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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.
ABSTRACT
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Background Observational and experimental data suggest that antioxidant and/or
zinc supplements may delay progression of age-related macular degeneration
(AMD) and vision loss.
Objective To evaluate the effect of high-dose vitamins C and E, beta carotene,
and zinc supplements on AMD progression and visual acuity.
Design The Age-Related Eye Disease Study, an 11-center double-masked clinical
trial, enrolled participants in an AMD trial if they had extensive small drusen,
intermediate drusen, large drusen, noncentral geographic atrophy, or pigment
abnormalities in 1 or both eyes, or advanced AMD or vision loss due to AMD
in 1 eye. At least 1 eye had best-corrected visual acuity of 20/32 or better.
Participants were randomly assigned to receive daily oral tablets containing:
(1) antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene,
15 mg); (2) zinc, 80 mg, as zinc oxide and copper, 2 mg, as cupric oxide;
(3) antioxidants plus zinc; or (4) placebo.
Main Outcome Measures (1) Photographic assessment of progression to or treatment for advanced
AMD and (2) at least moderate visual acuity loss from baseline ( 15 letters).
Primary analyses used repeated-measures logistic regression with a significance
level of .01, unadjusted for covariates. Serum level measurements, medical
histories, and mortality rates were used for safety monitoring.
Results Average follow-up of the 3640 enrolled study participants, aged 55-80
years, was 6.3 years, with 2.4% lost to follow-up. Comparison with placebo
demonstrated a statistically significant odds reduction for the development
of advanced AMD with antioxidants plus zinc (odds ratio [OR], 0.72; 99% confidence
interval [CI], 0.52-0.98). The ORs for zinc alone and antioxidants alone are
0.75 (99% CI, 0.55-1.03) and 0.80 (99% CI, 0.59-1.09), respectively. Participants
with extensive small drusen, nonextensive intermediate size drusen, or pigment
abnormalities had only a 1.3% 5-year probability of progression to advanced
AMD. Odds reduction estimates increased when these 1063 participants were
excluded (antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91; zinc: OR, 0.71;
99% CI, 0.52-0.99; antioxidants: OR, 0.76; 99% CI, 0.55-1.05). Both zinc and
antioxidants plus zinc significantly reduced the odds of developing advanced
AMD in this higher-risk group. The only statistically significant reduction
in rates of at least moderate visual acuity loss occurred in persons assigned
to receive antioxidants plus zinc (OR, 0.73; 99% CI, 0.54-0.99). No statistically
significant serious adverse effect was associated with any of the formulations.
Conclusions Persons older than 55 years should have dilated eye examinations to
determine their risk of developing advanced AMD. Those with extensive intermediate
size drusen, at least 1 large druse, noncentral geographic atrophy in 1 or
both eyes, or advanced AMD or vision loss due to AMD in 1 eye, and without
contraindications such as smoking, should consider taking a supplement of
antioxidants plus zinc such as that used in this study.
INTRODUCTION
AGE-RELATED macular degeneration (AMD) is the leading cause of visual
impairment and blindness in the United States and elsewhere among people 65
years or older.1-4
At present, there is no proven treatment that slows or prevents the development
of advanced AMD. Laser photocoagulation5-6
and photodynamic therapy7-8 reduce
the risk of either moderate or severe visual acuity loss in some persons with
the neovascular form of the disease. Other medical and surgical interventions
are under investigation but none has been demonstrated as being effective
in a large randomized clinical trial.9-13
Oxidative damage to the retina may be involved in the pathogenesis of
AMD.14-17
However, data from epidemiological studies18-26
as well as small randomized clinical trials27-29
do not show consistent associations between intake of antioxidants or zinc
and risk of AMD. One small, randomized, 2-year, placebo-controlled clinical
trial of zinc supplementation found a statistically significant reduction
in visual acuity loss in the zinc-treated group and recommended a more definitive
trial before a general recommendation could be made for zinc supplementation
in those at risk of vision loss from advanced AMD.27
Despite the lack of convincing evidence, the marketing and use of antioxidants
and zinc in eye-targeted formulations has become a common practice.30 Inconsistent evidence from observational studies,
the small clinical trial of zinc and AMD, and the public health concern regarding
the widespread use of unproven, high-dose antioxidant and zinc supplements
for AMD led the National Eye Institute (National Institutes of Health, Bethesda,
Md) to incorporate a clinical trial as part of the Age-Related Eye Disease
Study (AREDS). This randomized clinical trial was designed to evaluate the
effect of high doses of zinc and selected antioxidant vitamins (5 to about
15 times the recommended dietary allowance [RDA]31)
on the development of advanced AMD in a cohort of older persons.32
This report presents the results of a randomized comparison of the risks and
benefits of supplementing with either zinc, antioxidants (vitamins C and E
and beta carotene), or the combination of both on the rate of progression
to advanced AMD and on visual acuity outcomes.
