EPIDEMIOLOGY
A Randomized Trial of Beta Carotene and
Age-Related Cataract in US Physicians
William G. Christen, ScD; JoAnn E. Manson, MD, DrPH; Robert J. Glynn, ScD; J. Michael Gaziano, MD;
Robert D. Sperduto, MD; Julie E. Buring, ScD; Charles H. Hennekens, MD, DrPH
Objective: To examine the development of age-related
cataract in a trial of beta carotene supplementation in men.
Design: Randomized, double-masked, placebocontrolled trial.
Methods: Male US physicians aged 40 to 84 years
(n=22071) were randomly assigned to receive either beta
carotene (50 mg on alternate days) or placebo for 12 years.
Main Outcome Measures: Age-related cataract and extraction of age-related cataract, defined as an incident, agerelated lens opacity, responsible for a reduction in bestcorrected visual acuity to 20/30 or worse, based on selfreport confirmed by medical record review.
Results: There was no difference between the beta carotene and placebo groups in the overall incidence of cataract (998 cases vs 1017 cases; relative risk [RR], 1.00;
95% confidence interval [CI], 0.91-1.09) or cataract ex-
O
Author affiliations are listed
at the end of this article.
traction (584 vs 593; RR, 1.00; 95% CI, 0.89-1.12). In
subgroup analyses, the effect of beta carotene supplementation appeared to be modified by smoking status at
baseline (P=.02). Among current smokers, there were 108
cases of cataract in the beta carotene group and 133 in
the placebo group (RR, 0.74; 95% CI, 0.57-0.95). Among
current nonsmokers, there was no significant difference
in the number of cases in the 2 treatment groups (884
vs 881; RR, 1.03; 95% CI, 0.94-1.13). The results for cataract extraction appeared to be similarly modified by baseline smoking status (P =.05).
Conclusions: Randomized trial data from a large population of healthy men indicate no overall benefit or harm
of 12 years of beta carotene supplementation on cataract or cataract extraction. However, among current smokers at baseline, beta carotene appeared to attenuate their
excess risk of cataract by about one fourth.
Arch Ophthalmol. 2002;120:372-378
XIDATIVE PROCESSES are
believed to be an important contributing factor
in the development of
age-related cataract, a
leading cause of visual impairment in the
United States.1,2 Thus, there is considerable interest in determining whether vitamins with antioxidant properties lower
risks of cataract development and progression. Laboratory studies support this
possibility by showing that supplementation with antioxidant vitamins and minerals prevents or delays cataract development in vitro and in animal models.3-7
Observational epidemiologic studies in humans provide further support by showing that persons with higher intakes of
fruits and vegetables, or higher plasma levels of various antioxidant nutrients, tend
to have lower risks of cataract. The data
for individual nutrients, however, including vitamins C and E and the carotenoids, are inconsistent. More impor-
(REPRINTED) ARCH OPHTHALMOL / VOL 121, MAR 2003
372
tant, in these observational studies the
amount of uncontrolled and uncontrollable confounding may be as large as the
most plausible small to moderate effect
sizes, so data from randomized trials are
necessary.
Among the carotenoids, beta carotene received considerable early interest
as a possible anticataract agent, in part because it was known to be an effective antioxidant at low partial pressures of oxygen,8 conditions found in the lens, but also
because it is readily available in fruits and
vegetables and was not associated with any
harmful effects, even in the very large doses
used to treat patients with erythropoietic
protoporphyria.9,10 Subsequent investigations, however, have provided only modest support for a beneficial effect of beta
carotene against cataract. Thus, while
most,11-17 but not all,18,19 observational studies report an inverse association between
beta carotene level in the diet or blood and
risk of cataract, none attain statistical sig-
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nificance. Furthermore, findings from 3 randomized trials,
2 of which tested antioxidant vitamin cocktails20,21 and
a third that tested beta carotene alone in a population of
male heavy smokers in Finland,22 indicate that supplementation with beta carotene for 5 to 6 years has little
effect on the risk of cataract. These trial data, however,
are limited in interpretability by the duration of treatment, which may be insufficient to affect cataract development.
In this report, we describe the results for cataract
development and extraction during 12 years of randomized beta carotene treatment in Physicians’ Health Study
I (PHS I), a randomized trial among 22071 US male physicians. Because of the possible adverse effect of beta carotene on lung cancer in smokers,23-26 and because cigarette smoking is an important risk factor for cataract,27-30
we present results for cataract in the overall population,
as well as for subgroups according to smoking status at
baseline.
