had no effect on end-of-study
cataract prevalence.28-29 Several
prospective epidemiological studies have raised the possibility that lutein
and zeaxanthin, the only carotenoids that have been identified in the lens,44 may be better candidates for retarding cataract development
than beta carotene. Two prospective studies of the association between dietary
intake of antioxidant nutrients and subsequent cataract surgery reported beneficial
effects for lutein and zeaxanthin intake but not for intake of other carotenoids.18, 20 A third prospective study found a
lower incidence of nuclear cataracts with higher levels of intake of lutein
and zeaxanthin but again no effect from beta carotene intake.21
Prospective studies evaluating the effect on cataract of higher levels
of intake of vitamin E or of higher plasma levels of vitamin E have produced
inconsistent results.17, 19, 21-22,26
Neither of the 2 cancer prevention trials with end-of-study eye examinations
showed a statistically significant protective effect for interventions that
included vitamin E.28-29 Prospective
studies have provided little support for an association between vitamin C
intake and the risk of cataract, though one reported that the risk of cataract
was lower in women who had used vitamin C supplements for 10 years or longer.17 While the cumulative evidence from AREDS and other
studies does not support a beneficial role of vitamin C, vitamin E, or beta
carotene in preventing cataract development or progression, questions about
a possible role for other micronutrients with or without antioxidant properties
remain unanswered.
Interpreting the AREDS results also requires a consideration of the
timing and duration of use of the antioxidant intervention. All AREDS participants
were 55 years or older at enrollment in the study. The median age was 68 years.
At baseline 15% of the participants already had a nuclear grade of at least
4.0 U, 52% had some cortical opacities, and 10% had some PSC opacities. Even
for many participants with no clinically apparent lens opacities, it is likely
that cataracts had probably already started to develop. It may be that, for
many, the AREDS intervention was started too late in the process for it to
be effective. The AREDS was not designed to determine whether earlier intervention
with the micronutrients and/or a longer period of treatment would have been
effective. Following the unmasking of study participants, all consenting participants
will be followed up for at least another 5 years.
A modification of the Wisconsin System for Classifying Cataracts34 was used in AREDS. Lens photographs were taken in
a standardized fashion by certified photographers at the 11 clinical centers
and graded at a reading center by specially trained and certified observers.
A quality control program included masked replicate gradings of samples of
photographs to assess contemporaneous and temporal grading reliability. Replicate
gradings of photographs showed a high degree of reliability,35
but our ability to reliably detect change using serial photographs taken at
yearly intervals could have been affected by factors such as changes in the
characteristics of the film available for purchase, the film development processes,
and aging of the photographic equipment. To increase the probability that
lens events reflected "true" progression, we performed secondary analyses
in which a greater amount of change was required than in the primary analyses.
For the primary analyses, as described in the protocol, lens events were defined
as a 1.5-U increase in nuclear opacity, a 10% increase in cortical opacity,
or a 5% increase in PSC opacity. With events defined as a 2.5-U increase in
nuclear opacity or a 20% increase in cortical or PSC opacity, the null findings
were repeated. Moreover, no statistically significant treatment effect was
noted for cataract surgery, an event with little or no misclassification.
Any apparent regression of events was also considered in the primary analyses,
which used repeated-measures logistic regression that allows for event determination
at each visit, compared with models that are more appropriate for irreversible
and error-free events.
Fifty-five percent of the AREDS participants were taking dietary supplements
of a multivitamin or at least 1 of the ingredients in the AREDS formulation
prior to joining the study. About half (55%) of those taking a dietary supplement
were taking RDA dosages rather than the 5- to 15-fold higher dosages of the
AREDS ingredients. To accommodate these persons and to standardize the use
of nonstudy supplements, a daily dose of Centrum without lutein, a widely
available multivitamin and mineral preparation with RDA-level dosages, was
provided to each participant who wanted to take or continue taking a multivitamin.
Approximately 66% of participants chose to take Centrum; use was balanced
across treatment groups. Thus, in addition to their dietary intake of vitamins
C and E and beta carotene, these persons whether assigned to placebo or "active"
intervention had an increase in their intake by approximately 100% of the
RDA amount of each of the study ingredients. The statistical power of the
study to test its primary hypothesis about high doses of the study ingredients
might have been reduced to the extent that prior use or the continued use
of RDA-type doses of these nutrients or other nutrients in the Centrum formulation
affected the risk of cataract development. Analyses of the primary opacity
outcome stratified by Centrum use showed no differential effect from the antioxidant
treatment (data not shown).
Few possible adverse effects of prestudy concern were associated with
the use of high doses of the 3 antioxidants. Yellowing of the skin, a well-known
adverse effect of large doses of beta carotene, was noted more commonly by
participants in the antioxidant treatment arms. During the course of the trial
concerns were raised about the potential risk of antioxidants on mortality.
There was no significant deleterious effect of antioxidants on mortality although
the relative risk estimate is in the direction of harm (relative risk = 1.06;
99% confidence interval, 0.84-1.33).
After an average treatment time of 6.3 years in this cohort of relatively
well-nourished older adults, the AREDS antioxidant formulation containing
high doses of vitamins C and E, beta carotene, and/or zinc had no statistically
significant effect on the development or progression of age-related lens opacities
or cataract surgery. In addition, there was no statistically significant effect
on retarding visual acuity loss in the participants without AMD. Ongoing clinical
trials evaluating the effect of nutritional supplements on cataract development
will provide additional data about whether the ingredients in the AREDS formulation
and other nutrients can affect the risk of cataract development.45-49
AUTHOR INFORMATION
Accepted for publication August 8, 2001.