PARTICIPANTS AND METHODS
STUDY POPULATION
Details of the study design and methods presented elsewhere32 are briefly summarized here. Eleven retinal specialty
clinics enrolled participants aged 55 to 80 years from November 13, 1992,
through January 15, 1998, and followed them 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 citizen centers, and
other gathering places.
All participants had a best-corrected visual acuity of 20/32 or better
in at least 1 eye (the study eye[s]). Visual acuity was assessed by certified
examiners using the ETDRS logMAR chart and a standardized refraction and visual
acuity protocol (AREDS Manual of Operations; The
EMMES Corporation, Rockville, Md). Persons were enrolled in 4 AMD categories
determined by the size and extent of drusen and retinal pigment epithelial
abnormalities in each eye,33 the presence of
advanced AMD (each determined by evaluation of color photographs at a reading
center34), and visual acuity as presented in Table 1. Briefly, persons in Category 1
were essentially free of age-related macular abnormalities, with a total drusen
area less than 5 small drusen (<63 µm), and visual acuity of 20/32
or better in both eyes. Category 2 participants had mild or borderline age-related
macular features (multiple small drusen, single or nonextensive intermediate
drusen [63-124 µm], pigment abnormalities, or any combination of these)
in 1 or both eyes, and visual acuity of 20/32 or better in both eyes. Category
3 required absence of advanced AMD in both eyes and at least 1 eye with visual
acuity of 20/32 or better with at least 1 large druse (125 µm), extensive
(as measured by drusen area) intermediate drusen, or geographic atrophy (GA)
that did not involve the center of the macula, or any combination of these.
Category 4 participants had visual acuity of 20/32 or better and no advanced
AMD (GA involving the center of the macula or features of choroidal neovascularization)
in the study eye, and the fellow eye had either lesions of advanced AMD or
visual acuity less than 20/32 and AMD abnormalities sufficient to explain
reduced visual acuity as determined by examination of photographs at the reading
center. Persons aged 55 to 59 years were eligible only if they were in Category
3 or 4. Figure 1 shows photographic
examples of eyes of persons in Categories 2 and 3.
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Table 1. AMD Eligibility Categories
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Figure 1. Fundus photographs from participants
in the Age-Related Eye Disease Study (AREDS) illustrating eyes in age-related
macular degeneration Categories 2 and 3. A, Left eye in Category 2 shows nonextensive
intermediate drusen, mostly located superotemporal to the center of the macula.
No druse is 125 µm or greater in diameter, although some are 63 µm
or greater and their cumulative area is less than AREDS circle O-2 (about
0.2 disc areas). B, One left eye in Category 3 depicts the lower limit of
the category, having 1 large druse (125 µm in diameter) in the 8-o'clock
position from the center of the macula, while another left eye (C) shows many
large drusen (totaling at least 1 disc area) scattered throughout the macula.
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Individuals were not enrolled unless the ocular media were sufficiently
clear, as determined by reading center review, to obtain adequate quality
stereoscopic fundus photographs of the macula in all potential study eyes.
At least 1 eye of each participant had to be free from any eye disease that
could complicate assessment of AMD, lens opacity progression, or visual acuity
(eg, optic atrophy, acute uveitis), and that eye could not have had previous
ocular surgery (other than cataract surgery). 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.
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
postrandomization to be technically ineligible because 2 were aged 58 years
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 2). 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 and 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 2. Age-Related Eye Disease Study
(AREDS) randomization schema. AMD indicates age-related macular degeneration.
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As in all vitamin products, some ingredients degrade somewhat during
the life of the product (ie, prior to expiration date). The manufacturer formulated
each product with slightly different amounts of ingredients than listed above
in an effort to achieve appropriate potency at the 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. Participants in Categories 2, 3, and 4 were
assigned with probability one quarter to each treatment group: placebo, antioxidants,
zinc, and antioxidants plus zinc. Participants in Category 1 were assigned
with probability one half to placebo or antioxidants. These study participants
were at low risk for vision loss from AMD and there was no reason to suspect
that zinc use would reduce the risk of progression of lens opacities. Because
there was no apparent reason for these participants to supplement their diets
with zinc, it seemed inappropriate to subject them to the possible consequences
of high levels of zinc supplementation; thus, they were not enrolled in the
clinical trial of zinc and are not included in analyses of AMD progression.
