Article

Aspirin Use and Age-Related Macular Degeneration

Well-documented cardiovascular benefits of aspirin outweigh unproven added risk of AMD.

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Recent press releases regarding the potential adverse effects of aspirin on macular degeneration have caused patients with age-related macular degeneration (AMD) to discontinue their aspirin use without consulting their primary care physicians. There are many benefits to aspirin use and therefore many reasons that patients should continue taking the recommended aspirin dose prescribed by their primary physicians or cardiologists. As with any treatment, it is important to consider the risk-to-benefit ratio of aspirin use, especially in generally elderly and high-risk populations.

The benefits of aspirin have long been well documented, and it is highly recommended for the prevention and treatment of cardiovascular (CV) diseases, such as myocardial infarction, stroke, and death. The recent retrospective epidemiological eye studies suggesting that aspirin use may exacerbate macular degeneration are based on 3 limited studies, while the benefits of aspirin use for macular degeneration patients have been suggested in larger studies, including the Age-Related Eye Disease Study (AREDS), the Physicians Health Study (PHS), and the Women’s Health Study.1-4 Therefore, the data regarding the effects of aspirin on AMD are conflicting and inconclusive.

To understand the connection between AMD and aspirin, we must discuss how aspirin gets into our bodies. Aspirin is a classical non-steroidal anti-inflammatory drug, which works through both cyclooxygenase (COX)-dependent pathways and COX-independent pathways.5 Aspirin has various pharmacological effects, and it is logical to conclude that it could produce some effects on AMD, the pathophysiology of which remains unclear. Among risk factors for AMD are smoking, previous cataract surgery, age, and family history.6 The evidence regarding the relationship between aspirin use and the development or exacerbation of AMD are unproven, and the possible effects of aspirin on AMD from current experimental research can only be presumed.

REVIEW OF LARGE CARDIOVASCULAR STUDIES

First, we performed a review of numerous epidemiological and prospective, randomized, and placebo-controlled studies concerning aspirin use to establish the benefits of aspirin in the prevention of CV diseases (CVDs). We performed a meta-analysis utilizing 9 published trials by the Antithrombotic Trialists’ Collaboration, including the PHS, Hypertension Optimal Treatment Study, Primary Prevention Project, and Asymptomatic Atherosclerosis Trial, highlighting the effectiveness of aspirin in primary prevention of CV events. Approximately 90,000 individuals were analyzed among the 9 trials; 50,868 subjects were treated with aspirin, and 49,170 received placebo/control.7 The meta-analysis of total CV events showed significant advantage of aspirin over placebo. The table further illustrates all 9 primary prevention trials with the statistical significance of CV end points.

Another meta-analysis utilized 5 published trials, including the British Doctors’ Trial and Thrombosis Prevention Trial, containing 55,580 randomized participants showing a 32% reduction in the risk of nonfatal stroke (odds ratio [OR]: 0.68, 95% confidence interval [CI], 0.59-.79) among regular aspirin users.4 The study also demonstrated that aspirin users had a decrease in the risk of vascular events by 15% (OR: 0.85, 95% CI, 0.79-0.93).8 In another updated studywide meta-analysis of 11 primary prevention trials (n=118,335), aspirin use was associated with reductions in nonfatal myocardial infarction (relative risk [RR]=0.78; 95% CI, 0.71-0.87).9 In the 8 trials (n=87,524) in which aspirin doses were tested, there was a statistically significant reduction in nonfatal total stroke (RR=0.86; 95% CI, 0.76-0.98).9 Critical issues with meta-analysis studies include the selection and identification of studies, as well as their heterogeneity. Although these limitations are real, the CVD vs AMD meta-analyses mentioned above incorporated a variety of studies with positive and negative conclusions to avoid selection bias. Each CVD study included in the meta-analysis focused on a certain population, and the confidence interval bands were small, proving that it was significantly more prevalent (Table 1 and Figure 1).

