EXTENDED REPORT

The Antioxidants in Prevention of Cataracts Study: effects of

antioxidant supplements on cataract progression in South
India
D C Gritz, M Srinivasan, S D Smith, U Kim, T M Lietman, J H Wilkins, B Priyadharshini, R K John,
S Aravind, N V Prajna, R Duraisami Thulasiraj, J P Whitcher
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
See end of article for
authors affiliations
. . . . . . . . . . . . . . . . . . . . . . .
Correspondence to:
David C Gritz, MD, MPH,
280 W MacArthur Blvd,
Oakland, CA 94611,
USA; david.gritz@yahoo.
com
Accepted for publication
5 March 2006
. . . . . . . . . . . . . . . . . . . . . . .
Br J Ophthalmol 2006;90:847851. doi: 10.1136/bjo.2005.088104
Aim: To determine if antioxidant supplements (b carotene and vitamins C and E) can decrease the
progression of cataract in rural South India.
Methods: The Antioxidants in Prevention of Cataracts (APC) Study was a 5 year, randomised, triple
masked, placebo controlled, field based clinical trial to assess the ability of interventional antioxidant
supplements to slow cataract progression. The primary outcome variable was change in nuclear
opalescence over time. Secondary outcome variables were cortical and posterior subcapsular opacities
and nuclear colour changes; best corrected visual acuity change; myopic shift; and failure of treatment.
Annual examinations were performed for each subject by three examiners, in a masked fashion.
Multivariate modelling using a general estimating equation was used for analysis of results, correcting for
multiple measurements over time.
Results: Initial enrolment was 798 subjects. Treatment groups were comparable at baseline. There was
high compliance with follow up and study medications. There was progression in cataracts. There was no
significant difference between placebo and active treatment groups for either the primary or secondary
outcome variables.
Conclusion: Antioxidant supplementation with b carotene, vitamins C and E did not affect cataract
progression in a population with a high prevalence of cataract whose diet is generally deficient in
antioxidants.
T
he most common cause of blindness worldwide is
unoperated cataracts. There is a disproportionate impact
on blindness in the developing world, and access to
quality cataract surgery has a strong role in the growing
backlog of unoperated cataracts and increasing numbers of
blind patients.
15
In India, there may be earlier development
and more rapid progression of cataracts than in other
regions.
68
Despite efforts to increase availability of high
quality surgery with acceptable visual outcomes, there is still
a growing backlog of patients who are blind from cataracts. If
a practical, large scale intervention could slow the onset of
cataract by 10 years, the need for cataract surgery would be
decreased by 45%.
9
This would have a profound effect on the
increasing backlog of patients who cannot be reached by
surgery given the available resources.
A significant body of epidemiological evidence has been
published regarding the potential role of antioxidants in the
prevention of cataract.
7 1045
Although the majority of epide-
miological studies have shown a positive correlation between
higher dietary antioxidant intake and decreased cataract
formation,
7 1127
conflicting conclusions exist.
3643
Also, as
studies on b carotene and lung cancer have shown,
epidemiological evidence does not guarantee positive find-
ings in interventional studies.
4649
This is a report of the
results of the Antioxidants in Prevention of Cataract (APC)
Study, an interventional trial conducted in south India. The
APC study is the first prospective interventional trial for
cataract prevention to take place in a developing country and
includes baseline cataract evaluation.
MATERI ALS AND METHODS
The APC study was a prospective, randomised, placebo
control, triple masked, community based clinical trial to
assess whether antioxidant supplements (b carotene and
vitamins C and E) could slow the rate of cataract progression
in south India. (A triple masked trial is when, in addition to
the subjects and investigators being masked to the treatment
groups, the biostatistician is also masked the treatment
groups until analysis has been completed.) The study was
based in five villages surrounding Madurai, Tamil Nadu,
India, and was a collaborative project between the Aravind
Eye Hospital in Madurai, India, and the Francis I Proctor
Foundation for Research, in San Francisco, California. All of
the investigations planned are in accordance with the
guidelines of the Declaration of Helsinki. The study protocol
was approved by the committee on human research at the
University of California, San Francisco and the internal
research board and ethics committee at the Aravind Eye
Hospital. The methodology and baseline characteristics of the
APC study have been described elsewhere in more detail.