Persons in Categories 2, 3, and 4 were randomized to the 4 interventions (Figure 2). Multiple unique bottle codes were
randomly assigned to each of the 4 treatments for Categories 2, 3, and 4,
and also to each of the 2 treatments for participants in 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. Stereoscopic fundus photographs of the macula were taken at baseline
and annually beginning 2 years after randomization and graded centrally 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 reading center and successful participation in a 1-month run-in
with placebo, 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 4 treatment groups and then evaluated every
6 months. The run-in aspect of the study was considered important for 2 reasons.
Participants had to be willing to take 2 fairly large tablets 2 times per
day for up to 8 years and they had to agree that, for the duration of the
study, the only other supplement they might take that contained any of the
study medications would be Centrum (Whitehall-Robins Healthcare, Madison,
NJ), a multivitamin and mineral supplement with RDA-level doses. Fifty-seven
percent of the study participants were supplementing with zinc or antioxidant
vitamins prior to joining the study and 95% of this group chose to take Centrum,
which the study provided. In addition, although not encouraged, an additional
13% who were not taking vitamin supplements prior to the start of the study
chose to take Centrum. Among other differences, persons in the study who chose
to take Centrum during the course of the study were somewhat more likely to
be in the higher-risk AMD categories and therefore may differ from persons
who did not choose to take Centrum with regard to their risk of AMD progression.
At each visit, participants returned their used study medication bottles
and any unused tablets, and received new bottles of their study medication.
They received an ophthalmic examination every 6 months. In addition to the
scheduled fundus photography, photographs were also taken when a decrease
in visual acuity score of 10 or more letters from baseline was first observed
at a nonannual visit or at the first annual visit. If any submitted photographs
were inadequate to assess lens or AMD status, requests were made for these
photographs to be taken again. Best-corrected visual acuity was measured according
to the ETDRS protocol (AREDS Manual of Operations)
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 during participant follow-up: a modified Block
Food Frequency Questionnaire, a 24-hour dietary recall questionnaire, and
cognitive function tasks (AREDS Manual of Operations);
an ocular sunlight-exposure questionnaire derived from the Melbourne study35; and the National Eye Institute Visual Function Questionnaire
(NEI VFQ-25).36
Four clinical centers (The Johns Hopkins Medical Institutions [Baltimore,
Md], Devers Eye Institute [Portland, Ore], National Eye Institute Clinical
Center [Bethesda], and the Associated Retinal Consultants [Royal Oak, Mich])
collected blood samples at baseline, which were analyzed at the central laboratory
(Centers for Disease Control and Prevention, Atlanta, Ga) for total cholesterol,
high-density lipoprotein cholesterol, triglycerides, vitamins A, C, and E,
beta carotene, zinc, copper, alpha carotene, lutein and zeaxanthin,  -cryptoxanthin,
and lycopene. The first 3 centers also collected blood samples annually during
follow-up for estimation of adherence to the study medication regimen and
to assess the effect of the study medications during the course of the study
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 the possible development of anemia. Safety outcomes included serum
levels, adverse events, hospitalizations, and mortality. Participants also
were asked to report at each annual visit if they had experienced any 1 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. The data and safety
monitoring committee monitored safety outcomes annually. A network of collaborating
physicians from non-AREDS clinics was formed to assist in obtaining follow-up
visual acuity, fundus photographs, and ophthalmic examinations from participants
who could not return to an AREDS clinic.
Sample Size and Power
A total sample size of 4600 was selected. For the AMD trial, with an
estimated 3600 participants in Categories 2, 3, and 4, power was calculated
assuming 5 years of follow-up, 15% of participants lost to follow-up prior
to experiencing an event, 10% discontinuing study medication (and thereafter
assuming the placebo event rate), and 10% beginning a nonstudy supplement
containing study medication ingredients (and thereafter assuming the full
treatment [antioxidants plus zinc] event rate). The placebo 5-year rate of
progression to advanced AMD was assumed to be 17% based on the information
available.5, 37 After adjusting
for noncompliance, for 2-sided  = .05, a projected sample size of 3600
would provide at least 80% power to detect treatment effects of 25% to 50%
on progression to advanced AMD depending on possible interactions between
zinc and antioxidants.
OUTCOMES
At the start of the study, 2 primary outcomes were defined for study
eyes in the AMD trial: (1) progression to advanced AMD and (2) at least a
15-letter decrease in visual acuity score.
