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Retina  |   April 2014
Association Between Aspirin Use and Age-Related Macular Degeneration: A Meta-Analysis
Author Notes
  • Department of Ophthalmology, the Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, Zhejiang, China 
  • Correspondence: Juan Ye, Department of Ophthalmology, the Second Affiliated Hospital of Zhejiang University, College of Medicine, Jiefang Road 88, Hangzhou 310009, China; Yejuan@zju.edu.cn
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 2687-2696. doi:10.1167/iovs.13-13206
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      Juan Ye, Yu-Feng Xu, Jin-Jing He, Li-Xia Lou; Association Between Aspirin Use and Age-Related Macular Degeneration: A Meta-Analysis. Invest. Ophthalmol. Vis. Sci. 2014;55(4):2687-2696. doi: 10.1167/iovs.13-13206.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: We conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies to evaluate the association between aspirin use and age-related macular degeneration (AMD).

Methods.: The pertinent studies were identified via literature search through four databases (MEDLINE, Web of Science, Cochrane Library, Embase) and reference lists of retrieved studies. Randomized controlled trials and cohort and case–control studies meeting the predefined criteria were included. We extracted relative risk (RR) or odds ratio (OR) or hazard ratio (HR) and 95% confidence interval (CI) from each study. Overall and study-specific risk estimates were pooled using fixed-effects and random-effects models, respectively. Subgroup analyses based on several stratified factors were also performed.

Results.: In total, two RCTs, three cohort studies, and four case–control studies involving 177,683 subjects were included. The pooled effect of all nine studies showed no significant association between aspirin use and occurrence of AMD (RR, 1.00; 95% CI 0.96–1.04), and no significant association was observed in any specific study design (RR, 0.93; 95% CI 0.71–1.22 for RCT; RR, 1.02; 95% CI 0.87–1.20 for cohort study; RR, 1.00; 95% CI 0.96–1.04 for case–control study). However, subgroup analysis showed aspirin use to be significantly associated with an increased risk of neovascular AMD (RR, 1.59; 95% CI 1.09–2.31).

Conclusions.: The pooled effects from current literature suggest that aspirin use is not associated with AMD, but it increased the risk of the neovascular form of AMD.