METHODS
261 248
Questionnaires Mailed
112 528
Respondents
59 285
Willing
33 223
Willing and Eligible
(Enrolled in Run-in)
22 071
Randomized
11 037
Active Aspirin
11 034
Aspirin Placebo
5517
Active
Beta Carotene
5520
Placebo
Beta Carotene
5519
Active
Beta Carotene
5515
Placebo
Beta Carotene
286
Reported Cataract
at Baseline
278
Reported Cataract
at Baseline
275
Reported Cataract
at Baseline
264
Reported Cataract
at Baseline
5231
Included in
Analysis
5242
Included in
Analysis
5244
Included in
Analysis
5251
Included in
Analysis
STUDY DESIGN
Physicians’ Health Study I was a randomized, double-masked,
placebo-controlled, 2⫻2 factorial trial designed to evaluate lowdose aspirin and beta carotene in the primary prevention of cardiovascular disease and cancer. The methods of the trial have
been described in detail previously.31 Briefly, 22071 US male
physicians, who had no history of cancer (except nonmelanoma skin cancer), myocardial infarction, stroke, or transient
cerebral ischemia, were randomly assigned to aspirin (325 mg
on alternate days [Bufferin; provided by Bristol-Myers Products, New York, NY]) or its placebo, plus beta carotene (50 mg
on alternate days [Lurotin; provided by BASF Corporation, Mt
Olive, NJ]) or its placebo (Figure 1). Baseline information included height, weight, history of cigarette smoking, history of
alcohol use, blood pressure level, cholesterol levels, history of
diabetes mellitus, and history of multivitamin use. Information on personal history of cataract was also obtained at baseline. A total of 20968 physicians did not report cataract at baseline and are included in these analyses. Annual questionnaires
were sent to all participants to monitor their compliance with
assigned treatment and the occurrence of any relevant events,
including cataract. Informed consent was obtained from all participants, and the research protocol was reviewed and approved by the institutional review board at Brigham and Women’s Hospital, Boston, Mass.
The aspirin component of PHS I was terminated early, on
January 25, 1988, after a mean follow-up of 60.2 months, due
primarily to the emergence of a statistically extreme 44% reduced risk of a first myocardial infarction among those taking
aspirin.31 The randomized beta carotene component of the trial
continued uninterrupted until the scheduled termination date
of December 31, 1995.
By the end of 1995, participants had been taking beta carotene or placebo for a mean of 12 years (range, 11.6-14.2 years).
At the end of 11 years of follow-up (the last year completed
for all participants), 99.2% were still providing information on
morbidity, and follow-up for mortality was 99.9% complete.
In both the beta carotene group and the placebo group, 80% of
participants were still taking the study pills, with a mean compliance among pill takers of more than 97%. Thus, even after
11 years in the beta carotene group, 78% of the study pills were
reported as still being taken. In the placebo group, 6% reported taking supplemental beta carotene or vitamin A.
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373
Figure 1. Study design.
ASCERTAINMENT AND DEFINITION
OF END POINTS
Following the report of a cataract diagnosis or extraction, written consent was obtained to contact the treating ophthalmologist or optometrist. Ophthalmologists and optometrists were
contacted by mail and asked to complete cataract questionnaires 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. Cataract was defined as a self-report confirmed by medical record
review to be initially diagnosed after randomization, agerelated 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 to be 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.
STATISTICAL ANALYSIS
The Cox proportional-hazards model was used to estimate the
relative risk (RR) of cataract among those assigned to beta carotene compared with those assigned placebo after adjustment
for age (years) at baseline and randomized aspirin treatment.