Advanced AMD
Progression to advanced AMD (an "AMD event") for a study eye was defined
as follows: photocoagulation or other treatment for choroidal neovascularization
(based on clinical center reports), or photographic documentation of any of
the following (based on reading center reports)34:
GA involving the center of the macula, nondrusenoid retinal pigment epithelial
detachment, serous or hemorrhagic retinal detachment, hemorrhage under the
retina or the retinal pigment epithelium, and/or subretinal fibrosis.
In AREDS, the retinal outcomes are based on color fundus photography
rather than on fluorescein angiography or clinical examination.
Visual Acuity Loss
A decrease in 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 worse, or 20/50 to 20/100 or worse) was
the primary visual acuity outcome. Visual acuity was measured every 6 months.
Secondary Outcomes
Secondary AMD outcomes analyzed as part of the clinical trial included
development of neovascular AMD, incidence of GA (not necessarily in the center
of the macula), progression to advanced AMD with an associated visual acuity
decrease of at least 15 letters, and worsening of AMD classification in Category
2 participants to Category 3 or 4 during follow-up. Secondary visual acuity
outcomes included a decrease in the best-corrected visual acuity score from
baseline of 30 or more letters in a study eye (6 lines or a quadrupling
of the initial visual angle) and progression to a visual acuity score worse
than 20/100 in 1 or both eyes.
STATISTICAL ANALYSES
All comparisons were made on an intention-to-treat basis. Photographic
AMD events were determined from photographs taken at annual visits beginning
at year 2. Events of treatment for choroidal neovascularization from clinical
reports at nonannual visits were attributed to the next annual visit. Primary
comparisons for the development of advanced AMD and for a visual acuity decrease
were the overall (main) effects of zinc (treatments 1 and 2) vs no zinc (treatments
3 and 4) and antioxidants (1 and 3) vs no antioxidants (2 and 4) on persons
in Categories 2, 3, and 4. The 2 x 2 factorial design (Table 2) also permits comparisons of each of the 3 active treatment
strategies with the placebo. Because persons are the units of analysis, no
adjustment for correlation between paired eyes is needed.
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Table 2. Treatment Design
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Only 15 participants in Category 2 (3 in the placebo arm) developed
an AMD event by 5 years of follow-up. Therefore, assessment of treatment effect
of the size seen in Categories 3 and 4 was not possible in this group. Consequently,
analyses limited to Categories 3 and 4 were performed. Primary analysis of
treatment effect was done by repeated-measures logistic regression using the
SAS procedure GENMOD (SAS Institute, Cary, NC), a generalized estimating equations
method that allows for determining events at each visit for each participant.
The annual probability estimates of event occurrence for each treatment that
are derived from this model take into account the variability as well as the
correlation of observations at follow-up visits for a given participant. This
model was adopted because study events (either visual acuity loss or photographic
evidence of lesions of advanced AMD) can come and go during study follow-up.
We found that in approximately 8% of the identified cases of advanced AMD,
based on central grading of color stereo photographs, the AMD lesions were
not seen on subsequent yearly photographs. Possible reasons for this disappearance
include grading error, problems in photographic quality, and actual disappearance
of the lesions. Because some of the lesions that define the study outcome
are apparently transient, a life-table technique such as Kaplan-Meier to estimate
the probability of progression is problematic; in this method an event remains
an event despite evidence of reversal during follow-up. Cox proportional hazards
survival analyses for the AMD outcomes and repeated-measures analysis of variance
of mean change in visual acuity were used for comparison with the findings
of repeated-measure logistic regression to check for consistency of treatment
effects. 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 was given secondary importance
because it is more appropriate for irreversible and error-free events like
death, where subsequent observations are not relevant.
Repeated-measures logistic regression provides estimates of odds ratios
(ORs) for specified outcomes. Relative risk (RR) may be further estimated
from the algebraic relation RR = OR/[(1 - Po) + (Po x OR)], where
Po is the incidence of the outcome of interest in the nonexposed or control
group.38 For Po we use the estimated probability
of the outcome from the repeated-measures analysis in the placebo group at
7 years. Analyses are unadjusted and also adjusted for the following baseline
covariates: age (55-64, 65-69, and 70-80 years), sex, race, AMD category,
and smoking status.
