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Aspirin Use and Risk of Cataract in Posttrial Follow-up of Physicians' Health Study I
Arch Ophthalmol. 2001;119:405-412.
ABSTRACT
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Background In Physicians' Health Study I, randomized trial results indicated no
major beneficial effect of 5 years of low-dose aspirin treatment on total
cataract (relative risk [RR], 0.94; 95% confidence interval [CI], 0.79-1.13)
or cataract extraction (RR, 0.81; 95% CI, 0.65-1.01) during the period of
treatment.
Objective To examine the effect of assigned aspirin treatment and posttrial, self-selected
aspirin use on the risk of age-related cataract over the 15 years of follow-up
of Physicians' Health Study I.
Methods Participants were 20 968 US male physicians enrolled in Physicians'
Health Study I who did not report cataract at baseline. At 7 years, after
termination of the randomized aspirin component of the trial, self-selected
aspirin use was computed from annual questionnaires. The main outcome measures
were age-related cataract and extraction of age-related cataract, defined
as an incident, age-related lens opacity responsible for a reduction in best-corrected
visual acuity to 20/30 or worse based on self-report confirmed by medical
record review.
Results During a median of 14.9 years of follow-up, there were 2081 cataracts
and 1198 cataract extractions. Overall, the age- and beta carotene–adjusted
RR of cataract in men assigned to aspirin compared with those assigned to
placebo was 1.09 (95% CI, 1.00-1.18). For cataract extraction, the RR was
1.09 (95% CI, 0.98-1.22). During a median posttrial follow-up of 7.9 years,
a total of 1225 incident cataracts and 635 cataract extractions were documented.
The multivariate RR of cataract in men who reported using aspirin frequently
( 180 days per year) at 7 years compared with nonusers (0-13 days per year)
was 1.20 (95% CI, 1.03-1.40). For cataract extraction, the multivariate RR
was 1.22 (95% CI, 0.98-1.51). Results for diagnosis and extraction of cataract
subtypes were similar.
Conclusions Analyses based on randomized aspirin assignment indicated no long-term
benefit of 5 years of low-dose aspirin treatment on total cataract or cataract
extraction. Posttrial, observational data also indicated no decreased risk
of cataract in aspirin users and suggested a small increased risk of cataract
in aspirin users. Further randomized trial data to investigate the effect
of longer term treatment with low-dose aspirin are being collected as part
of the ongoing Women's Health Study, a randomized trial of low-dose aspirin
and vitamin E among 39 876 apparently healthy, postmenopausal US female
health professionals.
INTRODUCTION
A POSSIBLE ROLE for aspirin in reducing risks of cataract was first
suggested in studies of patients with arthritis or diabetes mellitus1-2 and in a study of patients undergoing
cataract surgery.3 Most subsequent observational
epidemiologic studies, however, have generally shown no association between
self-selected aspirin use and cataract.4-14
Results from 2 of 3 randomized trials that included an evaluation of the aspirin-cataract
hypothesis also indicate no apparent benefit of aspirin in reducing risks
of cataract. These trials include an investigation of 5139 British physicians
followed for an average of 6 years15 and a
study of 3711 participants in the Early Treatment Diabetic Retinopathy Study
followed for 5 to 7 years.16
In the third trial, comprising 21 000 participants in the Physicians'
Health Study I (PHS I), results excluded a large benefit of 5 years of low-dose
aspirin treatment on cataract development during the period of treatment but
could not rule out a modest benefit on cataract extraction.17-18
Subgroup analyses also indicated a modest protective effect of low-dose aspirin
on posterior subcapsular cataract, a particularly disabling subtype. Interpretation
of these results, however, is limited by the smaller than expected number
of cataract end points, a consequence of the early termination of the randomized
aspirin component of PHS I after 5 years of treatment and follow-up due primarily
to a statistically extreme benefit on the risk of a first myocardial infarction
(MI).19
In this article we present the results of posttrial follow-up for cataract
in PHS I. Specifically, we examine possible long-term effects of 5 years of
randomized aspirin treatment by extending the intention-to-treat analysis
to include cataracts and cataract extractions documented during 15 years of
follow-up. We also examine the relation of self-selection of aspirin use at
the end of the randomized aspirin component of the trial with the risk of
subsequent cataract and cataract extraction.