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Table 1. Baseline Characteristics According
to Beta Carotene Treatment Assignment*
Characteristics
Age, mean (SD), y
Age, y
40-49
50-59
60-69
70-84
Medical history
Systolic blood pressure,
mean (SD), mm Hg
Diastolic blood pressure,
mean (SD), mm Hg
Reported hypertension†
Cholesterol level, mean (SD), mg/dL
Reported high cholesterol level‡
Reported diabetes mellitus
Body mass index, mean (SD)§
History of angina pectoris
Parental history of myocardial
infarction㛳
Health habits
Cigarette smoking
Never
Past only
Current
Alcohol use
Daily
Weekly
Rarely or never
Physical activity¶
Multivitamin use (current)
Beta Carotene
(n = 10 475)
Placebo
(n =10 493)
52.6 (9.1)
52.6 (9.1)
42.7
34.6
17.6
5.1
42.7
34.5
17.7
5.1
125.8 (11.6)
125.9 (11.7)
78.8 (7.5)
78.8 (7.5)
22.9
212.2 (45.2)
11.7
2.1
24.9 (3.1)
1.2
13.0
23.2
211.6 (44.8)
12.1
2.4
24.9 (3.0)
1.3
13.6
50.1
39.0
10.9
49.9
39.3
10.8
24.3
50.0
25.7
27.6
19.0
24.4
49.2
26.4
27.7
19.9
*Data are given as the percentage of participants, unless otherwise
indicated.
†Hypertension is defined as reported systolic blood pressure of 160
mm Hg or higher, diastolic blood pressure of 95 mm Hg or higher, or history
of treatment for high blood pressure.
‡High cholesterol level is defined as reported high cholesterol, a reported
high blood cholesterol level of 260 mg/dL or higher, or history of treatment
with cholesterol-lowering medication.
§Body mass index is weight in kilograms divided by height in meters
squared.
㛳Myocardial infarction in either parent before age 60 years.
¶Reported vigorous exercise once or more per week.
Models were also fit separately within 4 age groups: 40 to 49
years, 50 to 59 years, 60 to 69 years, and 70 to 84 years. Tests
of trend of the effect of age on any association between beta
carotene and cataract were calculated by including a term for
the interaction of beta carotene and age (expressed as a continuous variable with values 1 to 4 corresponding to the 4 age
groups) in a proportional hazards model. For each RR, the 95%
confidence interval (CI) and 2-sided P value were calculated.
We also analyzed subgroup data by baseline smoking status to explore possible modification of any effect of beta carotene. Thus, tests of interaction were performed to evaluate the
statistical significance of any modifying effect of baseline smoking status on the effect of beta carotene on cataract. We also
used an interaction term with length of follow-up to test for a
trend of the RR over time and to evaluate the adequacy of the
proportional hazards assumption over time. Models were fit for
the overall population and for the subgroups of current smokers and nonsmokers at baseline.
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
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374
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
As is expected in a large randomized trial, baseline characteristics were equally distributed between the 2 treatment groups (Table 1). In each group, 11% of participants were current smokers at baseline.
During a mean of 12 years of treatment and followup, a total of 2015 cataracts and 1177 cataract extractions were confirmed by medical record review. Overall, there was no significant benefit or harm of beta
carotene supplementation on risk of cataract (998 cases
in the beta carotene group vs 1017 in the placebo group;
RR, 1.00; 95% CI, 0.91-1.09) (Table 2). Similarly, there
was no effect of beta carotene supplementation on risk
of cataract extraction (584 cases in the beta carotene group
vs 593 in the placebo group; RR, 1.00; 95% CI, 0.891.12) (Table 3). Relative risks decreased slightly with
increasing duration of treatment, but the trend was not
statistically significant (data not shown).
In subgroup analysis, the effect of beta carotene
supplementation on cataract appeared to be modified by
smoking status at baseline (P for interaction=.02). Among
current smokers, men assigned to the beta carotene group
had a statistically significant 26% reduced risk of cataract compared with those in the placebo group (108 cases
vs 133 cases; RR, 0.74; 95% CI, 0.57-0.95) (Table 4).
There was no apparent effect of beta carotene supplementation in men who were nonsmokers at baseline (884
cases vs 881 cases; RR, 1.03; 95% CI, 0.94-1.13). Similar results were observed for cataract extraction (P for
interaction = .05). Among current smokers, men assigned to beta carotene had a 27% reduced risk of extraction compared with men assigned to placebo (68 cases
vs 86 cases; RR, 0.73; 95% CI, 0.53-1.00). Among nonsmokers, there was no effect of beta carotene supplementation (512 cases in the beta carotene group vs 505
cases in the placebo group; RR, 1.04; 95% CI, 0.92-1.17).
For both cataract and cataract extraction, the reduction
in risk among current smokers assigned to beta carotene was apparent during the early years of treatment and
follow-up (years 1-5), although the confidence intervals around these RR estimates included the null value
of 1.0 because of the smaller number of events (Figure 2).