Introduction
Age-related macular degeneration (AMD) is a chronic disease affecting the central retina, retinal pigment epithelium, and choriocapillaris progressively. 1 In many developed countries, AMD is one of the leading causes of irreversible visual impairment, especially in elderly people. 2 In spite of its common occurrence, the treatment options for AMD are limited. 3 Furthermore, effective protective measures are not established, because few consistent modifiable risk factors have been identified apart from smoking. 4,5  
Several epidemiological studies have found that AMD shares some established risk factors with cardiovascular disease. 610 Moreover, research on postmortem eyes and surgically excised subretinal tissues from patients with AMD have revealed inflammatory cells or immune complexes within the lesions, 1114 which supports a vascular hypothesis for AMD involving the comprehensive interaction of inflammation, 15 atherosclerosis, 16 and oxidative processes. 17 If vascular factors do contribute to AMD pathogenesis, agents such as aspirin that affect blood circulation of the eye might influence the development and progression of AMD. However, results of epidemiologic studies of the relationship between aspirin use and risk of AMD are currently inconclusive. 1822 It has been estimated that more than 100 billion tablets of aspirin are used each year worldwide, 23 primarily for the prevention of recurrent cardiovascular disease. 24 Thus, these contradictory conclusions and indistinct associations confound clinical judgment. 
Although a meta-analysis of the correlation between aspirin use and risk of AMD was performed previously, 25 it appeared to be flawed because of confusion in the selection criteria, misclassification of study designs, and pooling of moderate-adjusted risk estimates instead of full-adjusted ones. In our current study, we strictly adhered to our inclusion criteria, covered two additional eligible articles, 18,26 and pooled the latest statistics from two updated cohort studies 27,28 in order to provide robust evidence based on high-quality literature. Several of the selected articles presented the results based on different categories of exposure, duration, or other factors, compared with a single reference category. Simply using the fixed-effects model to combine these kinds of different risk estimates in a single study might have substantially underestimated the width of the confidence intervals (CI). 29 Thus, we used a more rational combination method, recommended by Hamling et al., 29 to address risk estimates within a single study that involved the same reference group and performed intensive subgroup analyses to address the uncertain association of aspirin use and AMD. 
Methods
Search Strategy
We conducted a systematic search through four databases, including MEDLINE (1950 to April 2013), Web of Science (1900 to April 2013), Cochrane Library (up to April 2013), and Embase (1980 to April 2013), using the following search items: macular degeneration OR age-related maculopathy OR macular dystrophy OR age-related macular degeneration OR drusen OR retinal degeneration OR choroidal neovascularisation OR CNV OR geographic atrophy, combined with aspirin OR acetylsalicylic acid OR acylpyrin OR anticoagulant OR nonsteroidal anti-inflammatory OR fibrinolytic OR antiplatelet OR platelet aggregation inhibitor OR cyclooxygenase inhibitor OR antipyretic OR NSAIDs. Language was restricted to English. References in the retrieved publications were checked for other pertinent studies. 
Study Selection
We considered the studies eligible if they met the following criteria: (1) they were randomized controlled trials (RCTs) or cohort or case–control studies published as original articles; (2) they estimated the relationship between aspirin use and the risk of AMD with the relative risk ratio (RR) or odds ratio (OR) or hazard ratio (HR) and 95% CI or provided any other calculable information; and (3) the study quality assessment was no less than 15 according to the Downs and Black 30 instrument. When articles with overlapping participants were available, we chose only the latest or the most complete ones. We excluded the gray literature, such as conference abstracts, as they lacked adequate information for evaluation of their validity and reliability. We focused only on the effect of aspirin on AMD and excluded risk estimates of other medicines with effects or classification similar to aspirin. 
Two of the authors (Y-FX and J-JH) reviewed the titles and abstracts independently to exclude any obviously irrelevant studies. If uncertainty regarding suitability remained after that, full manuscripts were subsequently obtained. Any disagreements were resolved by discussion. 
Data Extraction and Study Quality Evaluation
For each study, the following characteristics were extracted: (1) last name of first author, (2) publication year, (3) country in which the study was conducted, (4) study design, (5) study period, (6) population type and sample size, (7) mean age or age range of study subjects, (8) follow-up time, (9) definition of aspirin exposure status, (10) AMD classification, (11) AMD diagnosis and grading criteria, and (12) covariates in the final adjusted models. We contacted the corresponding authors when additional data not included in the retrieved articles were needed. 
As RCTs and nonrandomized observational studies were included, methodological quality was assessed according to the validated Downs and Black scale, 30 which evaluates reporting, external validity, internal validity (bias and confounding), and power. Generally, the results were graded into four groups from best to worst: 26 to 28, 20 to 25, 15 to 19, and ≤14. 31 The assessments were carried out independently by the above-mentioned two authors (Y-FX and J-JH), and divergences were resolved by consensus. 
Data Synthesis
According to recent epidemiologic studies 1,3236 and the studies included in our meta-analysis, the incidence of AMD was up to 9.5% in the specified age group, 37 so ORs were accurate approximations of RRs, and HRs were directly considered RRs in this situation. 38 Different kinds of risk estimates from included studies were converted to RRs to calculate the pooled results. Several studies did not present the overall risk estimates of AMD but showed only results of bifurcation analyses (e.g., AMD stages). We used two methods of analysis: (1) A fixed-effects model was used to calculate a combined RR if the estimates did not involve the same reference group of nonusers of aspirin 39 ; and (2) if the same reference group was involved, we adopted the strategy recommended by Hamling et al. 29 (see Supplementary Table S1 for the computational formula). When confronted by different kinds of risk estimates in the same study, we preferred the latest and most completely adjusted one in our meta-analysis. 
Heterogeneity among included studies was tested by the Cochran Q and I 2 statistics. 40 Significant heterogeneity was detected if the P value was <0.1 or I 2 was >50%. 41 If so, the random-effects model was more appropriate; if not, the fixed-effects model was adopted. Although substantial heterogeneity did not show in the overall analysis (P = 0.69; I 2 = 0.0%), we conducted subgroup analyses based on study design, length of follow-up, participant source, adjustment for smoking, and diagnoses of early and late AMD, neovascular AMD, and geographic atrophy AMD in order to identify every possible influencing factor and provide robust evidence. Under the theory that random-effects model results are more conservative and that they more precisely approximate results from the fixed-effects model when no significant heterogeneity is detected, we used a random-effects model throughout all the subgroup analyses. Potential publication bias was assessed by Egger's test 42 and Begg's test. 43 A sensitivity analysis was performed to test the stability of our results by the following methods: removal of the article with the largest statistical weight, change of combination model (e.g., change fixed-effect model to random-effect model or change random-effect model to fixed-effect model), and removal of articles with volunteer subjects. All analyses were performed using Stata/SE version 12.0 (StataCorp LP, College Station, TX). The level of significance was set to P < 0.05, except where otherwise specified. 
Results
Identification and Selection of Studies
Our search of four databases identified 1058 articles. After screening of titles and abstracts, 1026 unrelated articles were excluded as nonrelevant. In further evaluation of the remaining 32 articles, 24 were excluded for the following reasons: 9 were conference abstracts (Sen H, et al. IOVS 2007;48:ARVO E-Abstract 2166; Marcus DM, et al. IOVS 1998;39:ARVO Abstract 2784; Gaudio A, et al. IOVS 1996;37:ARVO Abstract 517; Christen WG, et al. IOVS 1993;34:ARVO Abstract 2120; Christen WG, et al. IOVS 1997;38:ARVO Abstract 2191; Ajani UA, et al. IOVS 1997;38:ARVO Abstract 2188; Ajani U, et al. IOVS 1996;37:ARVO Abstract 1921; Cusick M, et al. IOVS 2005;46:ARVO Abstract 3306) 44 ; 5 were crosssectional studies 32,4548 ; 3 were reviews 25,49,50 ; 2 were reprinted 51,52 ; 2 53,54 were updated by later reports; 1 was a case-series study 22 ; 1 was a description of an RCT protocol 55 ; and 1 did not report 95% CI for risk estimates. 56 Two additional articles 18,26 were identified from reference lists. In the remaining 10 articles, 1 57 was excluded after quality evaluation. Finally, two RCTs, 58,59 three cohort studies, 18,37,60 and four case–control studies 26,6163 met our criteria (Fig. 1). 
Figure 1
 