METHODS
STUDY POPULATION
A detailed description of the subjects and methods of PHS I has been
presented elsewhere.20-21 Briefly,
PHS I was a randomized, double-blind, placebo-controlled trial of aspirin,
325 mg (Bufferin, Bristol-Myers Products, New York, NY), and beta carotene,
50 mg (Lurotin, BASF Corp, Mt Olive, NJ), in reducing risks of cardiovascular
disease and cancer among 22 071 US male physicians aged 40 to 84 years
in 1982. Eligible participants had no history of MI, stroke, transient cerebral
ischemia, or cancer (except nonmelanoma skin cancer). Baseline information
included height, weight, history of cigarette smoking, history of alcohol
use, blood pressure, cholesterol levels, history of diabetes mellitus, history
of arthritis, and history of multivitamin use. Information on a personal history
of cataract was also obtained at baseline. Annual follow-up questionnaires
were sent to all participants asking about their compliance with assigned
treatment and the occurrence of any relevant events, including cataract.
On January 25, 1988, the aspirin component of PHS I was terminated early,
primarily because of a statistically extreme benefit on the risk of a first
MI.20 At that time, the average length of follow-up
was 60.2 months. The beta carotene component of the trial continued uninterrupted
until its scheduled completion on December 31, 1995. Since that date, study
participants have been followed as an observational cohort, and we have continued
to document all study end points, including cataract. In this report, we include
all incident cataracts and cataract extractions that were documented to have
occurred before December 2, 1997, with a median follow-up for cataract of
14.9 years (interquartile range, 14.1-15.1).
DEFINITION OF ASPIRIN USE
Randomized Comparisons
For the analysis of long-term effects of 5 years of aspirin treatment,
we used the initial aspirin and placebo groups as assigned by randomization
and compared the incidence of cataract over the 15-year follow-up period.
Observational Analyses
For the posttrial observational analyses, we compared the incidence
of cataract according to self-selected frequency of aspirin use following
the termination of the aspirin component of the trial on January 25, 1988.
After that date, all physicians were asked whether they preferred active aspirin
or placebo to be included in their calendar packs. Detailed information on
self-selected use of aspirin and other platelet-active drugs in the posttrial
period continued to be collected on annual follow-up questionnaires.
The primary exposure in these observational analyses was aspirin use
as reported on the 7-year follow-up questionnaire since all participants had
entered the posttrial period (past January 25, 1988) by this time. On this
questionnaire, participants were asked how many days they had taken the white
pills from their calendar packs over the past 12 months, with possible answer
categories of 0, 1-13, 14-30, 31-60, 61-90, 91-120, 121-180, and 180+ days.
Participants were also asked on how many days they had taken additional aspirin
or medication containing aspirin, not including the white pills in the calendar
packs, using the same response categories. Total aspirin use was estimated
from both the white pill and reported outside use. Categories were then collapsed
into 4 groups (0-13, 14-120, 121-179, and 180 days in the past year) and
2 groups (<180 vs 180 days in the past year) of aspirin use.
ASCERTAINMENT AND DEFINITION OF END POINTS
Following the report of a cataract diagnosis or extraction, a written
consent identifying the treating ophthalmologist or optometrist was obtained.
Ophthalmologists and optometrists were contacted by mail and requested to
complete a cataract questionnaire supplying information about the presence
of lens opacities, date of diagnosis, visual acuity loss, cataract extraction,
other ocular abnormalities that could explain visual acuity loss, cataract
type, and origin (including age-related, traumatic, congenital, inflammatory,
or surgery- or steroid-induced). Ophthalmologists and optometrists were given
the option to provide the requested information by supplying copies of the
relevant medical records. Medical records were obtained for more than 92%
of participants reporting cataract.
End points included incident cataract and extraction of incident cataract.
Cataract was defined as a self-report confirmed by medical record review to
be initially diagnosed after randomization, age-related in origin (congenital
cataracts and those due to trauma, steroids, intraocular inflammation, or
surgery were excluded), with best-corrected visual acuity of 20/30 or worse
and with no alternate ocular disease to explain the visual acuity loss. In
the presence of alternate ocular disease, a lens opacity was considered a
cataract if in the judgment of the ophthalmologist or optometrist the opacity
was of sufficient severity to reduce visual acuity to 20/30 or worse when
considered alone. Extraction was defined as the surgical removal of an incident
cataract. Three cataract subgroups were also defined; any nuclear sclerosis
(NS), any cortical opacity, and any posterior subcapsular component (PSC).
