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Age-Related Maculopathy in a Randomized Trial of Low-Dose Aspirin Among US Physicians
William G. Christen, ScD;
Robert J. Glynn, ScD;
Umed A. Ajani, MBBS;
Debra A. Schaumberg, ScD;
Emily Y. Chew, MD;
Julie E. Buring, ScD;
JoAnn E. Manson, MD;
Charles H. Hennekens, MD
Arch Ophthalmol. 2001;119:1143-1149.
ABSTRACT
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Objective To examine the development of age-related maculopathy (ARM) in a large-scale
trial of low-dose aspirin treatment.
Methods The Physicians' Health Study I was a randomized, double-masked, placebo-controlled
trial of low-dose aspirin (325 mg every other day) and beta carotene (50 mg
every other day) in the prevention of cardiovascular disease and cancer conducted
among 22 071 US male physicians aged 40 to 84 years in 1982. A total
of 21 216 participants did not report ARM at baseline, were followed
up for at least 7 years, and are included in this analysis.
Main Outcome Measures Total ARM, defined as a self-report confirmed by medical record evidence
of an initial diagnosis subsequent to randomization, and ARM with vision loss,
defined as total ARM but with vision loss to 20/30 or worse attributable to
ARM.
Results Early termination of the randomized aspirin component of the Physicians'
Health Study I, after an average of 60.2 months of treatment and follow-up
due to a statistically extreme 44% reduced risk of first myocardial infarction,
resulted in a far lower number of incident cases of ARM during the aspirin
treatment period than would have accrued without early termination. Thus,
during an average of 60.2 months of follow-up, a total of 117 cases of ARM
were confirmed, including 57 cases responsible for vision loss to 20/30 or
worse. There were 51 cases of ARM in the aspirin group and 66 in the placebo
group (relative risk, 0.77; 95% confidence interval, 0.54-1.11). For ARM with
vision loss, there were 25 cases in the aspirin group and 32 in the placebo
group (relative risk, 0.78; 95% confidence interval, 0.46-1.32).
Conclusions These randomized trial data tend to exclude any large beneficial effect
of 5 years of low-dose aspirin treatment on ARM. However, a smaller, but potentially
important, beneficial effect cannot be ruled out and would require testing
in randomized trials of adequate size and duration.
INTRODUCTION
AGE-RELATED maculopathy (ARM) is the leading cause of vision loss in
older Americans.1 Despite its common occurrence,
however, the pathophysiology of ARM is poorly understood and treatment options
are limited.1 Although laser photocoagulation2-4 and, more recently,
photodynamic therapy5-6 have been
shown to be of benefit for a few patients with advanced disease, laser treatment
merely delays subsequent vision loss,2, 7
and the long-term effects of photodynamic therapy remain to be determined.
Moreover, other than cigarette smoking,8-10
and perhaps low levels of antioxidant nutrients,11-13
no avoidable risk factors have been identified. In the absence of an effective
means of disease prevention, the importance of ARM as a source of ocular morbidity
will only increase as the US population ages. For these reasons, identification
of inexpensive, safe strategies to prevent the common forms of ARM is of particular
public health importance.1
Results of laboratory studies14-17
have shown that blood flow in the choroid of eyes with ARM is impaired, raising
the possibility that vascular disease might contribute to the pathophysiological
mechanism of ARM. Consistent with this hypothesis, a variety of epidemiologic
studies have shown that the risk of ARM is increased for those with cardiovascular
disease (CVD)18-21
or CVD risk factors such as elevated blood pressure18, 20, 22-26
and elevated lipid levels,25, 27
although conflicting data have also been reported.25, 28-32
If vascular disease is a contributing factor in ARM, then agents that enhance
systemic circulation and decrease the risk of vascular events could also have
a beneficial effect on choroidal circulation and decrease the risks of ARM.
One possible agent is aspirin, which irreversibly inhibits platelet cyclooxygenase,
resulting in a marked inhibition of platelet function.33-34
The conduct of the Physicians' Health Study I (PHS I) presented a unique
opportunity to examine the development of ARM in a large-scale trial of low-dose
aspirin treatment. The PHS I was a randomized, double-masked, placebo-controlled
trial of the use of aspirin and beta carotene in the prevention of CVD and
cancer conducted among 22 071 US male physicians aged 40 to 84 years
in 1982. The randomized aspirin component of the trial was terminated early,
after an average of 5 years of treatment and follow-up, primarily because
of a statistically extreme 44% reduced risk of first myocardial infarction.
