Low-Dose Aspirin and Risks of Cataract in a Randomized Trial of US Physicians Johanna M. Seddon, MD; William G. Christen, PhD; JoAnn E. Manson, MD; Julie E. Buring, DSc; Robert D. Sperduto, MD; Charles H. Hennekens, MD \s=b\ Observational
studies have raised
question of a possible benefit of aspirin on the development of cataract. The Physicians' Health Study, a randomized double-masked placebo-controlled trial among 22 071 male physicians, aged 40 to 84 years, provided the opportunity the
to collect information about whether low\x=req-\ dose aspirin therapy (325 mg on alternate days) affects the development or extraction of cataract. There were 173 age-related cataracts among those physicians assigned to aspirin therapy and 180 among those given placebo (relative
^ ataract is
cause of im¬ and blindness world¬ wide.1 In the United States, approxi¬ mately 3.3 million people have visual impairment and at least 43 000 are legally blind from cataracts, most of which are age-related.2 Cataract sur¬ gery is now the most frequently per¬ formed operation in persons older than 60 years in the United States, with more than 1 million cataract operations
were less in the aspirin than in the placebo group, but this difference was not
frequent
statistically significant (relative risk, 0.80; 95% confidence interval, 0.56 to 1.15). Among younger men (aged 40 to 59
years),
the relative risks
were
0.62
(95% confidence interval, 0.40 to 0.94) for cataract development and 0.67 (95% confidence interval, 0.38 to 1.31) for cataract extraction. These randomized trial data tend to exclude any large benefit of aspirin. While the overall findings concerning cataract development seem to be null, the data on extraction of age-related cataract, while not statistically significant, cannot exclude a possible small to moderate benefit of alternate-day aspirin therapy on the extraction of age-related cataract.
(Arch Ophthalmol. 1991;109:252-255)
Accepted for publication July 19, 1990. From the Epidemiology Unit, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston (Dr Seddon); Channing Laboratory, Department of Medicine (Drs Christen, Manson, Buring, and Hennekens), and Department of Preventive Medicine (Dr Buring and Hennekens), Brigham and Women's Hospital, Boston; and the National Eye Institute, Bethesda, Md (Dr Sperduto). Reprint requests to 55 Pond Ave, Brookline, MA 02146 (Dr Hennekens).
leading
performed annually."
See also pp 196, 244, and 256.
risk, 0.95; 95% confidence interval, 0.74
to 1.22). Cataract extractions
a
paired vision
Recently, aspirin therapy has been postulated to prevent cataract forma¬ tion or to slow its progression,4 possi¬ bly by acetylation of lens proteins5 or by improving glucose tolerance.6 Some,4"'7 but not all,'"0 observational studies support this hypothesis. In the only previous randomized trial (to our
knowledge)," which mentions the asso¬
aspirin and cataract, statistically significant association was observed. Due to the relatively small number of end points in that trial, however, only large protective effects could be reliably detected or ciation between
no
excluded. The Physicians' Health Study (PHS), a randomized double-masked placebo-controlled trial involving 22 071 male physicians, designed to determine whether low-dose aspirin therapy reduces risks of cardiovascu¬ lar disease and whether ß-carotene decreases cancer incidence, has pro¬ vided an opportunity to determine the role of each of these agents in cataract development or the need for extrac¬ tion. Herein, we describe the available data concerning aspirin therapy and cataracts as of January 25, 1988, the date the randomized aspirin compo¬ nent of the study was terminated early due largely to a statistically extreme benefit on the risk of a first myocardial infarction.
Downloaded From: http://archopht.jamanetwork.com/ by a Michigan State University User on 06/10/2015
SUBJECTS AND METHODS
Study Population A detailed description of the subjects and methods of the PHS has been previously reported.12 Briefly, the PHS is a 2x2 facto¬ rial design study testing low-dose aspirintherapy (Bufferin, Bristol-Meyers Prod¬ ucts, New York, NY) (325 mg every other day) on the risks of cardiovascular disease and ß-carotene (50-mg supplement on alter¬ nate days) in the primary prevention of cancer. In 1982, a total of 22 071 apparently healthy male US physicians between the ages of 40 and 84 years were enrolled in the study. Baseline information included height, weight, history of cigarette smok¬ ing, history of alcohol use, blood pressure, cholesterol levels, history of diabetes mellitus, medication history, and history of cata¬ ract. A total of 11037 physicians were randomly assigned to receive aspirin thera¬ py and 11034 were assigned to receive
placebo.