Flow chart showing the study selection process.
Figure 1
 
Flow chart showing the study selection process.
Study Characteristics
Characteristics of selected studies are summarized in Table 1. The nine studies involved 177,683 participants from 1986 to 2010. One study was conducted in Australia, one in the United Kingdom, and seven in the United States. Participants in all the studies were 40 years of age or older. Three studies were population-based studies; four were clinic-based studies; and two were RCTs consisting of healthy volunteers—female professionals 58 and male physicians, 59 respectively. The follow-up length of the studies ranged from 3 to 15 years, with the exception of two case–control studies 26,63 that did not indicate time periods. Definition and duration of aspirin exposure varied among the studies, and most of them ascertained the exposure via standard questionnaires or checking of medical records. However, 100 mg 58 and 325 mg 59 aspirin every other day were the established regimen in the two RCTs. Not all studies specified subtypes of AMD. Different diagnostic methods (e.g., fundus photography, fluorescein angiography, or self-reported best-corrected visual acuity) and various grading criteria (e.g., the International AMD Classification, Wisconsin ARM Grading System) were used. The covariates used to adjust the risk estimates were not consistent, and two matched-pair case–control studies 26,62 reported unadjusted outcomes. There was no disagreement between the two independent reviewers who conducted the quality assessment. 
Table 1
 
Summary of Included Studies Evaluating Aspirin Use and Its Association With Age-Related Macular Degeneration
Table 1
 