In this study we examine the effect of assignment to low-dose aspirin treatment
on risks of ARM during the 5-year treatment period.
PARTICIPANTS AND METHODS
STUDY POPULATION
The PHS I was designed to evaluate use of low-dose aspirin (Bufferin;
Bristol-Myers Products, New York, NY) (325 mg every other day) and beta carotene
(50-mg supplement on alternate days) in the primary prevention of CVD and
cancer among 22 071 apparently healthy US male physicians aged 40 to
84 years in 1982. Baseline information included height, weight, history of
cigarette smoking, history of alcohol use, blood pressure, cholesterol level,
history of diabetes mellitus, medication history, and multivitamin use. Annual
questionnaires were sent to all participants to monitor their compliance with
the treatment regimen and the occurrence of any relevant events.
The aspirin component of the PHS I was terminated early, on January
25, 1988, after an average follow-up of 60.2 months because of a statistically
extreme 44% reduced risk of a first myocardial infarction among those taking
aspirin.35 (Adverse effects in the aspirin
group included increased risks of upper gastrointestinal tract ulcers and
bleeding problems, although the frequency and severity of these adverse effects
were far lower than those reported in previous trials of aspirin.35) The reported consumption of aspirin or other platelet-active
drugs was 86% in the aspirin group and 14% in the placebo group.
ASCERTAINMENT AND DEFINITION OF ARM END POINTS
Information concerning the occurrence of ARM during the first 7 years
of the trial was requested on the 84-month questionnaire. Physicians were
asked, "Have you ever had macular degeneration diagnosed in your right (left)
eye?" If yes, they were requested to provide the month and year of the diagnosis.
Subsequent annual questionnaires requested information on diagnoses during
the preceding year. Signed permission to examine medical and hospital records
pertaining to the diagnosis was also requested on the questionnaire and in
separate follow-up mailings when necessary. Ophthalmologists and optometrists
were contacted by mail and asked to complete an ARM questionnaire supplying
information about the date of initial diagnosis of ARM, the best-corrected
visual acuity at the time of diagnosis, and the date when visual acuity reached
20/30 or worse (if different from the date of initial diagnosis). Information
was also requested about the pathological findings observed (drusen, retinal
pigment epithelium [RPE] hypopigmentation/hyperpigmentation, geographic atrophy,
RPE detachment, subretinal neovascular membrane, or disciform scar) when visual
acuity was first noted to be 20/30 or worse and the date when exudative disease
was first noted (defined by the presence of RPE detachment, subretinal neovascular
membrane, or disciform scar). In addition, we asked whether there were other
ocular abnormalities that would explain or contribute to visual loss and,
if so, whether the ARM, by itself, was significant enough to cause best-corrected
visual acuity to be reduced to 20/30 or worse.
Diagnoses of ARM were divided into 2 categories: (1) ARM, defined as a self-report confirmed by medical record evidence
of an initial diagnosis of ARM subsequent to randomization but before January
25, 1988, and (2) ARM with vision loss, defined as
in (1) but with vision loss to 20/30 or worse attributable to ARM.
The present study includes the 21 216 participants who did not
report ARM at baseline and who were followed up for at least 7 years (ie,
physicians who died during the first 7 years of follow-up and therefore did
not respond to the 84-month questionnaire were excluded). As of November 1997,
a total of 117 reports of ARM were confirmed as incident cases diagnosed before
January 25, 1988. Of these, 57 cases were responsible for vision loss to 20/30
or worse.
STATISTICAL CONSIDERATIONS
Study Power
Due to the early termination of the aspirin component of the PHS I,
after an average of 60.2 months of follow-up, the number of incident cases
of ARM observed during the aspirin treatment period was far lower than would
have accrued without early termination. With the reduced number of end points,
the study had good statistical power (95%) to detect a 50% reduction in the
rate of total ARM but little power (<50%) to detect the most plausible
15% to 20% reduction in risk.