This investigation was supported by contracts from the National Eye
Institute, National Institutes of Health, Bethesda, Md, with additional support
from Bausch & Lomb Inc, Rochester, NY.
Corresponding author and reprints: AREDS Coordinating Center, The
EMMES Corp, 401 N Washington St, Suite 700, Rockville, MD 20850-1707 (e-mail: aredspub{at}emmes.com).
The AREDS investigators have no commercial or proprietary interest
in the supplements used in this study.
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The Age-Related Eye Disease Study Severity Scale for Age-Related Macular Degeneration: AREDS Report No. 17
Age-Related Eye Disease Study Research Group
Arch Ophthalmol 2005;123:1484-1498.
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Age-Related Eye Disease Study Severity Scale and Simplified Severity Scale for Age-Related Macular Degeneration
Mitchell and Foran
Arch Ophthalmol 2005;123:1598-1599.
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Plasma 8-Isoprostane Concentrations in Patients with Age-Related Cataracts
Wang et al.
Clin. Chem. 2005;51:1541-1544.
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Vitamin E in the Primary Prevention of Cardiovascular Disease and Cancer: The Women's Health Study: A Randomized Controlled Trial
Lee et al.
JAMA 2005;294:56-65.
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Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer: A Randomized Controlled Trial
The HOPE and HOPE-TOO Trial Investigators
JAMA 2005;293:1338-1347.
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Oxidant-Induced Apoptosis in Human Retinal Pigment Epithelial Cells: Dependence on Extracellular Redox State
Jiang et al.
IOVS 2005;46:1054-1061.
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Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality
Miller et al.
ANN INTERN MED 2005;142:37-46.
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Vitamin E Supplements: Good in Theory, but Is the Theory Good?
Greenberg
ANN INTERN MED 2005;142:75-76.
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Scanning Laser Entoptic Perimetry for the Detection of Age-Related Macular Degeneration
Freeman et al.
Arch Ophthalmol 2004;122:1647-1651.
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Oxidative Stress Plays an Important Role in the Pathogenesis of Drug-Induced Retinopathy
Toler
Exp. Biol. Med. 2004;229:607-615.
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Hormones and Supplements: Do They Work?: Micronutrient Supplementation in Later Life: Limited Evidence for Benefit
Dangour et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2004;59:B659-B673.
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Increased Expression of Iron-Regulating Genes in Monkey and Human Glaucoma
Farkas et al.
IOVS 2004;45:1410-1417.
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Doctor, What Vitamins Should I Take for My Eyes?
Mares et al.
Arch Ophthalmol 2004;122:628-635.
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Basal Laminar Deposit Formation in APO B100 Transgenic Mice: Complex Interactions between Dietary Fat, Blue Light, and Vitamin E
Espinosa-Heidmann et al.
IOVS 2004;45:260-266.
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Important Causes of Visual Impairment in the World Today
Congdon et al.
JAMA 2003;290:2057-2060.
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Relationship between Refraction and Prevalent as well as Incident Age-Related Maculopathy: The Rotterdam Study
Ikram et al.
IOVS 2003;44:3778-3782.
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Routine Vitamin Supplementation To Prevent Cancer and Cardiovascular Disease: Recommendations and Rationale
U.S. Preventive Services Task Force*
ANN INTERN MED 2003;139:51-55.
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Routine Vitamin Supplementation To Prevent Cardiovascular Disease: A Summary of the Evidence for the U.S. Preventive Services Task Force
Morris and Carson
ANN INTERN MED 2003;139:56-70.
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A Randomized Trial of Beta Carotene and Age-Related Cataract in US Physicians
Christen et al.
Arch Ophthalmol 2003;121:372-378.
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Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention
Padayatty et al.
J. Am. Coll. Nutr. 2003;22:18-35.
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National Eye Institute Visual Function Questionnaire in the Age-Related Eye Disease Study (AREDS): AREDS Report No. 10
Clemons et al.
Arch Ophthalmol 2003;121:211-217.
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Lens Aging in Relation to Nutritional Determinants and Possible Risk Factors for Age-Related Cataract
Berendschot et al.
Arch Ophthalmol 2002;120:1732-1737.
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Vitamin E supplementation and macular degeneration: randomised controlled trial
Taylor et al.
BMJ 2002;325:11-11.
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Vitamin C Is Associated with Reduced Risk of Cataract in a Mediterranean Population
Valero et al.
J. Nutr. 2002;132:1299-1306.
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The Effect of Five-Year Zinc Supplementation on Serum Zinc, Serum Cholesterol and Hematocrit in Persons Randomly Assigned to Treatment Group in the Age-Related Eye Disease Study: AREDS Report No. 7
The Age-Related Eye Disease Study Research Group
J. Nutr. 2002;132:697-702.
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Antioxidants and Zinc to Prevent Progression of Age-Related Macular Degeneration
Jampol and Ferris
JAMA 2001;286:2466-2468.
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Antioxidants and Zinc for Age-Related Eye Diseases
JWatch General 2001;2001:2-2.
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A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8
Age-Related Eye Disease Study Research Group
Arch Ophthalmol 2001;119:1417-1436.
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