50
The study objective was to determine if antioxidant
supplementation can slow the rate of cataract progression.
All outcome variables compared the treatment and placebo
groups. The primary outcome variable was mean change in
nuclear opalescence over time, clinically graded at the slit
lamp, using the Lens Opacification Classification System III
(LOCS III). Secondary outcome variables were nuclear colour
and cortical and posterior subcapsular opacities as clinically
judged using the LOCS III, best corrected spectacle visual
acuity, and failure of treatment. Failure of treatment was
Abbreviations: APC, antioxidants in prevention of cataract; BCVA, best
corrected visual acuity; EDTRS, Early Treatment of Diabetic Retinopathy
Study; GEE, general estimating equation; LOCS, Lens Opacification
Classification System; RCT, randomised controlled trial; SES,
socioeconomic status
847
www.bjophthalmol.com
defined as cataract necessitating surgery, or best corrected
visual acuity of 20/400 or worse.
Inclusion criteria were aged 3550 years and best corrected
visual acuity (BCVA) of 20/40 or better in both eyes and no
history of diabetes mellitus, intraocular surgery, radiation
therapy, corticosteroid therapy, or active use of vitamin
supplements. The relatively young age was included because
of the early progression of cataracts in south India, previously
reported by others and observed in this studys pilot
study.
6 51 52
Visual acuity was evaluated using the National
Eye Institute Early Treatment of Diabetic Retinopathy Study
logMAR (EDTRS) chart, using standard ETDRS methology.
50
On eye examination, no evidence of significant traumatic or
congenital cataract, active infectious keratitis, nor narrow
anterior chamber angle could be present. A potential subjects
random blood glucose testing could not be greater than
140 mg/100 dl.
Informed consent was obtained in the native language,
Tamil. There was no monetary compensation for participa-
tion. Benefits of participation included free eye and medical
care.
A field worker witnessed administration of active
and identical appearing placebo tablets three times weekly.
A single dose of active study medication contained vitamin
C, 500 mg; vitamin A (b carotene from commercially
grown algae in the all trans form with small amounts of
other carotenoids like lycopene), 25 000 IU (15 mg);
vitamin E (RRR-a-tocopherol from soya oil with small
amounts of other tocopherols), 400 IU. All tablets were
manufactured by Vitaline Corporation, Ashland, Oregon,
USA.
Slit lamp biomicroscopy was performed following dilata-
tion. Each cataract was graded on nuclear colour and
opalescence, cortical opacity, and posterior subcapsular
opacity, in 0.1 units, with the grader referring to the LOCS
III standard transparency as needed. Three ophthalmologists
each graded cataracts in both eyes of all patients, masked to
the other observers scores. Two teams of three ophthalmol-
ogists graded the same subjects over the course of the study.
Alternative ophthalmologist examiners were trained and
available if needed, however the alternatives were not
utilised.
Following enrolment, additional data were collected on
socioeconomic status (SES), education, and history of
exposure to tobacco, alcohol, sunlight, and cooking fuel
smoke. A culturally sensitive food frequency questionnaire
was administered three times during the course of the first
year of the study to evaluate the diet.
St at i sti cal anal ysi s
Statistical comparison of baseline characteristics between
treatment groups was made using a two sided t test for
continuous variables.
Analysis of the longitudinal data on LOCS III cataract
grades was done by multivariate statistical modelling using a
generalised estimating equation (GEE). The model used
accounted for time related correlations in the data, allowing
multiple measurements over time from the same individual.
Analyses were conducted for right and left eyes separately.
Analysis of the treatment effect included adjustment for
cofactors independently associated with cataract progression.
Potential cofactors were evaluated using multivariate analy-
sis and a cut off for inclusion in the treatment effect analysis
was a p value of ,0.05. These analyses were performed for
the primary and secondary outcome LOCS III scores for the
right and left eyes over time.
Analysis of change in logMAR visual acuity score was
undertaken by comparing final to initial acuity. A statistical
model accounting for correlation between eyes within an
individual was used, permitting analysis of both eyes of all
subjects within one statistical model.
Differences in the rate of cataract surgery between
treatment groups were evaluated by univariate analysis.