Data Analysis
Incidence rates of confirmed ARM cases in the aspirin and placebo groups
were calculated. Incidence rate was defined as the
number of participants with ARM divided by the number of person-years of follow-up.
An individual contributed person-time to total follow-up beginning at the
time of randomization and continuing until the initial diagnosis of ARM or
January 25, 1988, whichever came first. The relative risk (RR) of ARM in the
aspirin group vs the placebo group was calculated using Cox proportional hazards
regression models36 adjusted for age and beta
carotene treatment assignment. Because an extended duration of exposure to
aspirin may be required to achieve an effect, the analyses were repeated excluding
ARM cases diagnosed during the first year of treatment.
Stratified analyses and tests of interaction were performed to evaluate
possible modification of the effect of aspirin on ARM by several baseline
characteristics that have been suggested as possible risk factors, including
cigarette smoking (ever or never); hypertension (systolic blood pressure  160
mm Hg or diastolic blood pressure 95 mm Hg or hypertension being treated
currently) (yes or no); hypercholesterolemia (cholesterol level 261 mg/dL
[6.75 mmol/L] or being treated currently) (yes or no); and alcohol use
(daily, weekly, or rarely, with category values of 1, 2 and 3, respectively,
for a test of linear trend over categories).
For each RR, 2-sided P values and 95% confidence
intervals (CIs)37 were calculated. 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 based on disease severity.
RESULTS
As expected in this large randomized trial, baseline characteristics
that are possible risk factors for ARM were equally distributed between the
2 treatment groups (Table 1).
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Table 1. Baseline Characteristics of the Randomized Aspirin and Placebo
Treatment Groups
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During an average of 60.2 months of follow-up, a total of 117 cases
of ARM were confirmed by medical record review, including 57 cases with best-corrected
visual acuity reduced to 20/30 or worse due to ARM. The most common manifestation
of ARM for cases with vision loss (this information was not requested for
cases without vision loss) was a combination of drusen and RPE changes, which
was noted in 35% of cases (Table 2).
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Table 2. Retinal Signs Noted for 57 Cases of ARM With Vision Loss (to
20/30 or Worse) Due to ARM*
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There were 51 cases of ARM in the aspirin group and 66 in the placebo
group (RR, 0.77; 95% CI, 0.54-1.11; P = .16) (Table 3). The RR was similar when we considered
only ARM cases with vision loss (RR, 0.78; 95% CI, 0.46-1.32; P = .36) (Table 4). The
RRs tended to be lower in older men, but there was no statistically significant
trend with age.
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Table 3. Confirmed Cases of ARM With or Without Vision Loss According
to Treatment Group*
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Table 4. Confirmed Cases of ARM With Vision Loss According to Treatment
Group*
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To assess a possible delayed effect of aspirin therapy, we also conducted
analyses excluding ARM cases diagnosed during the first year of treatment.
The RR estimates in these analyses were 0.80 (95% CI, 0.54-1.19; P = .27) for total ARM and 0.96 (95% CI, 0.54-1.70; P = .88) for ARM with vision loss, indicating no delayed effect of
aspirin use during the 5-year treatment period.
In subgroup analyses, the effect of aspirin therapy on ARM did not differ
markedly within categories of cholesterol, cigarette smoking, or alcohol use
(Table 5). However, the effect
of aspirin treatment seemed to differ according to reported hypertension at
baseline. Among men who did not report hypertension at baseline, the RR was
0.95 (95% CI, 0.63-1.44; P = .82). For the subgroup
of men who reported hypertension at baseline, there was a statistically significant
65% reduced risk of ARM (RR, 0.35; 95% CI, 0.15-0.83; P = .02), but the numbers were small.
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Table 5. Risk of Confirmed ARM With or Without Vision Loss According
to Treatment Group, as Modified by Other Risk Factors*
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COMMENT
Men assigned to low-dose aspirin treatment, compared with those assigned
to placebo, had a statistically nonsignificant 23% reduced risk of total ARM
during the 5-year treatment period. Findings were similar when we considered
only cases of ARM that reduced visual acuity to 20/30 or worse. Thus, these
randomized trial data tend to exclude any large beneficial effect of 5 years
of low-dose aspirin treatment on ARM, although a smaller, but potentially
important, beneficial effect cannot be ruled out.