Information on cataract subtypes was available for 99.1% of confirmed cases.
DATA ANALYSIS
Randomized Comparisons
Analyses of the effect of 5 years of randomized aspirin treatment on
the occurrence of cataract over the entire 15-year follow-up period were based
on person-years from the time of randomization to the time of cataract or
December 2, 1997, whichever was earliest, in an intention-to-treat analysis.
These analyses included the 20 968 physicians who did not report a diagnosis
of cataract at baseline. Incidence rate ratios and 95% confidence intervals
(CIs) were calculated using Cox proportional hazards models that adjusted
for age (years) and beta carotene treatment assignment.22
Analyses were also conducted that examined the occurrence of cataract in consecutive
2-year periods. An interaction term with length of follow-up was used to test
for a trend of the rate ratio over time and to evaluate the adequacy of the
proportional hazards assumption over time. Data were analyzed separately for
cataract diagnoses, extractions, and subtypes.
Observational Analyses
We used an observational analysis to compare the occurrence of cataract
with frequency and duration of aspirin use in 19 228 physicians who were
alive and free of a confirmed diagnosis of cataract at the time of the year-7
questionnaire. Self-selected aspirin use between year 6 and year 7, as reported
on the year-7 questionnaire (described in the "Observational Analyses" section
in the "Definition of Aspirin Use" section), was considered the primary exposure
variable. Cataract end points accrued from follow-up year 7 through December
2, 1997, a median follow-up of 7.9 years (interquartile range, 7.5-8.1 years).
To assess the effect of the duration of aspirin use, participants were further
grouped according to whether they had been randomly assigned to receive aspirin
in the previous 5 years. Aspirin use after the year-7 questionnaire was not
considered.
The Mantel Haenszel  2 trend test and linear regression
were used to assess the association of participant characteristics with ordered
categories of self-selected aspirin use at 84 months. Cox proportional hazards
models were used to calculate the relative risk (RR) of cataract and 95% CIs
while adjusting for age (years); smoking (never, past, current); alcohol use
(daily, weekly, monthly, rarely); history of diabetes; history of hypertension
(systolic blood pressure of 160 mm Hg or greater, diastolic blood pressure
of 95 mm Hg or greater, or history of treatment for high blood pressure);
history of high cholesterol levels (reported high cholesterol, reported blood
cholesterol levels of 6.72 mmol/L [260 mg/dL] or higher, or history of treatment
with cholesterol-lowering medication); history for arthritis, obesity (body
mass index [calculated as weight in kilograms divided by the square of height
in meters] of 27.8 or higher), and physical activity (reported vigorous exercise
once per week or more); and parental history of MI. All of these variables
were assessed at the 7-year follow-up except obesity and parental history
of MI, which were assessed at baseline. We also adjusted for cardiovascular
end points (MI, ischemic stroke, hemorrhagic stroke, transient cerebral ischemia,
coronary revascularization, and angina) that were documented to have occurred
prior to the 7-year follow-up. Interaction terms were used to test for possible
interaction of randomized aspirin assignment and posttrial aspirin use in
Cox regression models.
In all analyses, for each RR, we calculated the 2-sided P value and 95% CI.23 Individuals, rather
than eyes, were the unit of analysis because eyes were not examined independently,
and participants were classified according to the status of the worse eye
as defined by the occurrence of cataract surgery or, in the absence of cataract
surgery, by an earlier date of diagnosis. When the 2 eyes had the same date
of diagnosis, the eye with the worse visual acuity at the most recent eye
examination was designated the worse eye. When the worse eye was excluded
because of visual acuity loss attributed to other ocular abnormalities or
a cause that was not age-related, the fellow eye was considered for classification.
RESULTS
RANDOMIZED ASPIRIN ASSIGNMENT AND RISK OF CATARACT: RESULTS OF EXTENDED
FOLLOW-UP
The baseline characteristics of the aspirin and placebo treatment groups
were virtually identical (Table 1).
To examine the long-term effects of 5 years of randomized aspirin treatment,
we extended the intention-to-treat analysis to include all cataracts and cataract
extractions documented during the 15 years of extended follow-up. During this
period, 2081 cataracts and 1198 cataract extractions were documented.