There was no significant trend toward greater benefit with
an increasing duration of treatment for either cataract end
point.
Cigarette smoking is a well-established risk factor
for cataract.27-30 To explore the relative effects of baseline smoking status and beta carotene treatment assignment on risk of cataract, models were fit with current nonsmokers assigned to placebo as the reference group. For
current smokers assigned to placebo, there was a statistically significant 65% increased risk of cataract (RR, 1.65;
95% CI, 1.37-1.98) compared with the reference group
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(Figure 3). This excess risk associated with being a current smoker was markedly attenuated by assignment to
beta carotene treatment (RR, 1.22; 95% CI, 1.00-1.49).
The results for cataract extraction were similar.
COMMENT
In this large-scale randomized trial among apparently
healthy, well-nourished men, there was no statistically significant benefit or harm of 12 years of beta carotene supplementation on overall risk of cataract or cataract extraction. The narrow CIs excluded even a modest effect of beta
carotene supplementation (ie, 15%-20% increase or decrease in risk) on cataract. In subgroup analyses, there was
a possible beneficial effect of beta carotene in men who
were current smokers at baseline. Cigarette smoking is a
well-established risk factor for cataract,27-30 and beta carotene appeared to attenuate the excess risk.
Several possible limitations of the trial should be considered, particularly in view of the overall finding of no
benefit or harm. Inadequate dosage of beta carotene is an
unlikely explanation for the findings. The dosage tested
in the trial (50 mg on alternate days) placed participants
in the top few percentiles of the general population with
respect to usual intake. Moreover, bioavailability studies
in our population showed that the alternate-day dosage
and formulation increased plasma beta carotene concentrations approximately 4-fold.32,33 The finding of a possible beneficial effect for beta carotene in the subgroup of
men who were current smokers at baseline provides some
support for the adequacy of the dosage tested. Poor compliance with assigned treatment is also not a plausible explanation for our overall findings, because there was 85%
compliance with beta carotene treatment after 5 years and
compliance was still 78% after 12 years. In the placebo
group, the use of beta carotene or vitamin A supplements
was reported by only 6% of participants, even by the end
of the trial. Random misclassification of cataract, which
would tend to shift the RR estimate toward the null, was
reduced by the use of medical records to confirm the selfreports and by the use of strict diagnostic criteria that included reduction in best-corrected visual acuity to 20/30
or worse owing to cataract. Nonrandom or differential misclassification was unlikely because medical records were
reviewed without knowledge of beta carotene treatment
assignment, and study participants and treating ophthalmologists and optometrists were unaware of beta carotene treatment assignment.
Randomized trial data regarding the effect of beta
carotene supplementation on cataract are limited to 3 trials
of 5 to 6 years’ duration. In 2 of these trials, beta carotene was tested as part of an antioxidant mixture. In a
poorly nourished population in China, 5 to 6 years of treatment with vitamin and mineral combinations that included beta carotene (15 mg daily) had no effect on endof-trial prevalence of cataract.20 In the recently completed
Age-Related Eye Disease Study, there was no apparent
effect of an antioxidant combination of vitamin E (400
IU), vitamin C (500 mg), and beta carotene (15 mg) on
the development and progression of lens opacities during 6.3 years of treatment and follow-up.21 The use of a
combined treatment regimen in these 2 trials precludes
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375
Table 2. Confirmed Cases of Cataract According
to Beta Carotene Treatment Assignment*
Confirmed Cases of Cataract
Participants
Age, y
40-49
50-59
60-69
70-84
Total
Beta Carotene
(n = 10 475)
Placebo
(n = 10 493)
RR† (95% CI)
78
280
444
196
998
62
303
450
202
1017
1.26 (0.90-1.76)
0.93 (0.79-1.09)
0.99 (0.87-1.13)
1.01 (0.83-1.22)
1.00 (0.91-1.09)
Abbreviations: CI, confidence interval; RR, relative risk.
*Test for trend of the effect of age on the association between beta
carotene and cataract, P = .85.
†Adjusted for aspirin treatment assignment.