Several possible limitations of the study merit consideration. The power
of the study to detect any true benefit of aspirin treatment was limited by
the small number of ARM end points, due largely to the early termination of
the randomized aspirin component of the PHS I. In addition, the general good
health of our study population might also have contributed to the small number
of ARM end points. The total mortality rate in both groups combined during
the 5-year aspirin treatment period of the PHS I was approximately 15% of
that expected for a general population of white men of the same age distribution
and period.38 To the extent that mortality
and ARM share common risk factors, a reduced number of ARM cases during this
period might also be expected (thus limiting the interpretation of a comparison
of incidence rates between this and other populations). With the reduced number
of cases, the trial had sufficient power to detect a 50% reduction in risk
but had insufficient power (<50%) to detect a risk reduction as small as
that observed in the trial (20%-25%). Another possible limitation of the study
is nonrandom or differential misclassification. This type of misclassification
seems unlikely, however, because the reviewers of the medical records and
the treating ophthalmologists and optometrists were all masked to the aspirin
treatment assignment. Most study participants were aware of their aspirin
treatment assignment when they were first requested to report on previous
diagnoses of ARM (84-month questionnaire), but it seems unlikely that this
knowledge would have materially affected the reporting of this end point.
Random misclassification, which would underestimate any true effect of aspirin
on ARM, was reduced by the use of medical records to confirm the self-reports
of ARM. Confounding is unlikely in this large, randomized trial because, as
expected, baseline characteristics were equally distributed between the aspirin
and placebo groups. This equal distribution of risk factors provides reassurance
that other potential confounders that were either unmeasured (eg, UV exposure39-40) or unknown were also likely to be
evenly distributed between the 2 treatment groups. Finally, these findings
from a population of healthy male physicians might not be generalizable to
women or to the general male population.
In addition to its effect on study power, early termination of the trial
also limited our ability to detect a possible delayed effect of aspirin treatment.
Analyses that excluded cases of ARM occurring during the first year of treatment
did not materially alter RR estimates. However, the average follow-up time
of 5 years is relatively short, especially for a disease that is believed
to develop slowly as a result of accumulated damage in the retina over several
years. Detection of an effect of aspirin on ARM, if one exists, might require
longer follow-up and exclusion of cases that develop during the first several
years after initiation of therapy.
We found no evidence that the effect of aspirin treatment on ARM differed
within baseline categories of cholesterol, cigarette smoking, or alcohol use.
We did find, however, that aspirin treatment was associated with a significantly
reduced risk of ARM among men who reported hypertension at baseline. Although
these findings raise the possibility that aspirin therapy might have a differential
impact in the subgroup of men with elevated blood pressure, results of subgroup
analyses, particularly where there are no overall effects, must be interpreted
with caution and might simply reflect the play of chance.
The few previous studies that examined aspirin use in ARM comprised
patients with prevalent disease and were prompted out of concern for possible
increased risk of hemorrhage for those who used aspirin. For example, the
Macular Photocoagulation Study conducted an analysis of patients entering
the study to determine whether those who regularly took aspirin had more hemorrhage
than those who did not. The results of evaluations of 732 patients showed
no difference between the 2 groups.41 That
study also found no significant difference between users and nonusers of aspirin
in the recurrence rate of macular degeneration after initially successful
laser treatment.2, 42 Several other
anecdotal reports43-45
of increased risk of retinal hemorrhage associated with the use of aspirin
or other antiplatelet agents in persons with ARM were limited by the absence
of a comparison group and thus were impossible to interpret. Thus, our study
seems to be the first to evaluate a possible beneficial effect of aspirin
use in reducing risks of ARM. The Early Treatment Diabetic Retinopathy Study46 examined a possible beneficial effect of aspirin
therapy (650 mg/d) in diabetic retinopathy, and although the overall results
of that trial indicated that aspirin use has no clinically important beneficial
effects on the progression of retinopathy, the data also indicated no clinically
important harmful effects either. Specifically, aspirin therapy had no effect
on the occurrence,46 or severity and duration,47 of vitreous/preretinal hemorrhages and no effect
on the occurrence of vitrectomy due to either vitreous hemorrhage or retinal
detachment with or without vitreous hemorrhage.48
In short, the Early Treatment Diabetic Retinopathy Study found no ocular contraindications
to aspirin use in persons with diabetes mellitus (with mild to severe nonproliferative
or early proliferative diabetic retinopathy) who require it for treatment
of CVD or for other medical indications.