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Table 1. Comparison of Baseline Characteristics of Physicians According
to Randomly Assigned Aspirin Treatment*
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There were 1084 cataracts in the aspirin group and 997 in the placebo
group. The overall RR of cataract, comparing men assigned to aspirin with
those assigned to placebo, was 1.09 (95%CI, 1.00-1.18). For cataract extraction,
627 were documented in the aspirin group and 571 in the placebo group. The
RR comparing the aspirin and placebo groups was 1.09 (95% CI, 0.98-1.22).
Figure 1 shows the number
of cataracts (Figure 1A) and cataract
extractions (Figure 1B) in the aspirin
and placebo groups, and the RRs and 95% CIs for random assignment to aspirin
in consecutive 2-year periods and over the total follow-up period. For both
cataract and cataract extraction, the 2-year RRs show no clear trend over
time and, except for one interval for cataract extraction, their CIs always
include 1. Thus, there was no evidence of a long-term benefit of 5 years of
aspirin treatment on total cataract or cataract extraction.
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Number of cataracts (A) and cataract extractions (B) in the aspirin
and placebo groups, and the relative risks (RRs) and 95% confidence intervals
(CIs) for random assignment to aspirin in consecutive 2-year periods and over
the total follow-up period.
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Results for specific subtypes also indicated no long-term benefit of
5 years of aspirin treatment. Among the 2081 confirmed cataracts, 1836 (88.2%)
had NS, 844 (40.6%) had a PSC, and 781 (37.5%) had a cortical opacity. The
RRs for the diagnosis of subtypes, comparing the aspirin and placebo groups,
were NS, 1.11 (95% CI, 1.01-1.21); PSC, 1.03 (95% CI, 0.90-1.18); and cortical
opacity, 1.10 (95% CI, 0.96-1.27). The RRs for extraction of subtypes were
NS, 1.10 (95% CI, 0.98-1.24) (n = 1076); PSC, 1.04 (95% CI, 0.89-1.22) (n
= 623); and cortical opacity, 1.27 (95% CI, 1.06-1.52) (n = 471). The patterns
of RRs over time for diagnosis and extraction of subtypes (data not shown)
were broadly similar to those for total cataract and total cataract extraction,
and none of the trends over time were statistically significant.
SELF-REPORTED POSTTRIAL ASPIRIN USE AND SUBSEQUENT CATARACT AND CATARACT
EXTRACTION
After the end of the aspirin component of the randomized trial, 72%
of participants chose to take aspirin more than 120 days per year, and 61%
reported taking aspirin at least 180 days per year (66% of those who had been
randomized to the aspirin group reported taking aspirin 180 days per year
compared with 55% of those who had been randomized to the placebo group).
Men who reported more frequent use of aspirin were slightly older and were
more likely to have been randomly assigned to aspirin (Table 2). They also reported more alcohol use, hypertension, high
cholesterol levels, multivitamin use, and physical activity. They were also
more likely to report a family and personal history of MI, coronary bypass
surgery, and angina. Frequent users of aspirin were less likely to report
a history of hemorrhagic stroke and history of arthritis.
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Table 2. Correlates of Self-Selected Aspirin Use at 7-Year Follow-up
Among Subjects With No Confirmed Cataract Diagnosis*
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Following the completion of the aspirin arm of the study, 1225 incident
cataracts and 635 cataract extractions were documented during a median follow-up
of 7.9 years. Men who reported use of aspirin for at least 180 days per year
compared with nonusers (0-13 days per year) had a statistically significant
20% increased risk of total cataract after adjustment for age and beta carotene
treatment assignment (Table 3).
Risks were not increased for men in the 2 intermediate groups of aspirin use.
Regarding subtypes, men who reported using aspirin at least 180 days per year
when compared with nonusers had significantly increased risks of NS (RR, 1.22;
95% CI, 1.04-1.43), PSC (RR, 1.33; 95% CI, 1.04-1.70), and cortical opacity
(RR, 1.61; 95% CI, 1.23-2.11) after adjustment for age and beta carotene treatment
assignment. These estimates changed little after further adjustment for other
cataract risk factors.