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.32 Sequential monitoring of end points assumed no interaction
between the antioxidant formulation and the zinc formulation, so that only
main effects were analyzed. An -spending function group-sequential
method39 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.40 A separate monitoring of mortality used a Pocock-type
boundary.41 Comparisons were made with spending
of when requested by the data and safety monitoring committee. Treatment
effects at the end of the trial that are significant at P = .01 can be considered statistically significant at = .05
after adjustment for multiple outcomes and interim analyses. Nominal P values greater than .01 but less than .05 should not
be considered statistically significant and should only be considered as suggestive,
owing to the multiple outcomes and interim analyses performed.
CHANGE IN TREATMENT
In 1994 and 1996, AREDS participants were informed of the results of
2 studies suggesting potential harmful effects of beta carotene among smokers.42-43 Participants who were current cigarette
smokers at the time of enrollment were contacted in 1996 and offered the option
of continuing or discontinuing their masked AREDS study medication. Participants
in Categories 2, 3, and 4 who were current or former smokers at baseline were
also given the opportunity to be reassigned to a masked study medication that
excluded any antioxidant component. As a result, 72 participants (2.0% of
all participants and 18% of smokers) stopped taking medications (15 or 1.7%
in the placebo arm) and 84 participants (2.3%) were reassigned from a study
medication containing beta carotene to one without beta carotene. The original
treatment group assignments were retained for all analyses.
RESULTS
ENROLLMENT AND PARTICIPANT CHARACTERISTICS
A total of 4757 participants were enrolled in AREDS. The 1117 in AMD
Category 1 had few if any drusen. Only 5 of these 1117 participants developed
advanced AMD during the course of the study, and we cannot assess the effects
of antioxidants in this group on this outcome. Therefore, this report focuses
on the 3640 study participants enrolled in the AMD clinical trial. Individual
clinical centers enrolled 95 to 414 participants in the AMD clinical trial.
Of those enrolled, 1063 had extensive small drusen, pigment abnormalities,
or at least 1 intermediate size druse (Category 2); 1621 had extensive intermediate
drusen, GA not involving the center of the macula, or at least 1 large druse
(Category 3); and 956 had advanced AMD or visual acuity less than 20/32 due
to AMD in 1 eye (Category 4). Thirty-one participants had no photographic
assessment of AMD during annual study follow-up visits, leaving 3609 participants
in whom the effect of intervention on AMD could be assessed. Forty-three participants
had no ETDRS visual acuity measurements obtained during follow-up, leaving
3597 participants in whom the effect of intervention on visual acuity could
be assessed. Participants without photographic or visual acuity follow-up
were evenly distributed across treatment groups.
Participant characteristics by treatment assignment for the 3609 participants
with photographic data available from an AREDS clinic are presented in Table 3. The frequency of these characteristics
was similar among the 4 treatment groups and no large or statistically significant
differences were found. Fifty-six percent of participants were women, 96%
were white, and the median age was 69 years. At baseline 8% were current cigarette
smokers and 67% chose to take Centrum, a multivitamin supplement. Of those
who elected to take Centrum, 30% had been taking multivitamins or a supplement
containing a study ingredient for more than 5 years before study entry. 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 Survey (data not shown).44 Baseline dietary intake of the study nutrients was
balanced across treatment groups.
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Table 3. Baseline Characteristics by Treatment Group*
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DATA QUALITY
Only 2.4% of AREDS participants were lost to follow-up (missed at least
their last 2 consecutive visits). Losses to follow-up were balanced across
treatment groups. As of the 5-year study visit, 13.6% of participants had
withdrawn from their study medication—a figure that includes the 18%
of current smokers who withdrew from study medication after the results of
the clinical trials of beta carotene and lung cancer were announced. By the
end of the trial this increased to 14.7%. Figure 3 shows the number of participants with follow-up and adherence
to the study medication regimens by year of follow-up. Overall, adherence
was estimated to be 75% or greater (ie, participants took 75% or more of their
study tablets) for 71% of the participants at 5 years. At the time of the
5-year study visit, 19% of study participants reported taking some nutritional
supplements containing at least 1 of the study medication ingredients in addition
to the study medication and Centrum (18% for current smokers and 20% for former
or nonsmokers). Four participants (0.1%) were reported to have been unmasked
during the trial. Compliance with fundus and lens photography decreased during
the course of the study. At the last study visit, 16% of participants did
not follow the protocol for photography (missed photographs); 9% of expected
photographs were missed in the study overall. Of almost 50 000 possible
follow-up visits, 10% were missed. The frequency of missed visits and mean
follow-up time (6.3 years) did not differ by treatment group. 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 = 3640). B, Percentage of participants taking at least
75% of their study tablets.