Summary of Included Studies Evaluating Aspirin Use and Its Association With Age-Related Macular Degeneration
Source (Publication Year, Country) Design Study Period Population (Sample Size) Mean Age, y Follow- Up, y Aspirin Exposure Status AMD Classification AMD Definition and Grading Adjusted Variables Quality
Liew et al. 61 (2013, Australia) Cohort 1992–2010 Blue Mountains Eye Study, population based (N = 2,389) 64.1 15 Questionnaire confirmed by medicine lists and/or bottles
Regular: ≥once/wk
Occasional: <once/wk
Nonregular: none and occasional
Dosage: 150 mg/d, assumed from common Australian prescription
Early Geographic  atrophy
Neovascular
Stereoscopic retinal photograph
International AMD Classification
Age, sex, smoking, cardiovascular disease, systolic blood pressure, BMI 16
Klein et al. 37 (2012, US) Cohort 1988–2010 Beaver Dam Eye Study, population based (N = 4,926) 43–86 14.8 Self-report confirmed by medicine at every visit
Ever: ≥twice/wk for more than 3 mo
Never
Early
Late
Neovascular
Geographic  atrophy
Photographs of the retina Wisconsin ARM Grading System Age, sex 19
Rudnicka et al. 62 (2010, UK) Case-control 1996–2002 Clinic based (N = 158) ≥45 3 Questionnaire confirmed by medicine
Ever: any dosage
Never
Late Fundus photography; International ARM Epidemiological Study Group criteria Age, sex, smoking, blood pressure, BMI, total cholesterol 17
Christen et al. 59 (2009, US) RCT 1994–2004 Women's Health Study, volunteer health professionals, female only (N = 39,876) ≥45 10 Low-dose aspirin, 100 mg every other day
Placebo
Visually significant
Advanced: neovascular and geographic atrophy with or without vision loss
Self-report confirmed by medical records review
BCVA ≤ 20/30
Age, vitamin E, beta-carotene treatment 24
Douglas et al. 63 (2007, UK) Case-control 1987–2002 General Practice Research Database, population based (N = 104,176) ≥50 4 Medical records
Ever
Never
Any status Medical records confirmed by letters or reports Consultation rate 15
Clemons et al. 18 (2005, US) Cohort 1992–2004 Age-Related Eye Disease Study, clinic based (N = 4,757) 55–80 6.3 Questionnaires
Ever: ≥5 y
Never
Neovascular Geographic atrophy Stereoscopic color fundus photographs confirmed by annual visiting Age, sex, treatment assignment 17
DeAngelis et al. 64 (2004, US) Case-control 1998–2003 Clinic based (N = 136) ≥50 none Questionnaires
Ever
Never
Neovascular Fundus photography, fluorescein angiography, home examination None 15
Christen et al. 60 (2001, US) RCT 1982–1988 Physicians' Health Study I, volunteer health physicians, male only (N = 21,216) 40–84 7 Aspirin 325 mg every other day Placebo Without vision loss
With or without vision loss
Self-report confirmed by medical records BCVA ≤ 20/30 Age, beta-carotene treatment assignment 23
Blumenkranz et al. 26 (1986, US) Case-control 1986 Clinic based (N = 49) 75.7 none Questionnaires
Ever or current
Never
Neovascular Color fundus photograph None 15
Association Between Aspirin Use and AMD
In the overall analysis, we detected no significant heterogeneity among RCTs, cohort, and case–control studies (P = 0.69; I 2 = 0.0%), and found that aspirin use (RR, 1.00, 95% CI 0.96–1.04) was not associated with overall risk of AMD (Fig. 2). We then conducted subgroup analyses based on the following stratified factors (Table 2): 
Figure 2
 
Risk estimates of aspirin use with age-related macular degeneration in overall analysis. ES, effect size (in our analysis, ES means risk ratio).
Figure 2
 
Risk estimates of aspirin use with age-related macular degeneration in overall analysis. ES, effect size (in our analysis, ES means risk ratio).
Table 2
 