A consistent finding in histological studies14, 49-51
of ARM is atrophy of the choriocapillaris, namely, a decrease in the number
and diameter of capillaries in the macular region of the eye. Although some
atrophy of the choroid occurs naturally with aging,51-52
the degradative process seems to be accelerated in ARM.51
A corresponding age-related decrease in choroidal blood flow53-55
also is accelerated in ARM15, 56-58
and has recently been reported to be evident during the early, nonexudative
stages of disease development.17 It remains
unclear, however, whether this decreased choroidal perfusion is an important
contributor to the development of ARM59-60
(and thus a potential avenue of disease prevention) or is merely a consequence
of degradative changes in the outer retinal layers and RPE.61-64
At the dose tested in the PHS I (325 mg every other day), aspirin irreversibly
inhibits platelet cyclooxygenase, resulting in a rapid and marked inhibition
of platelet function.33-34 An
immediate decrease in platelet aggregability and risk of thrombosis is believed
to underlie the protective effects of low-dose aspirin in CVD and could contribute
to any beneficial effect that might be postulated for aspirin treatment in
ARM. However, a more plausible mechanism in ARM might involve the long-term
effects of platelet inhibition on initiation and progression of atherosclerosis.
Platelet inhibition might limit platelet adherence or aggregation on vascular
endothelium and existing plaque. In addition, activated platelets modify the
chemotactic and adhesive properties of endothelial cells, which might be an
important early pathophysiological event in atherogenesis.65
Activated platelets also induce secretion of proinflammatory cytokines (eg,
IL-8) that likely play an important role in vascular inflammation and atherogenesis66 and can be stimulated to release substances that
increase vessel wall permeability67 and induce
smooth muscle cell proliferation.68 Thus, long-term
inhibition of platelet function could reduce risks of ARM by altering the
initiation and progression of atherosclerosis. In addition, because platelet
activation frequently results from contact with subendothelial connective
tissue exposed by endothelial denudation, our observation in subgroup analyses
of a possible beneficial effect of aspirin use among those who reported hypertension
at baseline is intriguing. Hypertension is believed to be a source of chronic
injury to the arterial wall and is frequently associated with endothelial
dysfunction and platelet activation. Although this subgroup finding might
simply be a chance observation, it is also possible that men who reported
hypertension at baseline might have been more likely to benefit from platelet
inhibition than those who did not report hypertension. This possibility should
be investigated in other populations.
In summary, these randomized trial data indicate that 5 years of low-dose
aspirin treatment has no significant, large protective effect on the development
of ARM. However, a smaller, but potentially important, beneficial effect could
not be ruled out and requires testing in randomized trials of adequate power,
such as the ongoing Women's Health Study of 39 876 female health professionals.69
AUTHOR INFORMATION
Accepted for publication January 12, 2001.
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, Md.
Corresponding author and reprints: William G. Christen, ScD, Division
of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital,
900 Commonwealth Ave E, Boston, MA 02215-1204.
From the Division of Preventive Medicine, Department of Medicine (Drs
Christen, Glynn, Ajani, Schaumberg, Buring, and Manson), the Department of
Ambulatory Care and Prevention (Dr Buring), and Channing Laboratory, Department
of Medicine (Dr Manson), Harvard Medical School and Brigham and Women's Hospital,
Boston, Mass; the Departments of Biostatistics (Dr Glynn) and Epidemiology
(Drs Buring and Manson), Harvard School of Public Health, Boston; and the
National Eye Institute, Bethesda, Md (Dr Chew). Dr Hennekens is a Visiting
Professor of Medicine and of Epidemiology and Public Health, University of
Miami School of Medicine, Miami, Fla.
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