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The network of collaborating, non-AREDS clinic physicians provided data
for 42 annual follow-up visits and 7 nonannual follow-up visits made by 28
participants. The results reported do not include these data, although inclusion
of this information had no discernible effect on results.
PHOTOGRAPHIC QUALITY
More than 99% of fundus photographs taken during the clinical trial
were judged by the reading center to be of gradable quality for the development
of advanced AMD.
PRIMARY OUTCOME— PROGRESSION TO ADVANCED AMD
By AMD Category
Figure 4 shows repeated-measures
probability estimates of AMD events in at least 1 eye by baseline AMD category
for participants in the placebo group and demonstrates that Category 2 participants,
with extensive small drusen, pigment abnormalities, or at least 1 intermediate
size druse (but not extensive in area), had only a 1.3% probability of progression
to advanced AMD by year 5. The 5-year estimated probability of progression
to advanced AMD in either eye in participants with extensive intermediate
drusen, large drusen, or noncentral GA (Category 3) was 18%. Within the Category
3 group, half of the participants had large drusen in each eye or noncentral
GA in at least 1 eye at enrollment, and these participants were 4 times as
likely to progress to advanced AMD (about 27% probability of progression to
advanced AMD at 5 years in the placebo group) compared with the remaining
Category 3 participants (about 6% probability of progression to advanced AMD
at 5 years in the placebo group). Participants with advanced AMD in 1 eye
or vision loss due to nonadvanced AMD in 1 eye (Category 4) had a 43% expected
probability of progression to advanced AMD in the fellow study eye at 5 years.
In the original study design, participants in Categories 2, 3, and 4 were
pooled for data analysis and that remains the primary analysis. However, by
5 years there were only 15 AMD events in Category 2 distributed across all
4 treatment groups (3 in the placebo group). The low event rate makes it impossible
to assess treatment effects in this category for the AMD outcome and less
likely that any of the treatments would be recommended. Therefore, analyses
are also presented for those participants most likely to benefit from an effective
treatment (Categories 3 and 4).
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Figure 4. Repeated-measures estimates of
the probability of the development of advanced age-related macular degeneration
(AMD) in at least 1 eye of participants assigned to placebo by baseline AMD
category. Events before year 2 reflect only photocoagulation.
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By Treatment
Figure 5 shows repeated-measures
estimates of the probability of progressing to advanced AMD over time by treatment
for participants in AMD Categories 3 and 4. At 5 years, the estimated probability
of progression to advanced AMD was 28% for those assigned to placebo, 23%
and 22% for those assigned to antioxidants and zinc, respectively, and 20%
for those assigned to antioxidants plus zinc. Treatment effects, estimated
by repeated measures, for progression to advanced AMD for participants in
Categories 2, 3, and 4 and in Categories 3 and 4, are presented in Table 4. Results include comparisons of
the main effects of antioxidants vs no antioxidants and zinc vs no zinc (interactions
between treatments are omitted here and throughout because they were not significant)
and comparisons of each of the individual treatments vs placebo. When evaluating
main effects, there is a suggestive reduction in the risk of developing advanced
AMD for persons assigned to zinc (ie, combining those participants taking
zinc alone with those taking zinc plus antioxidants; OR, 0.82; 99% confidence
interval [CI], 0.66-1.03), and a nonsignificant effect on persons assigned
to antioxidants (ie, combining those participants taking antioxidants alone
with those taking antioxidants plus zinc; OR, 0.87; 99% CI, 0.70-1.09). Single-arm
comparisons with placebo found risk reductions statistically significant for
antioxidants plus zinc and suggestive for the zinc arm but not for the antioxidants
arm (antioxidants: OR, 0.80; 99% CI, 0.59-1.09; zinc: OR, 0.75; 99% CI, 0.55-1.03;
antioxidants plus zinc: OR, 0.72; 99% CI, 0.52-0.98).
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Figure 5. Repeated-measures estimates of
the probability of development of advanced age-related macular degeneration
(AMD) in at least 1 study eye of participants in Categories 3 and 4 by treatment
group. The study eye is an eye without disqualifying lesions or evidence of
advanced AMD, and with a visual acuity score of greater than 73 letters (20/32
or better) at baseline. Events before year 2 reflect only photocoagulation.