Table 3. Confirmed Cases of Cataract Extraction
According to Beta Carotene Treatment Assignment*
Confirmed Cases
of Cataract Extraction
Participants
Age, y
40-49
50-59
60-69
70-84
Total
Beta Carotene
(n = 10 475)
Placebo
(n = 10 493)
RR† (95% CI)
57
176
237
114
584
48
184
251
110
593
1.19 (0.81-1.74)
0.96 (0.78-1.18)
0.95 (0.79-1.13)
1.06 (0.81-1.37)
1.00 (0.89-1.12)
Abbreviations: CI, confidence interval; RR, relative risk.
*Test for trend of the effect of age on the association between beta
carotene and cataract extraction, P = .88.
†Adjusted for aspirin treatment assignment.
estimation of the effect of any specific nutrient. In the
Alpha-Tocopherol, Beta Carotene Cancer Prevention
(ATBC) study,22 which was the first large-scale randomized trial to test antioxidant vitamins in a wellnourished population, a total of 29 133 Finnish male
smokers aged 50 to 69 years were randomly assigned in
a 2⫻2 factorial trial to ␣-tocopherol (50 mg daily) or placebo and beta carotene (20 mg daily) or placebo. Four
hundred twenty-five cataract surgeries were documented during about 6 years of treatment and followup. Overall results indicated little effect of beta carotene
supplementation on the incidence of cataract surgery (RR,
0.97; 95% CI, 0.79-1.19). Because all participants smoked,
effect modification could not be evaluated in that study,
but there were no interactions with duration or amount
smoked per day. In the PHS I, among current smokers,
a subgroup more comparable to the study population in
ATBC, we did observe a 25% to 30% reduced risk of cataract and cataract extraction for those assigned to beta carotene. This apparent benefit among current smokers does
not appear simply to reflect the longer treatment period
in PHS I. Specifically, analyses of data for the first 5 years
in PHS I (comparable to the period of treatment in the
ATBC study) suggested a beneficial effect on cataract exWWW.ARCHOPHTHALMOL.COM
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Table 4. Risk of Confirmed Cataract and Cataract Extraction According
to Beta Carotene Treatment Assignment and Baseline Smoking Status
Beta Carotene
Cataract and Smoking Status
Cataract
Current smoker
Current nonsmoker
Cataract extraction
Current smoker
Current nonsmoker
Placebo
No. of
Participants
Cases
No. of
Participants
Cases
P Value
(Interaction)
1140
9305
108
884
1133
9329
133
881
0.74 (0.57-0.95)
1.03 (0.94-1.13)
.02
1140
9305
68
512
1133
9329
86
505
0.73 (0.53-1.00)
1.04 (0.92-1.17)
.05
RR* (95% CI)
Abbreviations: CI, confidence interval; RR, relative risk.
*Adjusted for age (years) and aspirin treatment assignment.
Smoking at Baseline
Current Nonsmokers
Current Smokers
2.0
2.0
A Cataract
1.5
Relative Risk
Relative Risk
1.5
B Cataract Extraction
1.0
0.5
1.0
0.5
0
1-5
0
>10
5-10
>5-10
1-5
Follow-up, y
>10
Follow-up, y
Figure 2. Relative risks (95% confidence intervals) of cataract (A) and cataract extraction (B) for beta carotene supplementation by time after randomization,
according to smoking status at baseline. Analyses were adjusted for age (years) and aspirin treatment assignment.
Beta Carotene
2.0
Placebo
2.0
A Cataract
1.77
(1.41-2.23)
B Cataract Extraction
1.65
(1.37-1.98)
1.5
1.03
(0.94-1.13)
1.0
1.22
(1.00-1.49)
Relative Risk
Relative Risk
1.5
1.00
(Reference)
0.5
1.29
(1.00-1.66)
1.04
(0.92-1.17)
1.0
1.00
(Reference)
0.5
0
0
Not Current
Current
Not Current
Smoking Status at Baseline
Current
Smoking Status at Baseline
Figure 3. Relative risks (95% confidence intervals) of cataract (A) and cataract extraction (B) by beta carotene treatment assignment and smoking status at
baseline. Analyses were adjusted for age (years) and aspirin treatment assignment. Reference group was defined as current nonsmokers at baseline who were
assigned to placebo.
traction (RR, 0.57; 95% CI, 0.32-1.03) during the early
years of the trial.