RESULTS
Details on the baseline characteristics have been described in
a separate publication.
50
A brief overview follows.
There were 4007 eligible subjects living in five main target
villages; 954 subjects were screened for the study. Of those,
798 subjects were enrolled. Best corrected visual acuity worse
than 20/40 was the most common factor leading to exclusion.
There were no statistically significant differences in base-
line prevalence of potential cataract risk factors between the
study groups. The baseline LOCS III scores for all cataract
subtypes were comparable between the two groups. At
baseline, slightly more than 73% of eyes had significant
nuclear opalescence and almost 59% of eyes had significant
nuclear colour changes (defined as a grade of >2.0 on the
LOCS III scale). Significant cataract, as per LOCS III
definitions, of at least one of the cataract category was
present in at least one eye of 79% of the subjects. Despite the
degree of cataract present, 84.2% of right eyes had acuity of
20/20 or better and a similar condition existed in left eyes.
Over 84% of all eyes were within 1 dioptre of emmetropia. A
detailed report of the baseline characteristics has been
reported elsewhere.
50
Table 1 Mean change per year in different LOCS III categories for all right eyes involved in the study, along with the
associated p values. Left eye results were similar
LOCS III category Age group*
LOCS III score
mean change per
year placebo group
LOCS III score
mean change per
year vitamin group
Difference in slope
between groups (95% CI) p Value
Nuclear opalescence 3539 0.057 0.048 20.009 (20.022 to 0.005) 0.20
4044 0.086 0.086 0.000 (20.023 to 0.022) 0.93
4550 0.101 0.131 0.031 (0.007 to 0.055) 0.01
Nuclear colour 3539 0.07 0.063 20.007 (20.019 to 0.005) 0.26
4044 0.089 0.083 20.006 (20.029 to 0.014) 0.49
4550 0.107 0.125 0.018 (20.004 to 0.042) 0.12
Cortical cataract 3539 0.026 0.025 20.001 (20.001 to 0.016) 0.92
4044 0.047 0.033 20.014 (20.036 to 0.010) 0.27
4550 0.078 0.07 20.008 (20.037 to 0.021) 0.57
Posterior subcapsular
cataract
3539 0.006 0.004 20.002 (20.012 to 0.008) 0.68
4044 0.019 0.024 0.005 (20.021 to 0.031) 0.70
4550 0.029 0.011 20.018 (20.043 to 0.023) 0.08
*Age refers to the age at enrolment.
848 Gritz, Srinivasan, Smith, et al
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Compliance with the study medication was excellent with
90.1% of subjects receiving >95% of the intended doses and
an additional 6.1% of subjects receiving between 90% to
,95% of their intended doses. Only 0.8% of subjects received
,85% of intended tablets. There were no differences in
compliance based on sex (p =0.55) or age (p =0.71) of
subjects.
Risk factors associated with more rapid cataract progres-
sion included age, sex, sun exposure, random blood glucose
over 140 mg/dl during the course of the study, and body mass
index. Further details on these associations are the subject of
a future paper.
There were no differences in cataract progression between
treatment groups for the primary or any secondary outcome
variables. Because there were differences in cataract progres-
sion according to age, the amount of progression was
stratified by age at enrolment in table 1.
Table 1 lists the details of the amount of progression in
cataract over time for the primary and secondary LOCS III
outcome variables. Some p values were less than 0.05, with
the placebo group having less progression compared to the
treatment group. The absence of a consistent trend suggests
that no treatment effect was present. When p was less than
0.05, the differences between the groups in rate of cataract
change was small and not clinically significant. Occasional
small p values were likely by chance because of multiple
statistical comparisons. No significance was observed for any
category when all age groups were combined. The 95%
confidence intervals for the amount of change per year
between the two groups demonstrated that very small
degrees of change in cataract could have been detected
within the conditions of the study methodology and
execution.
There were no differences in the change in visual acuity
between the two groups (p =0.8). The BCVA of the placebo
group was a mean of 1.66 letters less (SD 4.96) at year 5
compared to baseline, while the BCVA of the treatment group
was a mean of 21.64 letters less (SD 4.74) at year 5 compared
to baseline.