Table 1. Cardiovascular Studies vs AMD Studies: Statistics
STUDY TYPE STUDY STUDY SIZE ODDS RATIO/RELATIVE RISK CONFIDENCE INTERVAL
Cardiovascular Studies British Medical Doctors 5,139 1.023 0.820-1.275
Physicians Health Study (CV) 22,071 0.769 0.656-0.900
Thrombosis Prevention Trial 5,085 0.741 0.565-0.972
Hypertension Optimal Treatment 18,790 0.824 0.690-0.985
Primary Prevention Project 4,495 0.72 0.483-1.075
Women’s Health Study 39,876 0.912 0.804-1.034
Aspirin for Asymptomatic Atherosclerosis Trial 28,980 0.956 0.735-1.244
Prevention of Progression of Arterial Disease and Diabetes 1,276 0.967 0.720-1.298
Japanese Prevention of Atherosclerosis with Aspirin in Diabetes 2,539 0.865 0.562-1.332
AMD Studies Against Aspirin Use Blue Mountain Eye Study 2,389 2.46 1.25-4.83
European Eye Study 4,691 wet AMD 1.26; grade 2 1.42 1.61-3.05; 1.18-1.70
Beaver Dam Eye Study 4,926 2.2 1.20-4.15

Figure 1. The proportional effects of aspirin (an antiplatelet) on numerous cardiovascular events (MI, stroke, or vascular death) and AMD studies are shown above. The diamonds represent the odds ratio of the high-risk events, while the horizontal lines demonstrate the 95% confidence intervals for each category. All results to the left of the dashed line represent the benefits of aspirin for patients with risk for vascular events while any data to the right of the dashed line show the negative effect of aspirin for AMD patients.
AMD, age-related macular degeneration; CV, cardiovascular.

REVIEW OF AMD EPIDEMIOLOGICAL STUDIES

We analyzed 10 studies, including the anti-aspirin studies, the Blue Mountain Eye Study (BMES) and the European Eye Study (EES), involving 171,729 individuals, examining the association of aspirin use with AMD risk.1-2,10-17 We found that a random-effects meta-analysis of studies concluded that aspirin use had neither beneficial nor harmful effects on AMD and was not associated with AMD risk (RR, 1.09; 95% CI, 0.96-1.24; I2, 67.3%).18 In addition, we performed subgroup analyses by AMD stage, adjustment status, country, smoking status, study type, and hypertension and hyperlipidemia status. The results of the analysis of stages of AMD revealed that aspirin use was correlated with neither early-stage (RR, 1.02; 95% CI, 0.87-1.29; P=.872; I2, 54.7%) nor late-stage AMD (RR, 1.11; 95% CI, 0.77-1.60; P=.587, I2, 0.00%).18 No associations were detected in a randomized, controlled trial (RCT) group when subgroup analyses were conducted according to study type (RR, 0.81; 95% CI, 064-1.02; I2, 0.00%), cohort group (RR, 1.17%; 95% CI, 0.96-1.14; I2, 0.00%), and case-control group (RR, 1.02; 95% CI, 0.92-1.14; I2, 44.8%). These results indicate that aspirin use is unlikely to be associated with the risk of AMD.18

THE BLUE MOUNTAIN EYE STUDY

However, we wanted to focus on the specific, smaller AMD epidemiological studies to illustrate the results and limitations of the publications causing people to discontinue aspirin. The 3 ophthalmological studies suggesting adverse effects of aspirin on AMD are the BMES, the EES, and the Beaver Dam Eye Study (BDES). The BMES database contained 2,389 individuals, but only 257 were regular aspirin users (10.8%). A post hoc analysis was performed to determine whether regular aspirin use interacted with AMD. This study was conducted over a 15-year period in which only 63 of the 2,389 patients developed neovascular AMD. The BMES 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).19 The increase in neovascular AMD (wet AMD) progressed from 1.9% at 5 years to 7% at 10 years, and 9.3% at 15 years in regular aspirin users (OR: 2.46, 95% CI: 1.25-4.83, n=257).19

THE EUROPEAN EYE STUDY

The EES pooled 4,691 participants at 65 years of age and older, collected using random sampling. The study 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 regular aspirin use, the odds ratios increased with the severity of the AMD (n=839, grade 1, 1.26 [95% CI, 1.08-1.46; P<.001], grade 2, 1.42 [95% CI, 1.18-1.70], and wet late AMD, 2.22 [95% CI, 1.61-3.05]).12 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 subjects older than 85 years.12

