Abstract
Purpose: To review current literature of the benefits that aspirin provides for patients’
cardiovascular health compared to the risk of AMD worsening.
Methods: We performed a review and critically analyzed six cardiovascular and four
ophthalmological trials. The cardiovascular trials consisted of over 95,000 individuals in
primary and secondary prevention trials while the smaller ophthalmological trials had
over 2,749 subjects.
Results: The reviewed meta-analysis literature demonstrated a 32 % reduction in the
risk of non-fatal stroke with regular aspirin users. The study also documented that
aspirin users decreased the risk of vascular events by 15 %. Of the four ophthalmological
studies, three suggested an exacerbation of AMD and one a possible benefit for AMD.
Conclusion: Overall the number, size, and quality of the cardiovascular studies
recommending aspirin use is much greater than the fewer, smaller and conflicting
studies suggesting a possible adverse effect of aspirin use in relation to AMD. The
benefits of aspirin usage include preserving the duration and quality of life by
decreasing stroke and heart attack risk. These benefits seem to far outweigh the
theoretical risks of possibly exacerbating wet AMD, which can be reasonably controlled
with anti-VEGF therapy.
Macular Degeneration and Aspirin use
Many recent press releases regarding the potential adverse effects of aspirin in
macular degeneration have caused some of my patients to discontinue their aspirin
use.1-2 I advise my patients to continue with their doctor recommended aspirin use for
many reasons. As with any treatment, it is important to weigh the risk / benefit ratio of
aspirin use in this generally elderly and high-risk population. The benefits of aspirin have
been well documented and highly recommended for the prevention and treatment of
cardiovascular disease such as myocardial infarction, stroke, and death. The recent
epidemiological studies suggesting that aspirin use may exacerbate macular
degeneration are based on three studies, while the benefits of aspirin use for macular
degeneration patients have been suggested in the larger Age-Related Eye Disease Study
(AREDS) and the Physicians Health Study.10-13
Large cardiovascular studies:
A review of numerous studies concerning regular aspirin users have been
conducted in order to establish the benefits of aspirin in the prevention of
cardiovascular diseases. The ATT Collaboration conducted a study on the effects of
aspirin on primary and secondary prevention of vascular disease. The study performed a
meta-analysis of six prevention trials (subjects had no history of occlusive disease),
which consisted of 95,000 individuals of which 3554 had serious vascular events (MI,
stroke, or vascular death) and secondary prevention trials (subjects with previous MI or
stroke or transient cerebral ischemia) contained 17,000 participants with 3306 serious
vascular events.3
The results showed that aspirin reduced vascular mortality (OR:0.91 (.82-1.00),
p=0.06) which reduced total mortality by 10 % (OR: 0.90 (0.82-0.99), p=0.02)4. The
findings also demonstrated that aspirin reduced major coronary events (OR: 0.80 (0.750.88) as well as ischemic stroke (OR:0.83 (0.73-0.95), p=0.005)4. Another meta-analysis
study utilized five published trials (Physicians’ Health Study, British Doctors’ Trial,
Thrombosis Prevention Trial, the Hypertension Optimal Treatment Study, and Primary
Prevention Project) containing 55,580 randomized participants to illustrate a 32 %
reduction in the risk of non-fatal stroke (OR:0.68, 95% CI, 0.59-.79) with regular aspirin
users4. The study also documented that aspirin users decreased the risk of vascular
events by 15 % (OR:0.85, 95 % CI, 0.79-0.93).5
Smaller AMD epidemiological studies:
The three ophthalmological studies suggesting adverse effects of aspirin on
ADM are the Blue Mountain Eye Study (BMES), the European Eye Study (EES), and the
Beaver Dam Eye Study (BDES). There are 2 studies suggesting a benefit to AMD
patients, AREDS and the Physicians Heath Study.