There was no difference in the myopic shift observed
between the two groups. Table 2 shows the mean myopic
shift data.
DI SCUSSI ON
The incidence of cataract in the developing world far
surpasses the cataract surgical rate.
53
Cataract incidence will
increase as the worlds population ages. The ability to meet
the need for quality surgery will probably diminish
further.
54 55
Even if innovative ways of providing quality
surgery to large populations can be developed, there will
probably be a significant increase in cataract blindness.
Finding preventive methods to delay the onset of cataract can
help to narrow the gap between the incidence of cataract
blindness and our ability to provide surgical treatment. The
developing world has a disproportionate degree of cataract
blindness. This results in a huge economic burden and loss of
productivity.
56
Thus, the development of a strategy for
cataract prevention could have a great impact.
Epidemiological evidence indicates a possible role for
antioxidants in the prevention of cataract. However, con-
flicting results exist between different epidemiological
studies. Epidemiological study findings also do not necessa-
rily equate with interventional measures.
At present, several studies have examined interventional
cataract prevention. The majority, all in urban populations in
developed countries, had negative results.
3235 45 57 58
Despite
the five trials with negative results, three trials had some
potentially positive findings. Sperduto and associates exam-
ined patients at the end of two clinical trials in China. The
Lixian studies showed a positive effect on nuclear cataract for
two interventions, one with a combined multivitamin and
mineral supplement and another trial with a riboflavin and
niacin supplement.
44
Chylack and associates performed a
multicentre study in the United States and the United
Kingdom.
58
They observed a decrease in cataract progression
with antioxidant supplements, particularly in patients from
the United States, however, there was a large loss to follow
up. Christen and associates found a positive effect of
antioxidants on cataract in male physicians who were
smokers at the onset of the 12 year clinical trial, but the
effect did not hold for physicians who continued to smoke at
the conclusion of the study.
33
Subgroup analysis and multiple
analyses cast doubt on whether there is a real effect of the
intervention in this study.
The interventional studies performed to date demonstrate
an apparent disconnect between epidemiological data and
interventional studies. There are several possible reasons for
this. Given the inconsistencies in the epidemiological data, it
may be that dietary antioxidants, taken through fruits and
vegetables, actually do not influence cataract progression as
previously thought. The tendency for studies with positive
findings to be published could potentially bias our body of
knowledge. It is possible that the epidemiological data reflect
a global effect of lifestyle that coincides with the dietary
intake of antioxidants. It is also possible that substances
within the food, other than b carotene and vitamin C and E,
are responsible for decreasing cataract formation. Since this
and other trials have been performed, the potential positive
effect of other caratenoids, such as lutein and lycopene, have
been the subject of epidemiological and laboratory studies.
The intervention doses of antioxidant vitamins being given
in the APC study exceeded the US recommended minimum
daily allowance of 5000 IU for vitamin A, 60 mg for vitamin
C, and 30 IU for vitamin E. The US recommended minimum
daily allowance, however, is based on the minimal dose
required to avoid vitamin deficiency diseases. The optimal
dose of vitamins for maximum health has not been
established. The doses of vitamins being given in this study
are considered very safe.
5962
Much lower doses of b carotene
were used in this study compared to trials of b carotene and
lung cancer.
4649
In the lung cancer trials, the doses given were
3.1 (140 mg/week),
47
3.9 (350 mg/2 weeks),
48 49
and 4.7
Table 2 Mean spherical equivalent refractive error in the treatment and placebo groups over time
Treatment
group
Mean spherical equivalent (95% CI)
Baseline Year 1 Year 2 Year 3 Year 4 Year 5
Placebo group 20.13
(20.19 to 20.06)
20.22
(20.29 to 20.14)
20.29
(20.37 to 20.21)
20.21
(20.29 to 20.14)
20.31
(20.40 to 20.21)
20.26
(20.35 to 20.18)
Vitamin group 20.07
(20.12 to 20.03)
20.17
(20.21 to 20.11)
20.16
(20.23 to 20.11)
20.13
(20.19 to 20.08)
20.17
(20.24 to 20.09)
20.52
(20.34 to 20.18)
Patients were excluded from this table if they were pseudophakic.) There were no significant differences between the two groups
Nine subjects reached the failure of treatment end point, three in the placebo group and six in the antioxidant group (p=0.51).