THE BEAVER DAM EYE STUDY

The BDES is a longitudinal population-based study performed every 5 years for a 20-year period containing 4,926 participants between the ages of 43 to 86 years old. Regular aspirin use 10 years prior to retinal examination (n=1,462) was associated with late AMD (n=58, hazard ratio [HR], 1.63 [95% CI, 1.01-2.63]; P=.05) and with an 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 (n=58, HR, 2.20 [95% CI, 1.20-4.15]; P=.01) but not pure geographic atrophy (n=24, HR, 0.66 [95% CI, 0.25-1.95]; P=.45). Aspirin use for 5 years (HR, 0.86 [95% CI, 0.71-1.05]; P=.13) or 10 years (HR, 0.86 [95% CI, 0.65-1.13]; P=.28) prior to retinal examination was not associated with incidence early AMD.12 Additionally, aspirin use 5 years prior to incidence was not associated with early or late AMD.

LIMITATIONS OF BLUE MOUNTAIN EYE STUDY

The BMES had several limitations as noted by the authors. The dose of aspirin that each participant consumed was not collected; thus, it was assumed that every “regular user” consumed 150 mg daily, based on most aspirin prescriptions in Australia. However, different brands have different dosages available, and aspirin can be bought without a prescription. Additionally, the length of exposure to aspirin was not accurately accounted for. Patient recollection of usage is subject to recall error, and the reported usage for a certain year does not guarantee the usage in preceding years. Additionally, the sample size of the regular aspirin users in the cohort study (n=257) was small and not randomized. There was a small number of late AMD cases (n=63), and only 56% of the participants had follow-up examinations at the 15-year mark.20 Comorbidities are more likely for those taking aspirin, and increased use for other conditions was considered but not controlled for adequately. The cohorts were not balanced with respect to age, incidence of stroke, heart diseases, and diabetes, which is important because these groups have a significantly higher incidence of aspirin intake.20

The BMES has been overinterpreted due to excessive media commentary focusing on the 2.5 factor of increased risk of developing wet AMD when patients take aspirin. However, the absolute risk over 15 years was 9.3% for aspirin users and 3.7% for those not taking aspirin.19-21 No conclusions were drawn about correlations in the BMES, and the authors noted that the results do not reach statistical significance when adjusted for other risk factors (body-mass index, blood pressure, diabetes mellitus, blood total cholesterol level, and fish consumption).19

LIMITATIONS OF BEAVER DAM EYE STUDY

Another study indicating AMD risk with aspirin use is the BDES, which contains numerous limitations, as noted by the authors. A total of 17,693 regular aspirin users participated in the study, of whom 58 developed late AMD. Regular aspirin users were defined as participants who took aspirin at least twice per week for more than 3 months, with a cumulative dose of only 24 pills. These criteria may not properly define a regular aspirin user.17 Similar to in the BMES, aspirin users may have taken considerably larger amounts of the drug during the course of the study, and aspirin use in these individuals may have been for CVDs or arthritis treatment or for those at high risk for these diseases. Confounding factors such as CVD were not included, such as hyperlipidemia history, cholesterol, triglycerides, and lipoprotein cholesterol levels. It is likely that subjects who regularly use aspirin have higher blood lipid levels than those who do not use aspirin, and high cholesterol is thought to contribute to AMD pathogenesis.22 Also, it is important to note that geographic atrophy and neovascular AMD are 2 distinct disorders with different pathophysiologies, risk factors, and genetic backgrounds. The authors considered the 2 groups a single entity when evaluating for the association of aspirin use.23,24 The association between regular aspirin use and neovascular AMD may be a product of type I error, because of potential bias in observational studies and the limitations of group definitions and statistical analysis.16 This claim is supported by the inability of authors to confirm such relationships in auxiliary analyses.