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Table 4. Effect of Treatment on Risk of Progression to Advanced AMD*
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The odds reduction increases when the analysis is restricted to participants
in Categories 3 and 4, who have more severe AMD (extensive intermediate drusen,
large drusen, or noncentral GA in 1 or both eyes or advanced AMD or vision
loss due to nonadvanced AMD in 1 eye) and who are at the highest risk for
progression to advanced AMD (antioxidants: OR, 0.76; 99% CI, 0.55-1.05; zinc:
OR, 0.71; 99% CI, 0.52-0.99; and antioxidants plus zinc: OR, 0.66; 99% CI,
0.47-0.91). An analysis adjusted for age, sex, race, AMD Category, and smoking
status at enrollment did not materially alter the size or direction of these
estimates. There was no evidence of significant clinic differences in treatment
effect. Results from the Cox proportional hazards model (not shown) are consistent
with observations from the repeated-measures analysis.
PRIMARY OUTCOME— VISUAL ACUITY LOSS
Figure 6 shows repeated-measures
estimates of the probability of at least a 15-letter decrease in the visual
acuity score between baseline and each follow-up visit (equivalent to at least
a doubling of the initial visual angle) in at least 1 study eye, by treatment,
for participants in Categories 3 and 4. At 5 years, the estimated probability
of at least a 15-letter decrease in visual acuity score from baseline was
29% for those assigned to placebo, 26% for those assigned to antioxidants,
25% for those assigned to zinc, and 23% for those assigned to antioxidants
plus zinc. Treatment effects are tested using repeated measures and results
for all participants in the AMD trial and for participants in Categories 3
and 4 only are presented in Table 5.
Comparisons of zinc vs no zinc and antioxidants vs no antioxidants (main effects)
showed no statistically significant treatment difference. The antioxidants
plus zinc arm (OR, 0.79; 99% CI, 0.60-1.04) showed a suggestive reduction
compared with placebo in the risk of visual acuity loss of 15 letters or more,
among participants in Categories 2, 3, and 4. There were 175 visual acuity
events in participants in Category 2. However, only 13 of these events (7%)
were thought by the examining ophthalmologist to be primarily related to macular
degeneration. In addition, an advanced AMD event simultaneously occurred with
vision loss during at least 1 visit in only 15 of these participants (9%).
In an analysis restricted to participants in Categories 3 and 4, whose vision
loss was more likely to be associated with progression of AMD, the combination
of antioxidants plus zinc statistically significantly reduced the odds of
visual acuity loss (OR, 0.73; 99% CI, 0.54-0.99). There are trends that favor
treating with zinc alone or antioxidants alone but no statistically significant
differences. Comparisons between the group taking the combination of antioxidants
plus zinc with the groups taking either zinc or antioxidants were not statistically
significant but favor the combination arm (combination vs zinc alone: OR,
0.88; 99% CI, 0.65-1.18; combination vs antioxidants alone: OR, 0.86; 99%
CI, 0.63-1.16) (data not shown). An analysis adjusted for age, sex, race,
AMD category, and baseline smoking status did not materially alter the size
or direction of these OR estimates. Results from an analysis of mean change
in visual acuity (data not shown) were consistent with results from the repeated-measures
analysis.
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Figure 6. Repeated-measures estimates of
the probability of a loss in the visual acuity score of at least 15 letters
in at least 1 study eye of participants in age-related macular degeneration
(AMD) Categories 3 and 4 by treatment group. The study eye is an eye without
disqualifying lesions or evidence of advanced AMD and with a visual acuity
score greater than 73 letters (20/32 or better) at baseline.
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Table 5. Effect of Treatment on Risk of Loss of Visual Acuity Score
of 15 Letters From Baseline*
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Figure 7 shows the proportion
of participants in AMD Categories 3 and 4 with evidence of at least a 15-letter
decrease in visual acuity in at least 1 study eye at each year of follow-up
for participants followed that year without regard to follow-up or visual
acuity status at earlier or later years. The antioxidants plus zinc arm had
proportionally fewer participants with visual acuity loss at each follow-up
visit. Participants assigned to receive zinc or antioxidants also have fewer
events than participants assigned to placebo but had a higher proportion of
events than participants assigned to antioxidants plus zinc, beginning around
year 3.
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Figure 7. Proportion of participants with
visual acuity loss of 15 letters or more in at least 1 study eye by treatment
group and follow-up time among participants in age-related macular degeneration
(AMD) Categories 3 and 4.
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SECONDARY OUTCOMES
Several secondary visual acuity and AMD outcomes were analyzed to examine
the consistency of observed findings with the primary outcomes. Analysis of
secondary outcomes is restricted to Categories 3 and 4. Figure 8 shows a summary of the ORs and 99% CIs for each of the
treatments compared with placebo for the visual acuity primary and secondary
outcomes and the AMD primary and secondary outcomes, respectively.