Subgroup Analyses of Aspirin Use and Age-Related Macular Degeneration
Table 2
 
Subgroup Analyses of Aspirin Use and Age-Related Macular Degeneration
Subgroups No. of Studies Summary Effect RR (95% CI) P Value Study Heterogeneity
I 2, % P Value
Study design
 RCT 2 0.93 (0.71–1.22) 0.62 52.30 0.15
 Cohort 3 1.02 (0.87–1.20) 0.78 0.00 0.49
 Case-control 4 1.00 (0.96–1.04) 0.98 0.00 0.59
Follow-up length
 Less than 10 years 3 0.99 (0.96–1.03) 0.77 0.00 0.46
 More than 10 years 6 1.05 (0.93–1.19) 0.41 0.00 0.92
Source of subjects
 Population based 3 1.00 (0.97–1.04) 0.86 0.00 0.70
 Clinic based 4 0.87 (0.66–1.15) 0.34 0.00 0.62
 Volunteer based 2 0.93 (0.71–1.22) 0.62 52.30 0.15
Adjusted for smoking
 Yes 2 0.99 (0.65–1.51) 0.96 23.90 0.25
 No 7 1.00 (0.96–1.04) 0.93 0.00 0.66
AMD stage
 Early 2 0.90 (0.69–1.16) 0.41 0.00 0.74
 Late 7 1.07 (0.84–1.37) 0.57 27.10 0.22
AMD subtype
 Neovascular 5 1.59 (1.09–2.31) 0.02 31.50 0.21
 Geographic atrophy 3 0.84 (0.58–1.22) 0.35 0.00 0.65
  1.  
    Study design: In the study-specific analysis, no significant association was identified in the RCT group (RR, 0.93; 95% CI 0.71–1.22; P = 0.15, I 2 = 52.3%), cohort group (RR, 1.02; 95% CI 0.87–1.20; P = 0.49, I 2 = 0.0%), or case–control group (RR, 1.00; 95% CI 0.96–1.04; P = 0.59, I 2 = 0.0%; Fig. 3).
  2.  
    Length of follow-up: Considering the cumulative effect of aspirin and considering that AMD is a chronic and progressive disease, we divided the nine studies into two groups based on length of follow-up. The longer follow-up group included three studies 37,58,60 with follow-up periods of no less than 10 years. The shorter follow-up group consisted all the other studies. 18,26,59,6163 No significant relationship between aspirin use and AMD was observed in either the longer follow-up group (RR, 1.05; 95% CI 0.93–1.19; P = 0.92, I 2 = 0.0%) or the shorter follow-up group (RR, 0.99; 95% CI 0.96–1.03; P = 0.46, I 2 = 0.0%).
  3.  
    Study participant source: Despite the different participant sources, there was no contradiction in pooled estimates among population-based studies 37,60,62 (RR, 1.00; 95% CI 0.97–1.04; P = 0.70, I 2 = 0.0%), clinic-based studies 58,59 (RR, 0.87; 95% CI 0.66–1.15; P = 0.62, I 2 = 0.0%), and volunteer-based studies 18,26,61,63 (RR, 0.93; 95% CI 0.71–1.22; P = 0.15, I 2 = 52.3%).
  4.  
    Adjustment for smoking: Increasing age and smoking 4,5 have been consistently demonstrated to be risk factors for AMD. Since all the studies in this meta-analysis adjusted or matched for age, we checked the outcomes in both the smoking-adjusted group 60,61 (RR, 0.99; 95% CI 0.65–1.51; P = 0.25, I 2 = 23.9%) and the group not adjusted for smoking 18,26,37,58,59,62,63 (RR, 1.00; 95% CI 0.96–1.04; P = 0.66, I 2 = 0.0%). No significant association was uncovered.
  5.  
    Early- and late-stage AMD: We considered late-stage AMD to include neovascular and geographic atrophy subtypes. No significant correlation with aspirin use was revealed in the early-stage group 37,60 (RR, 0.90; 95% CI 0.69–1.16; P = 0.74, I 2 = 0.0%) or the late-stage group 18,26,37,58,60,61,63 (RR, 1.07; 95% CI 0.84–1.37; P = 0.22, I 2 = 27.1%).
  6.  
    Neovascular and geographic atrophy subtypes: It is of particular interest that when the neovascular and geographic atrophy subtypes were analyzed, the neovascular group 18,26,37,60,63 was found to be associated with borderline but significantly increased risk (RR, 1.59; 95% CI 1.09–2.31; P = 0.21, I 2 = 31.5%). In contrast, no significant correlation was found in the geographic atrophy group 18,37,60 (RR, 0.84; 95% CI 0.58–1.22; P = 0.65, I 2 = 0.0%; Fig. 4).
Figure 3
 
Risk estimates of aspirin use with age-related macular degeneration in study-specific analysis.
Figure 3
 
Risk estimates of aspirin use with age-related macular degeneration in study-specific analysis.
Figure 4
 
Risk estimates of aspirin use with age-related macular degeneration in subgroup analysis based on neovascular and geographic atrophy subtypes. Neo, neovascular; ga, geographic atrophy.
Figure 4
 