LIMITATIONS OF EUROPEAN EYE STUDY

The EES, also a post hoc analysis, contained a small sample size of regular aspirin users (n=839), of whom only 45 developed late AMD. Their results had an extremely wide confidence interval due primarily to the small sample size. In this study, the authors also noted a possibility that people with AMD took aspirin after experiencing visual problems.12 There are no data regarding the quantity of aspirin that the subjects used (ie, 81 mg vs 300 mg). Additionally, the authors did not eliminate the potential influence of CV deaths or angina in the analyses.12 There are also no data on other morbidities, such as arthritis, for which aspirin may have been prescribed. The authors also suggested that aspirin has no effect on AMD risk at the 5-year mark of the study, unlike the 10-year data.12

STUDIES SHOWING NO ADVERSE ASSOCIATION BETWEEN AMD AND ASPIRIN

In contrast, there are numerous studies that found no adverse effects of aspirin on AMD. The Physicians’ Health Study 1 (PHS1) reported that there was no increase in AMD over 7 to 10 years among regular aspirin users. In this randomized, prospective, placebo-controlled trial, 22,071 participants enrolled at the baseline, and a minimum of 7-year follow-up was conducted. A total of 10,617 were regular aspirin users, of whom there were 51 cases of age-related maculopathy (ARM) in the aspirin group and 66 in the placebo group (RR, 0.77; 95% CI, 0.54-1.11). For ARM with vision loss, there were 25 cases in the aspirin group and 32 in the placebo group (RR, 0.78; 95% CI, 0.46-1.32).1 These data demonstrated the protective effects of aspirin and that people taking aspirin were less likely to develop macular degeneration than those taking placebo.1

AREDS reported that aspirin is actually beneficial in the protection of dry AMD patients.3-4,25 A larger study, AREDS showed the possible benefits of aspirin use for macular degeneration. AREDS studies 1, 3, and 19 noted that the association between aspirin and AMD is not statistically significant.3-4,25 The case-controlled AREDS reported that the use of anti-inflammatory medications, including aspirin, did have a protective effect on dry AMD. A recent review and meta-analysis demonstrated that there were no differences between novel oral anticoagulants and other antithrombotic drugs in the risk of substantial intraocular bleeding.26 In the Comparison of AMD Treatments Trials (CATT), the investigators attempted to determine the association between the use of anticoagulants/antiplatelets and retinal hemorrhage. Among 1,165 participants with active neovascular AMD, they found no significant association between the use of antiplatelets/anticoagulants and retinal hemorrhage at baseline.26

SUMMARY

The BMES, the EES, and the BDES received a great deal of attention in the press without an adequate context or the consequences being explained to the public and to the medical community. The risk for developing macular degeneration increases with aging. The small and still unconfirmed added risk of AMD is far outweighed by the solid benefits of cardioprotective aspirin. The BDES cannot conclude for certain whether aspirin causes late-life vision loss. CVDs or underlying inflammatory conditions could have affected the individuals in these studies, who may be at higher risk for developing AMD due to aspirin use. Additionally, individuals with CVDs or a history of CVD are more susceptible to developing AMD.6 Thus, it is difficult to disentangle whether the correlation is due to aspirin or underlying risk factors that lead people to use aspirin.1-2

Even if aspirin use were confirmed as an AMD risk factor using more robust study data, it is already apparent that the risk would be quite small in absolute terms, at approximately 1% for aspirin users and 0.5% for nonusers, which is not clinically meaningful.17 There are currently good treatment options for neovascular AMD, yet for CVDs and other similar conditions, aspirin is one of the main treatment options. The AMD and aspirin association is extremely limited, and the presumptions that have been made are not based on persuasive empirical data.

Several problems, such as the definition of aspirin use, the inclusion and exclusion of the participants, and the required long-term follow-up, make it difficult to conclude that a confirmatory relationship exists between aspirin use and AMD. In the studies mentioning the adverse effects of aspirin on AMD, confounding factors were not accounted for, which are crucial to making any conclusions. Overall, the number, size, and quality of the studies recommending aspirin use are much greater than those of the few studies suggesting a possible adverse effect of aspirin use. This fact is reflected in the much tighter confidence intervals, as shown in the figure, of the benefits of aspirin use. Additionally, many AMD studies that monitored AMD progression per couple of years have data preceding optical coherence tomography usage, which affects the accurate diagnosis and monitoring of AMD. However, the studies suggesting that subjects 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 serious medical conditions, such as stroke and heart attack, and death outweigh the potential minor increase in the incidence of wet AMD possibly associated with aspirin use. Patients who are taking aspirin for CV health should not fear the possible, theoretical, and exaggerated risks of exacerbating their AMD. Inaccurate press releases have endangered the public by frightening many of the nation’s elderly into discontinuing their needed prescribed aspirin use, which could mean the difference between life and death. RP

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