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Figure 8. Odds ratios (squares) and 99%
confidence intervals (colored bars) for each treatment compared with placebo
for participants in age-related macular degeneration (AMD) Categories 3 and
4. A, Visual acuity outcomes. B, AMD outcomes. GA indicates geographic atrophy.
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Other Visual Acuity Outcomes
Visual Acuity Loss Attributable to AMD.
An analysis of the development of advanced AMD, coincident with a decrease
in visual acuity from baseline of at least 15 letters, in study participants
in Categories 3 and 4 is presented in Table
6 (Categories 3 and 4 combined and separately). For participants
in Categories 3 and 4, the OR estimates for this combined outcome for the
antioxidants arm and the zinc arm compared with placebo are 0.79 (99% CI,
0.55-1.13) and 0.75 (99% CI, 0.53-1.07), respectively. An OR estimate of 0.63
(99% CI, 0.44-0.92) was obtained for the antioxidants plus zinc vs placebo
contrast. The OR for antioxidant plus zinc vs placebo estimated separately
for participants in Categories 3 (OR, 0.76; 99% CI, 0.45-1.30) and 4 (OR,
0.52; 99% CI, 0.31-0.89) is in the direction of benefit for both groups.
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Table 6. Effect of Treatment on Risk of Loss of Visual Acuity Score
of 15 Letters Coincident With Progression to Advanced AMD*
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Marked Visual Acuity Loss.
Visual acuity in all study eyes was 20/32 or better at baseline. Twenty
percent of participants in Categories 3 and 4 experienced a decrease in visual
acuity to worse than 20/100 in at least 1 eye. The estimated 5-year probability
of this severe vision event from repeated-measures analysis was 17% for participants
assigned to placebo compared with 14% for those assigned to antioxidants (OR,
0.80; 99% CI, 0.55-1.16), 13% to zinc (OR, 0.75; 99% CI, 0.52-1.08), and 12%
to antioxidants plus zinc (OR, 0.68; 99% CI, 0.46-1.01). The 5-year probability
estimate of bilateral visual acuity worse than 20/100 in Category 3 participants
assigned to placebo was 11% and was 10% for antioxidants plus zinc (antioxidants
plus zinc: OR, 0.86; 99% CI, 0.50-1.49). For Category 4 placebo participants
the 5-year probability estimate was 28% and 17% for antioxidants plus zinc
(antioxidants plus zinc: OR, 0.53; 99% CI, 0.30-0.94) (data not shown).
The estimated 5-year probability of a 6-line (30-letter) loss in visual
acuity from the baseline score was 18% for participants assigned to placebo
compared with 15% for participants assigned to either zinc (OR, 0.78; 99%
CI, 0.55-1.12) or antioxidants (OR, 0.78; 99% CI, 0.55-1.12), and 13% for
participants assigned to antioxidants plus zinc (OR, 0.67; 99% CI, 0.46-0.98).
Visual Acuity Loss in Eyes with Advanced AMD at Baseline.
Separate repeated-measures analyses were performed to assess whether
study formulations would reduce the risk of losing 15 or more letters in the
Category 4 eyes with neovascular AMD at baseline (nonstudy eye). Results are
presented in Table 7. Analyses
were restricted to eyes without GA at baseline (because there were too few
eyes with GA) and with a baseline visual acuity of 20/100 or better (visual
acuity score of 49 or more, n = 260) and separately for eyes with visual acuity
of 20/200 or better (visual acuity score of 34, n = 352). Odds ratio estimates
showed protection for all treatment formulations (antioxidants: OR, 0.35;
99% CI, 0.15-0.81 and OR, 0.56; 99% CI, 0.27-1.13, respectively; zinc: OR,
0.65; 99% CI, 0.28-1.50 and OR, 0.93; 99% CI, 0.46-1.89, respectively; antioxidants
plus zinc: OR, 0.53; 99% CI, 0.23-1.24 and OR, 0.72; 99% CI, 0.36-1.46, respectively).
The largest benefit was seen for the antioxidants arm but the differences
between treatments were not statistically significant.
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Table 7. Effect of Treatment on Risk of Loss of VA Score of 15
Letters From Baseline in AMD Category 4 Eyes With Advanced Neovascular AMD*
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Components of Advanced AMD
Analyses of the components of the AREDS definition of advanced AMD,
neovascular disease development and GA involving the center of the macula,
were performed on participants in Categories 3 and 4. Results are presented
in Table 8.
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