Each year, questionnaires were sent to all participants to monitor their compliance with the treatment regimen and the occur¬ rence of any relevant events, including cat¬ aract. When a participant reported a diag¬ nosis of cataract, written consent forms identifying the treating ophthalmologists were obtained. Ophthalmologists were con¬ tacted by mail and asked to complete cata¬ ract questionnaires that requested informa¬ tion about the presence of lens opacities, visual acuity loss, cataract extraction, other ocular abnormalities that could explain de¬ creased visual acuity, and cause(s) of cata¬ ract, if present (including age-related, trau¬
matic,
congenital,
surgery-
or
inflammatory,
or
steroid-induced cataract). Al¬ ternatively, ophthalmologists could supply the requested information by providing photocopies of the relevant medical records. Medical record information was available for 86.9% of subjects in the aspirin group and 86.7% in the placebo group. When the aspirin component of the trial was terminated, the average follow-up time was 60.2 months, with 109 408 person-years of observation. The average compliance with assigned treatment was 85.71% in the aspirin group and 85.77% in the placebo group. (Compliance was defined as taking at least 90 of the 180 assigned pills in the
alternate-day regimen per year for the aspi¬ rin group and not taking aspirin or other nonsteroidal anti-inflammatory drugs at least 90 days per year for the placebo group.)
The present report includes cataracts di¬ agnosed after randomization but before January 25, 1988, among the 21 316 male physicians who did not report cataract at baseline.
Table
Data
repeated, excluding cataracts report¬ during the first year of treatment.
were
ed
The incidence rates of cataract extraction also compared to test for a difference in progression or severity between the aspi¬ rin and placebo groups. The relative risk of cataract extraction in the aspirin group vs the placebo group was calculated with the use of stratified analyses that adjusted for age and ß-carotene treatment assignment. An analysis was also conducted that ex¬ cluded cataracts extracted during the first year of treatment. Stratified analyses were performed to evaluate possible modification of the effect of aspirin on cataract by several baseline characteristics that have been suggested as possible risk factors, including diabetes mellitus (yes, no); cigarette smoking''14 were
(never, past, current); hypertension (systol¬
ic blood pressure, S160
mm
Hg or diastolic
=
Demographics
52.8 ± 9.2 42.1
Mean age, y 40-49
According
Placebo
(N
-
Group 662)
10
52.8 ± 9.2 42.2
50-69
Geographic region Northeast Midwest
South
or
26.1
southwest
22.4
Mountains of far west Other Medical history Mean systolic BP,
0.9
Hg Hg Reported hypertensiont Mean cholesterol level, mmol/L Reported high cholesterol} Reported diabetes mellitus Mean body mass index, kg/m2 History of angina pectoris Parental history of Ml mm
0.8
78.9 ± 7.5
125.9 ± 11.6 78.7 ± 7.5
5.45 ± 1.15
5.45 ± 1.15
mm
Mean diastolic BP,
2.2 1.3
24.9 ± 2.99 1.2
13.2
Health habits
Cigarette smoking 49.5
Never Past
Analysis
Two cataract end points were considered: confirmed and cataract extraction. To ex¬ amine whether 325 mg of aspirin taken every other day reduces the development of cataracts, we calculated incidence rates of reported and confirmed cataract cases in the aspirin and placebo groups. Each inci¬ dence rate was defined as the number of participants with cataract divided by the number of person-years during which treat¬ ment was received. An individual contrib¬ uted person-time to total follow-up begin¬ ning at the time of randomization and continuing until the initial diagnosis of cata¬ ract or January 25, 1988, whichever came first. The relative risk of cataract in the aspirin group vs the placebo group was calculated with the use of stratified ana¬ lyses that adjusted for age and ß-carotene treatment assignment. Because an extend¬ ed duration of exposure to aspirin may be required to achieve an effect, the analyses
Aspirin Group 10 654) (N
Characteristics
Definition of Cataract
Cataract was defined as a lens opacity that reduced the best corrected visual acu¬ ity to 20/30 or worse in the absence of alternate ocular disease (eg, macular dis¬ ease or amblyopia) to explain the visual loss. In the presence of alternate ocular disease, a lens opacity was considered a cataract if, in the judgment of the ophthal¬ mologist, the severity was sufficient to re¬ duce the best corrected visual acuity to 20/30 or worse when considered alone. In addition, the cataract must have been age related, so that congenital cataracts and those due to trauma, steroids, intraocular inflammation, or surgery were excluded. A case was defined as a participant who re¬ ported cataract in one or both eyes after randomization.