Risk estimates of aspirin use with age-related macular degeneration in subgroup analysis based on neovascular and geographic atrophy subtypes. Neo, neovascular; ga, geographic atrophy.
Publication Bias and Sensitivity Analysis Study
The Begg rank correlation test and Egger linear regression test indicated no evidence of significant publication bias among studies (Begg, P = 0.60; Egger, P = 0.45). Sensitivity analysis was carried out in three ways, and there were no significant changes with the following: (1) removal of the article 62 with the largest statistical weight (RR, 1.00; 95% CI 0.90–1.11; P = 0.59, I 2 = 0.0%), (2) use of the random-effects model (RR, 1.00; 95% CI 0.96–1.04; P = 0.69, I 2 = 0.0%), and (3) removal of the studies that used volunteers 58,59 (RR, 1.00; 95% CI 0.96–1.04; P = 0.75, I 2 = 0.0%). 
Discussion
Regular consumption of aspirin is widespread in America, increasing with the increased survival years of the population. 23 Therefore, any elevated risk of disabilities or morbidities with aspirin use would be significant and would affect many people. Inconsistent results on the association between aspirin use and AMD have been addressed through different studies. In our current meta-analysis of RCTs and observational studies, we found no correlation in the overall and subgroup analyses except for a small but statistically significant risk of neovascular AMD (RR, 1.59; 95% CI 1.09–2.31). 
“Mixing apples and oranges” in meta-analysis refers to combining results from different study designs, subject populations, and statistical methods, and this approach is open to criticism. Nevertheless, inclusion of as many studies as possible is encouraged, if the studies to be pooled show no significant heterogeneity in heterogeneity test, in order to prevent misleading conclusions. 64 Thus, mixing apples and oranges can sometimes be desirable. In our current study, nonsignificant heterogeneity (P = 0.69; I 2 = 0.0%) was detected among studies of different designs. To test the robustness of our results, we conducted a study-specific investigation and found similar conclusions. We might attribute the marginal heterogeneity (P = 0.148, I 2 = 52.3%) between two RCTs 58,59 to the single-sex study populations, different dosages (325 or 100 mg every other day), and differing follow-up length (7 or 10 years). 
The subjects in the two studies by Christen and colleagues 58,59 were health care professionals who would be likely to be more conscientious about maintaining a healthy lifestyle. This selection bias might dilute the association between aspirin use and AMD toward null, if any association existed. Conversely, in the several studies 18,26,61,63 among participants from clinic populations, who are typically likely to have other diseases, or when unrecognized confounders like smoking were present, this would enhance the association. In any case, our subgroups based on population source and adjusted for smoking did not reveal contradictory results, implying that these limitations were unlikely to cause large bias. 
Most of the studies included in our meta-analysis reported nonsignificant outcomes, showing neither positive nor negative effects, except for the studies of Liew et al. 60 and Klein et al. 37 (In the study by Clemons et al., 18 aspirin showed a protective effect regarding geographic atrophy AMD in the group with unilateral AMD but shifted toward null when the values were combined with those of the other group who had bilateral AMD.) A 2-fold increased incidence of neovascular AMD was found by Liew et al. 60 (OR 2.46; 95% CI 1.25–4.83) and by Klein et al. 37 (HR 2.20; 95% CI 1.20–4.15), in keeping with the recent cross-sectional association in the European Eye Study (OR 2.22; 95% CI 1.61–3.05). 47 Both of these studies had a long observational time period (no less than 10 years) and full-stratified AMD stage, which may explain why other included studies failed to detect the potential association. 
To test our hypothesis, further evaluation based on follow-up time, early and late AMD stages, and neovascular and geographic atrophy AMD subtypes was performed. Although nonsignificant results were the same in the long- and short-term groups and in the early and late AMD groups, an interesting finding was that a borderline but significant hazard effect of aspirin appeared in the neovascular group (RR, 1.59; 95% CI 1.09–2.31) but not in the geographic atrophy group (RR, 0.84; 95% CI 0.58–1.22). 