Antioxidants in prevention of cataract 849
www.bjophthalmol.com
(210 mg/week)
46
times higher than those being given in this
study.
The present study demonstrated no effect of the anti-
oxidants b carotene and vitamins E and C on cataract
progression. Negative results of well performed studies are
important. When assessing a study with negative findings it
is important to examine the methodology.
Did this study provide adequate power to show a difference
and avoid a b type error (missing a positive finding because it
was underpowered)? The initial enrolment was 143% of the
original sample size estimate for a 3 year study.
52
An interim
analysis after 3 years resulted in the study being extended an
additional 2 years. Given the results, the model used in this
study worked very well and could have detected small
differences between the study groups. The 95% confidence
intervals show that for all categories of cataract change, a
difference between the groups in the range of only 0.05 LOCS
III units would have been detected as statistically signifi-
cant, if the definition for significance were set at a p value of
0.05. Given the number of calculations performed and the
interim analysis, that common arbitrary cut off of statistical
significance would likely not be applicable. More importantly
clinical significance would probably not hinge on a p value
of 0.05 for a single analysis in this study.
The APC study is the first prospective, randomised, double
masked, placebo controlled clinical trial performed specifi-
cally to assess the effect of antioxidant vitamins on cataract
progression and performed in a developing country. The
findings of this study, while negative, are important because
previously it was not known whether intervention with
vitamin C, E, and A supplements could decrease cataract
formation in this setting. The fact that this study was
negative in a population that may have been most likely to
benefit from intervention (one in which the dietary anti-
oxidant intake is low) should put to rest thoughts that b
carotene and vitamins C and E, in isolation, can influence
cataract progression. The model used to test this intervention
was robust and could be applied to other interventions to
assess cataract prevention. This study also demonstrates that
a long term clinical trial performed in rural south India can
have excellent follow up and robust data and results.
ACKNOWLEDGEMENTS
We gratefully acknowledge support from the Francis I Proctor
Foundations South Asia Research Fund; Aravind Eye Hospital and
Postgraduate Institute of Ophthalmology, Madurai, India; Lions
Aravind Institute of Community Ophthalmology, Madurai, India; the
Peierls Foundation; the Jack and DeLoris Lange Foundation; the
Harper-Inglis Trust; and generous donations to the Proctor
Foundation from individual patients.
We gratefully acknowledge the following members of the Data and
Safety Monitoring Committee: Perumalsamy Namperumalsamy, MD,
Aravind Eye Hospital, Madurai, Tamil Nadu, India; KV Santha, MD,
Aravind Eye Hospital, Madurai, Tamil Nadu, India; Stephen D
McLeod, MD, Francis I Proctor Foundation for Research in
Ophthalmology and the Department of Ophthalmology, University
of California, San Francisco, San Francisco, CA, USA; Paul S Lietman,
MD, PhD, Department of Medicine, Pharmacology, Molecular
Science, and Pediatrics, Johns Hopkins University, Baltimore, MD,
USA; and Sivakumar Rathinam, MD, Aravind Eye Hospital, Madurai,
Tamil Nadu, India.
Authors affiliations
. . . . . . . . . . . . . . . . . . . . .
D C Gritz, T M Lietman, J P Whitcher, Francis I Proctor Foundation for
Research in Ophthalmology and the Department of Ophthalmology,
University of California San Francisco, San Francisco, CA, USA
D C Gritz, The Permanente Medical Group, Oakland and Richmond
Kaiser Permanente Medical Centers and Department of Research,
Oakland, CA, USA
M Srinivasan, U Kim, S Aravind, N V Prajna, R D Thulasiraj, Aravind
Eye Hospital, Madurai, Tamil Nadu, India
S D Smith, Cole Eye Institute, The Cleveland Clinic Foundation,
Cleveland, OH, USA
J H Wilkins, Casey Eye Institute, Oregon Health Sciences University and
the Lions Eye Bank of Oregon, Portland, OR, USA
B Priyadharshini, Orbis International, New Dehli, India
R K John, Delve Data Systems, Coimbatore, India
Conflicts of interest: none.
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