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Table 3. Self-Selected Aspirin Use at 7 Years and Subsequent Diagnosis
of Cataract and Subtypes*
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For total cataract extraction, men in the 3 higher categories of aspirin
use had nonsignificant 10% to 20% increased risks of cataract extraction after
adjustment for age and beta carotene treatment assignment (Table 4). The test of linear trend over categories of aspirin use
also failed to attain significance (P = .08). In
analysis of subtypes, men in the 3 higher categories of aspirin use had an
approximate 2-fold increased risk of extraction of cortical cataract compared
with nonusers. Adjustment for other possible risk factors for cataract had
no material impact on these RR estimates.
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Table 4. Self-Selected Aspirin Use at 7 Years and Subsequent Cataract
Surgery*
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To examine the effect of duration of aspirin use, we repeated these
observational analyses stratifying on randomized aspirin treatment assignment
in the years before the self-selected use. A 2-level variable for self-selected
aspirin use in the posttrial period (180 vs <180 days per year) was
used to conserve statistical power. As given in Table 5 and Table 6,
RRs for total cataract and total cataract extraction during the posttrial
period were generally higher among those who had been randomly assigned to
the aspirin group vs the placebo group. This pattern was observed for both
total cataract and cataract extraction, as well as for specific subtypes.
However, none of the interactions of randomized aspirin assignment and posttrial
aspirin use attained statistical significance.
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Table 5. Multivariate* RR of Cataract and Cataract Subtypes After the
Randomized Aspirin Component of Physicians' Health Study I According to Self-Selected
Aspirin Use and Previous Random Assignment to Aspirin
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Table 6. Multivariate* RR of Cataract Surgery After the Randomized
Aspirin Component of Physicians' Health Study I According to Self-Selected
Aspirin Use and Previous Random Assignment to Aspirin
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COMMENT
The previously published final results for the randomized aspirin component
of PHS I, based on 501 cases of cataract diagnosed during the 5-year treatment
period, indicated that 5 years of low-dose aspirin therapy was unlikely to
have a major benefit on total cataract (RR, 0.94; 95% CI, 0.79-1.13) during
the period of treatment.18 The data were consistent,
however, with a modest reduction in the risk of cataract extraction (RR, 0.81;
95% CI, 0.65-1.01), as well as a possible beneficial effect of aspirin on
the PSC subtype (RR, 0.74; 95% CI, 0.57-0.98). In the present report, we examined
a possible delayed effect of aspirin treatment by extending the intention-to-treat
analysis to include all 2081 cases of cataract and 1198 cataract extractions
documented during the 15 years of extended follow-up. We found evidence neither
for a long-term benefit of 5 years of low-dose aspirin treatment on total
cataract or cataract extraction nor for a beneficial effect on any of the
cataract subtypes, including posterior subcapsular cataract. Our observational
analyses of posttrial, self-selected aspirin use also failed to indicate a
decreased risk of cataract in aspirin users and suggested a possible increased
risk for aspirin users. Together with the results of completed trials, these
data indicate that low-dose aspirin treatment for up to 6 years is unlikely
to alter materially the risk of cataract during the period of treatment or
in the years following this duration of aspirin treatment.
Several possible limitations of this study need to be considered. Random
misclassification of the cataract end point was reduced by the use of medical
records to confirm the self-reports and by the use of strict diagnostic criteria
that included reduction in best-corrected visual acuity to 20/30 or worse
due to cataract. Nonrandom misclassification was unlikely in the randomized
comparisons since medical records were reviewed without knowledge of aspirin
treatment assignment, and study participants and treating ophthalmologists
and optometrists were unaware of aspirin treatment assignment. In the observational
analyses, however, nonrandom misclassification would have occurred if knowledge
of the participant's self-selected aspirin use influenced a treating physician's
likelihood of diagnosing cataract or, more plausibly, if aspirin users had
more medical contacts, and thus were more likely to have an existing cataract
diagnosed. Finally, confounding is unlikely in the randomized comparisons
since, as expected, baseline characteristics were equally distributed between
the aspirin and placebo groups (Table 1). In the observational analyses, men who elected to use aspirin
differed in several respects from nonusers of aspirin (Table 2). Although we did control for a number of measured confounders,
other potential confounders that were either unmeasured or unknown may have
contributed to the findings of the observational analyses.