The Blue Mountains Eye Study (BMES) database contained 2389 individuals, but
only 257 were regular aspirin users (10.8%). A post hoc analysis was performed to
determine if regular aspirin use interacted with age-related macular degeneration. This
study was conducted over a 15-year period in which only 63 of the 2389 developed
neovascular AMD. Their results suggested that regular aspirin users had a 2.5-fold
increase in neovascular AMD compared with nonusers but no significant association was
found between aspirin and geographic atrophy (dry AMD)6. The increase in neovascular
AMD (wet AMD) went from 1.9 % in five years, 7 % in ten years, and 9.3 % in fifteen
years in regular aspirin users (OR: 2.46, 95 % CI: 1.25-4.83, n=257).6
The European Eye Study pooled 4691 participants with early and late age related
macular degeneration (ARMD) at 65 years of age and older, collected by random
sampling. They found that early AMD was present in 36.4% of the participants and late
AMD was present in 3.3% of participants. They also stated that with aspirin use, the
odds ratios increased with the severity of the AMD (grade 1, 1.26 (95% confidence
interval [CI], 1.08–1.46; P<0.001); grade 2, 1.42 (95% CI, 1.18–1.70), and wet late AMD,
2.22 (95% CI, 1.61–3.05).7 They reported that with early AMD only grades 1 and 2, but
not grade 3 were associated with aspirin use. They found no association between aspirin
use and pooled early or late AMD, nor with late AMD in those older than 85 years.7
The Beaver Dam Eye study is a longitudinal population-based study
performed every five years for a 20-year period containing 4926 participants
between the ages of 43 to 86 years old.8 Regular aspirin use 10 years prior to retinal
examination was associated with late AMD (hazard ratio [HR], 1.63 [95% CI, 1.012.63]; P = .05) and with estimated incidence of 1.76% (95% CI, 1.17%-2.64%) in
regular users and 1.03% (95% CI, 0.70%-1.51%) in nonusers. Regular aspirin use
10 years prior to retinal examination was significantly associated with neovascular
AMD (HR, 2.20 [95% CI, 1.20-4.15]; P = .01) but not pure geographic atrophy (HR,
0.66 [95% CI, 0.25-1.95];P = .45). Aspirin use 5 years (HR, 0.86 [95% CI, 0.711.05]; P = .13) or 10 years (HR, 0.86 [95% CI, 0.65-1.13]; P = .28) prior to retinal
examination was not associated with incident early AMD. They found that aspirin
use 5 years prior to incidence was not associated with incident early or late AMD.
However, they found that regular aspirin use 10 years prior was associated with a
small but statistically significant increase in the risk of incident late and neovascular
AMD.8
Limitations in the Epidemiological Studies
The Blue Mountain Eye Study, a post hoc analysis, contained several limitations
and thus the authors felt no valid conclusions could be made. There was no data
obtained concerning the dose of aspirin each participant took and thus assumed that
every “regular user” consumed 150 mg, when, in fact, most people take aspirin without
a prescription and are subject to ingesting more than 150 mg daily (e.g. 300 mg). 6 In
addition, the size of the cohort study was small and not randomized with a small
number of AMD cases and only 56 % of the participants eligible for a follow-up were
examined at the 15-year mark.9 Also, the study did not balance the number of subjects
with possible risk factors such as age, occurrence of diabetes, heart disease, and strokes
in accordance with the number of regular aspirin users. Furthermore, the number of
regular aspirin users actually contained a higher percentage of participants with these
conditions. Additionally, the authors note that the results do not reach statistical
significance when adjusted for other risk factors (BMI, blood pressure, diabetes mellitus,
blood total cholesterol level, and fish consumption).9
Additionally, the European Eye Study also a post hoc analysis contained a small
sample size of aspirin users and presented results with an extremely wide confidence
interval. In this study, there is also a possibility that people with AMD took aspirin after
experiencing visual problems.7 There are no data regarding the amount of aspirin the
participants used. Additionally, confounding by indication cannot be ruled out
completely they did not eliminate the potential influence of cardiovascular deaths or
angina in the analyses.7 There are also no data on other morbidities, such as arthritis, for
which aspirin may be indicated.