These subgroup findings among smokers in PHS I
must be interpreted with caution. Although a possible
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376
beneficial effect for beta carotene supplementation in
smokers was observed for both end points of cataract and
cataract extraction, these findings are not independent
because participants undergoing extraction are a subset
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of participants with incident cataract. Furthermore, these
results in smokers appear to be at odds with randomized trial data from the ATBC study,22 and evidence from
several observational studies provides little support for
a beneficial effect of beta carotene supplementation in
smokers.13,15-17 Additionally, the subgroup of current
smokers in PHS I was small (11% current smokers at baseline), and, thus, the result in smokers could simply be
due to chance. However, if real, these findings raise questions about mechanisms by which supplemental beta carotene might exert a beneficial effect on cataract among
smokers. Beta carotene has not been detected in the normal or cataractous human lens,34-36 nor has it been detected in the human lens following extensive dietary
supplementation.34 Thus, a direct effect of beta carotene
supplementation on lens concentrations seems unlikely. Beta carotene could have an indirect effect by increasing concentrations of other antioxidant nutrients in
the lens. Ascorbate, ␣-tocopherol, and the xanthophylls
lutein and zeaxanthin have been detected in the human
lens,34,35 and evidence suggests that plasma concentrations of ascorbate and perhaps lutein and zeaxanthin (but
probably not ␣-tocopherol) are reduced in smokers.37-41
There is no evidence, however, that beta carotene supplementation has any effect on plasma levels of ␣-tocopherol or ascorbate, and plasma levels of lutein and zeaxanthin may even decrease with beta carotene
supplementation.33,42-46 Thus, an indirect effect, mediated by an increase in plasma concentrations of other antioxidant nutrients, also appears unlikely. Alternatively, beta carotene might interact directly with oxidants
present in the gas phase of cigarette smoke and thereby
decrease oxidative stress in the environment surrounding the lens. Beta carotene may also minimize the deleterious effects of smoking-related oxidants on other antioxidant nutrients. Consistent with this possibility, recent
laboratory data have shown that both ␣-tocopherol and
ascorbate are oxidized more slowly by gas-phase smoke
exposure in liposomes containing beta carotene.47
In summary, these randomized trial data from a
large population of apparently healthy US male physicians indicate no overall benefit or harm of 12 years of
beta carotene supplementation on cataract or cataract
extraction. The subgroup finding of a possible beneficial effect of beta carotene in current smokers should be
interpreted with caution,48 particularly in view of findings in 2 previous trials of possible adverse effects of
beta carotene on lung cancer in smokers.23,24 However,
if real, this finding could have important scientific implications and needs to be confirmed in other randomized trials in men and women.49-51
Submitted for publication June 7, 2002; final revision received November 1, 2002; accepted November 14, 2002.
From the Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital (Drs
Christen, Manson, Glynn, Gaziano, and Buring), the Departments of Epidemiology (Dr Manson) and Biostatistics
(Dr Glynn), Harvard School of Public Health, the Department of Ambulatory Care and Prevention, Harvard Medical School (Dr Buring), and the Massachusetts Veterans Epidemiology Research and Information Center, Department
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377
of Veterans Affairs Boston Healthcare System (Dr Gaziano), Boston, Mass; the National Eye Institute, Bethesda,
Md (Dr Sperduto); and the Department of Epidemiology and
Public Health, University of Miami School of Medicine, Miami, Fla (Dr Hennekens). Dr Hennekens serves as a consultant, including as chairman or a member of data and safety
monitoring boards, to AstraZeneca, Bayer, Bristol-Myers
Squibb, GlaxoSmithKline, McNeil Pharmaceutical, Novartis, Pfizer, and Reliant Pharmaceuticals. The other authors
have no relevant financial interest in this article
This study was supported by research grants HL 26490,
HL 34595, CA 34944, CA 40360, and EY 06633 from the
National Institutes of Health, Bethesda.
We thank the entire staff of the PHS, under the leadership of Charlene Belanger, MA, as well as Mary Breen,
Vadim Bubes, PhD, Jean MacFadyen, BA, Geneva McNair,
David Potter, BA, Leslie Power, Harriet Samuelson, MA, Miriam Schvartz, MD, Mickie Sheehey, Joanne Smith, BS, and
Phyllis Johnson Wojciechowski, BS, for their crucial contributions. We are also indebted to the 22071 dedicated and
committed participants of the PHS.
Corresponding author and reprints: William G. Christen, ScD, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Third floor, Boston, MA 02215-1204 (email: [email protected]).
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