Our study is the first to examine the possible long-term effects of
randomized aspirin treatment on cataract. The totality of evidence from 3
completed randomized trials that evaluated the aspirin-cataract hypothesis
clearly show no major beneficial effect of 5 to 6 years of aspirin therapy
over a range of doses during the period of treatment. In addition to PHS I,17-18 these trials include a study of 5139
British physicians who were allocated to 500 mg of aspirin daily or placebo
and followed for an average of 6 years15 and
a study of 3711 diabetic patients who were assigned to 650 mg of aspirin daily
or placebo and followed for an average of 5 years.16
The present report extends our previous findings from PHS I by showing that
5 years of randomized aspirin therapy has no beneficial effect on the rate
of cataract development during the posttrial period. Whether longer duration
aspirin treatment can materially reduce risks of cataract during and following
the period of treatment remains unknown. Age-related cataract develops slowly
as a result of accumulated biochemical and biophysical damage in the lens
over a number of years,24 and the average length
of treatment of 5 to 6 years in these trials may have been insufficient to
materially reduce risks of cataract.
The results of posttrial, observational analyses of self-selected aspirin
use in PHS I suggest a small increased risk of cataract for those who use
aspirin regularly. These findings contrast somewhat with the trial results
for PHS I, which ruled out a large benefit but were consistent with a possible
small decreased risk of cataract extraction and the PSC subtype among those
assigned to aspirin. Reasons for the apparently discrepant findings are unclear.
In the observational analyses, adjustment for a range of cataract risk factors
had little impact on RR estimates, suggesting that residual confounding is
unlikely to explain the excess risk. However, unmeasured and therefore uncontrolled
confounding (eg, steroid use), as well as confounding by indication may have
contributed to the findings. It is also possible that the apparent excess
risk in the observational analyses is due, at least in part, to surveillance
bias. Those who chose to use aspirin regularly tended to be older and to report
more hypertension, elevated cholesterol levels, personal history of coronary
artery disease, and parental history of MI. These men may also have had more
medical contacts (we have no information on the number of medical contacts
for study participants) and may therefore have been more likely to have an
existing cataract detected. None of these possibilities, however, can explain
the finding that RRs associated with self-selected aspirin use in the posttrial
period were generally higher for those randomized to aspirin during the treatment
period (Table 5 and Table 6). If real, this finding would suggest a deleterious effect
of long-term aspirin treatment on risk of cataract. Finally, it is possible
that the small excess risk observed in the observational analyses and the
modest but nonsignificant beneficial effect found for aspirin during the randomized
treatment period17-18 are simply
a result of chance.
Experimental evidence supports a possible protective effect of aspirin
against cataract. Plausible mechanisms include acetylation of lens proteins
and inhibition of glycation,25-27
improved glucose tolerance,28-30
and an indirect antioxidant effect.31 To the
best of our knowledge, however, there is no experimental evidence of a mechanism
through which aspirin might accelerate the rate of cataract development.
In summary, these results from a large cohort of US male physicians
indicate that 5 years of low-dose aspirin treatment has no long-term beneficial
effect on risks of cataract over an extended follow-up period of 15 years.
If aspirin therapy is capable of reducing risks of cataract, it seems that
a duration of treatment in excess of the 5 to 6 years tested in completed
trials will be required before a beneficial effect can emerge. Toward this
end, important new data to address this and other vision-related hypotheses
are being collected as part of the ongoing Women's Health Study, a randomized,
double-blind, placebo-controlled trial of aspirin and vitamin E in the prevention
of cancer and cardiovascular disease, conducted among 39 876 apparently
healthy, postmenopausal US female health professionals.
AUTHOR INFORMATION
Accepted for publication July 26, 2000.
Corresponding author and reprints: William G. Christen, ScD, 900
Commonwealth Ave E, Boston, MA 02215-1204.
William G. Christen, ScD;
Umed A. Ajani, MBBS;
Debra A. Schaumberg, ScD;
Robert J. Glynn, ScD;
JoAnn E. Manson, MD;
Charles H. Hennekens, MD
From the Division of Preventive Medicine (Drs Christen, Ajani, Schaumberg,
Glynn, and Manson) and Channing Laboratory (Dr Manson), Department of Medicine,
Harvard Medical School and Brigham and Women's Hospital, Boston, Mass, and
the Departments of Biostatistics (Dr Glynn) and Epidemiology (Dr Manson),
Harvard School of Public Health, Boston. Dr Hennekens is now with the University
of Miami School of Medicine, Miami, Fla.
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