The Beaver Dam Eye Study contained numerous limitations that could have
affected the conclusions. Regular aspirin users were defined as participants who
took aspirin at least twice per week for >3 months, with a cumulative dose of only
24 pills which may not properly define a regular aspirin user.8 Regular aspirin users
may have taken considerably larger amounts of the drug during the course of the
study. Their definition fails to accurately distinguish between regular aspirin users
and nonusers. Considering the inherent risk of bias in observational studies and the
limitations in group definition and statistical analysis, the association between
regular aspirin use and neovascular AMD may be a product of type I error.8 There
are also multiple confounding factors that were not mentioned in the study. It is
likely that subjects who regularly use aspirin have higher blood lipid levels than
those who do not use aspirin, so blood lipid levels could be a confounding factor.
Furthermore, high cholesterol is thought to contribute to the pathogenesis of AMD
and thus should be reported to make the study more convincing.8
Studies contradicting AMD epidemiological results:
In addition to the limitations contained in the BMES, BDES, and EES, there have
been other studies suggesting a benefit of aspirin use in AMD. The Physicians’ Health
Study reported that there was no increase in AMD during 7-10 years among the regular
aspirin users. There were only 51 cases of age-related maculopathy (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).10
The Age-Related Eye Disease Study (AREDS) reported that aspirin is actually
beneficial in the protection of dry AMD patients11-13. AREDS, a larger study, shows the
possible benefits of aspirin use for macular degeneration. AREDS studies 1, 3, and
19 have noted that the association between aspirin and AMD is not statistically
significant.11-13 The case-controlled Age-Related Eye Disease Study (AREDS)
reported that the use of anti-inflammatory medications, including aspirin, had a
protective effect on dry AMD.13
Data from the BDES and the EES also suggested that aspirin has no effect on
AMD risk at the 5-year mark of the study unlike the 10-year data.7,8 BDES and EES did
not control for confounding variables such as other medical conditions requiring aspirin
use such as arthritis.
A recent review and meta-analysis demonstrated that there were no
differences that exist between novel oral anticoagulants and other antithrombotic
drugs for risk of substantial intraocular bleeding. In the Comparison of AMD
Treatments Trials (CATT), Martin et al. attempted to seek the association between
use of anticoagulant/antiplatelet and retinal hemorrhage. Among 1165 participants
with active neovascular AMD, they found no significant association between the use
of antiplatelet/anticoagulant with retinal hemorrhage at baseline.14
Conclusion:
The BMES, BES, EES Blue Mountains Eye Study, the European Eye Study, and the
Beaver Dam Eye Study received a great deal of press without the adequate context and
consequences being explained to the public and to the medical community. The New
York Times and CBS News have released newspaper articles discussing the results of the
Blue Mountain Eye Study that resulted in patients stopping their recommended aspirin
intake.1,2 However, Dr. Gregg Fonarow from UCLA stated that “individuals prescribed
aspirin for high-risk primary or secondary cardiovascular prevention should not be
concerned or discontinue this beneficial therapy.”1 Dr. George Diamond and Dr. Sanjay
Kaul, cardiologists at Cedars-Sinai Hospital, also described how individuals should
maintain the “status quo” and keep taking their recommended daily aspirin because the
Blue Mountain Eye Study was observational and did not prove cause and effect.2 Dr.
Rosenfeld added some context by noting how the correlation between aspirin and wet
AMD is a marginal increase and thus may not represent a real-world significance.15
Patients who are taking aspirin for cardiovascular health should not fear the possible,
theoretical and exaggerated risks of exacerbating their AMD. The inaccurate press
releases have endangered the public by frightening many of the nation’s elderly into
discontinuing their prescribed aspirin use.
Overall the number, size, and quality of the studies recommending aspirin use is
much greater than the few studies suggesting a possible adverse effect of aspirin use.
This is reflected in the much smaller confidence intervals as shown in figure 1. The
studies suggesting subjects to discontinue aspirin are post hoc analyses with small
subject sizes and extremely wide confidence intervals. Substantial evidence exists to
support the conclusion that the benefits of aspirin in decreasing the risk of stroke, heart
attack, and death outweigh the potential minor increase in incidence of wet AMD
caused by aspirin. Therefore, patients should continue taking their daily aspirin dose
recommended by their primary physician.
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