of Physicians in Two Randomized Treatment Groups to Baseline Characteristics at the Initial Questionnaire*
1.—Comparison
50.1
only
Current Mean No. of
studies have raised
question of a possible benefit of aspirin on the development of cataract. The Physicians' Health Study, a randomized double-masked placebo-controlled trial among 22 071 male physicians, aged 40 to 84 years, provided the opportunity the
to collect information about whether low\x=req-\ dose aspirin therapy (325 mg on alternate days) affects the development or extraction of cataract. There were 173 age-related cataracts among those physicians assigned to aspirin therapy and 180 among those given placebo (relative
^ ataract is
cause of im¬ and blindness world¬ wide.1 In the United States, approxi¬ mately 3.3 million people have visual impairment and at least 43 000 are legally blind from cataracts, most of which are age-related.2 Cataract sur¬ gery is now the most frequently per¬ formed operation in persons older than 60 years in the United States, with more than 1 million cataract operations
were less in the aspirin than in the placebo group, but this difference was not
frequent
statistically significant (relative risk, 0.80; 95% confidence interval, 0.56 to 1.15). Among younger men (aged 40 to 59
years),
the relative risks
were
0.62
(95% confidence interval, 0.40 to 0.94) for cataract development and 0.67 (95% confidence interval, 0.38 to 1.31) for cataract extraction. These randomized trial data tend to exclude any large benefit of aspirin. While the overall findings concerning cataract development seem to be null, the data on extraction of age-related cataract, while not statistically significant, cannot exclude a possible small to moderate benefit of alternate-day aspirin therapy on the extraction of age-related cataract.
(Arch Ophthalmol. 1991;109:252-255)
Accepted for publication July 19, 1990. From the Epidemiology Unit, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston (Dr Seddon); Channing Laboratory, Department of Medicine (Drs Christen, Manson, Buring, and Hennekens), and Department of Preventive Medicine (Dr Buring and Hennekens), Brigham and Women's Hospital, Boston; and the National Eye Institute, Bethesda, Md (Dr Sperduto). Reprint requests to 55 Pond Ave, Brookline, MA 02146 (Dr Hennekens).
leading
performed annually."
See also pp 196, 244, and 256.
risk, 0.95; 95% confidence interval, 0.74
to 1.22). Cataract extractions
a
paired vision
Recently, aspirin therapy has been postulated to prevent cataract forma¬ tion or to slow its progression,4 possi¬ bly by acetylation of lens proteins5 or by improving glucose tolerance.6 Some,4"'7 but not all,'"0 observational studies support this hypothesis. In the only previous randomized trial (to our
knowledge)," which mentions the asso¬
aspirin and cataract, statistically significant association was observed. Due to the relatively small number of end points in that trial, however, only large protective effects could be reliably detected or ciation between
no
excluded. The Physicians' Health Study (PHS), a randomized double-masked placebo-controlled trial involving 22 071 male physicians, designed to determine whether low-dose aspirin therapy reduces risks of cardiovascu¬ lar disease and whether ß-carotene decreases cancer incidence, has pro¬ vided an opportunity to determine the role of each of these agents in cataract development or the need for extrac¬ tion. Herein, we describe the available data concerning aspirin therapy and cataracts as of January 25, 1988, the date the randomized aspirin compo¬ nent of the study was terminated early due largely to a statistically extreme benefit on the risk of a first myocardial infarction.
Downloaded From: http://archopht.jamanetwork.com/ by a Michigan State University User on 06/10/2015
SUBJECTS AND METHODS
Study Population A detailed description of the subjects and methods of the PHS has been previously reported.12 Briefly, the PHS is a 2x2 facto¬ rial design study testing low-dose aspirintherapy (Bufferin, Bristol-Meyers Prod¬ ucts, New York, NY) (325 mg every other day) on the risks of cardiovascular disease and ß-carotene (50-mg supplement on alter¬ nate days) in the primary prevention of cancer. In 1982, a total of 22 071 apparently healthy male US physicians between the ages of 40 and 84 years were enrolled in the study. Baseline information included height, weight, history of cigarette smok¬ ing, history of alcohol use, blood pressure, cholesterol levels, history of diabetes mellitus, medication history, and history of cata¬ ract. A total of 11037 physicians were randomly assigned to receive aspirin thera¬ py and 11034 were assigned to receive
placebo.
Each year, questionnaires were sent to all participants to monitor their compliance with the treatment regimen and the occur¬ rence of any relevant events, including cat¬ aract. When a participant reported a diag¬ nosis of cataract, written consent forms identifying the treating ophthalmologists were obtained. Ophthalmologists were con¬ tacted by mail and asked to complete cata¬ ract questionnaires that requested informa¬ tion about the presence of lens opacities, visual acuity loss, cataract extraction, other ocular abnormalities that could explain de¬ creased visual acuity, and cause(s) of cata¬ ract, if present (including age-related, trau¬
matic,
congenital,
surgery-
or
inflammatory,
or
steroid-induced cataract). Al¬ ternatively, ophthalmologists could supply the requested information by providing photocopies of the relevant medical records. Medical record information was available for 86.9% of subjects in the aspirin group and 86.7% in the placebo group. When the aspirin component of the trial was terminated, the average follow-up time was 60.2 months, with 109 408 person-years of observation. The average compliance with assigned treatment was 85.71% in the aspirin group and 85.77% in the placebo group. (Compliance was defined as taking at least 90 of the 180 assigned pills in the
alternate-day regimen per year for the aspi¬ rin group and not taking aspirin or other nonsteroidal anti-inflammatory drugs at least 90 days per year for the placebo group.)
The present report includes cataracts di¬ agnosed after randomization but before January 25, 1988, among the 21 316 male physicians who did not report cataract at baseline.
Table
Data
repeated, excluding cataracts report¬ during the first year of treatment.
were
ed
The incidence rates of cataract extraction also compared to test for a difference in progression or severity between the aspi¬ rin and placebo groups. The relative risk of cataract extraction in the aspirin group vs the placebo group was calculated with the use of stratified analyses that adjusted for age and ß-carotene treatment assignment. An analysis was also conducted that ex¬ cluded cataracts extracted during the first year of treatment. Stratified analyses were performed to evaluate possible modification of the effect of aspirin on cataract by several baseline characteristics that have been suggested as possible risk factors, including diabetes mellitus (yes, no); cigarette smoking''14 were
(never, past, current); hypertension (systol¬
ic blood pressure, S160
mm
Hg or diastolic
=
Demographics
52.8 ± 9.2 42.1
Mean age, y 40-49
According
Placebo
(N
-
Group 662)
10
52.8 ± 9.2 42.2
50-69
Geographic region Northeast Midwest
South
or
26.1
southwest
22.4
Mountains of far west Other Medical history Mean systolic BP,
0.9
Hg Hg Reported hypertensiont Mean cholesterol level, mmol/L Reported high cholesterol} Reported diabetes mellitus Mean body mass index, kg/m2 History of angina pectoris Parental history of Ml mm
0.8
78.9 ± 7.5
125.9 ± 11.6 78.7 ± 7.5
5.45 ± 1.15
5.45 ± 1.15
mm
Mean diastolic BP,
2.2 1.3
24.9 ± 2.99 1.2
13.2
Health habits
Cigarette smoking 49.5
Never Past
Analysis
Two cataract end points were considered: confirmed and cataract extraction. To ex¬ amine whether 325 mg of aspirin taken every other day reduces the development of cataracts, we calculated incidence rates of reported and confirmed cataract cases in the aspirin and placebo groups. Each inci¬ dence rate was defined as the number of participants with cataract divided by the number of person-years during which treat¬ ment was received. An individual contrib¬ uted person-time to total follow-up begin¬ ning at the time of randomization and continuing until the initial diagnosis of cata¬ ract or January 25, 1988, whichever came first. The relative risk of cataract in the aspirin group vs the placebo group was calculated with the use of stratified ana¬ lyses that adjusted for age and ß-carotene treatment assignment. Because an extend¬ ed duration of exposure to aspirin may be required to achieve an effect, the analyses
Aspirin Group 10 654) (N
Characteristics
Definition of Cataract
Cataract was defined as a lens opacity that reduced the best corrected visual acu¬ ity to 20/30 or worse in the absence of alternate ocular disease (eg, macular dis¬ ease or amblyopia) to explain the visual loss. In the presence of alternate ocular disease, a lens opacity was considered a cataract if, in the judgment of the ophthal¬ mologist, the severity was sufficient to re¬ duce the best corrected visual acuity to 20/30 or worse when considered alone. In addition, the cataract must have been age related, so that congenital cataracts and those due to trauma, steroids, intraocular inflammation, or surgery were excluded. A case was defined as a participant who re¬ ported cataract in one or both eyes after randomization.
of Physicians in Two Randomized Treatment Groups to Baseline Characteristics at the Initial Questionnaire*
1.—Comparison
50.1
only
Current Mean No. of