In general, geographic atrophy and neovascular AMD have different characteristics in natural history, and their susceptibility to a given risk factor may vary. 65 Furthermore, the exact mechanism of aspirin in AMD pathogenesis is unknown, although it may act in several possible ways. Its most common effect is irreversible inhibition of cyclooxygenase 1 and 2, which are expressed in human RPE and in surgically excised choroidal neovascular membranes, 66 resulting in a remarkable decrease in platelet aggregability and risk of thrombosis. 67 Aspirin may also initiate secretion of endogenous anti-inflammation mediator 15-epi-lipoxin A4. 68 Moreover, it has been reported that endothelial cells can be protected from the deleterious effects of oxidative stress by aspirin. 69 However, the roles of vascular 70 or inflammatory 71 factors in AMD pathogenesis remain obscure. The mechanism may differ among the various stages and subtypes of AMD by the immediate and long-term effects of aspirin. Aside from inhibiting clotting, aspirin can enhance choroidal neovascularization via hypoxia caused by reduction in the synthesis of prostacyclin, an endothelium-derived vasodilator in blood vessels. 72 Other potential mechanisms include inhibition of the C1 inactivator 73 and disordering of the balance of lipid oxidation, especially low-density lipoprotein. 47 Thus, it is possible that aspirin encourages the growth of aberrant new vessels after the early injury of the retina. 37  
Several limitations in our work cannot be ignored. First, our literature search covered only articles published in English. Second, we excluded studies with a quality score lower than 15 for the purpose of providing high-quality evidence, even though no significant publication bias was observed in Begg's and Egger's tests. Third, only nine studies with three different designs, which were all based on white people, were included in this meta-analysis. Although meta-analysis showed good homogeneity among studies, we should be cautious about generalizing our conclusions to other races. Fourth, most studies used self-reported questionnaires or medical records to estimate the exposure to aspirin, and variability in degree of recall bias cannot be avoided. We failed to evaluate the dosage–response association due to insufficient data on aspirin dosage and different durations. The standard objective and subjective diagnosis and grading criteria varied among studies. Even self-reported best-corrected visual acuity was used in some studies, and this was criticized for underestimation of AMD incidence and misclassification of cases and controls. Finally, there were a limited number of studies in the subgroup analyses; OR or HR were directly considered as RR, and overestimation and underestimation of the pooled estimates cannot be excluded. 
In conclusion, this meta-analysis of RCTs and observational studies revealed no large beneficial or harmful effects of aspirin related to overall AMD but detected significant increased risk toward neovascular AMD. We provided additional evidence that proved robust by several methods of sensitivity analysis, partially resolving the current inconsistent opinions on the association between aspirin use and AMD. However, due to the limitations of our work and borderline statistic significance (RR, 1.59; CI 1.09–2.31; P = 0.211), one should be conservative regarding the pooled estimates of aspirin in relation to neovascular AMD and cautious about applying this conclusion to clinical decisions. Currently, evidence is still insufficient to recommend changing clinical practice; any decision concerning whether to stop aspirin therapy is thus complex and needs to be individualized. Further long-term population-based prospective studies with validated quantitative exposure ascertainment and use of standardized diagnostic methods and full-stratified grading criteria are warranted to confirm our findings. 
Supplementary Materials
Acknowledgments
Supported by Natural Science Foundation of China (81070756); National Twelfth Five-Year Plan for Science & Technology Support of China (2012BAI08B01); Zhejiang Provincial Program for Cultivation of High-Level Innovative Health Talents; Specialized Key Science & Technology Foundation of Zhejiang Provincial Science & Technology Department (2012C13023-2); and Zhejiang Provincial Key Project of Medicine and Health (2011ZDA014). 
Disclosure: J. Ye, None; Y.-F. Xu, None; J.-J. He, None; L.-X. Lou, None 
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Figure 1
 
Flow chart showing the study selection process.
Figure 1
 
Flow chart showing the study selection process.
Figure 2
 
Risk estimates of aspirin use with age-related macular degeneration in overall analysis. ES, effect size (in our analysis, ES means risk ratio).
Figure 2
 
Risk estimates of aspirin use with age-related macular degeneration in overall analysis. ES, effect size (in our analysis, ES means risk ratio).
Figure 3
 
Risk estimates of aspirin use with age-related macular degeneration in study-specific analysis.
Figure 3
 
Risk estimates of aspirin use with age-related macular degeneration in study-specific analysis.
Figure 4
 
Risk estimates of aspirin use with age-related macular degeneration in subgroup analysis based on neovascular and geographic atrophy subtypes. Neo, neovascular; ga, geographic atrophy.
Figure 4
 
Risk estimates of aspirin use with age-related macular degeneration in subgroup analysis based on neovascular and geographic atrophy subtypes. Neo, neovascular; ga, geographic atrophy.
Table 1
 
Summary of Included Studies Evaluating Aspirin Use and Its Association With Age-Related Macular Degeneration
Table 1
 
Summary of Included Studies Evaluating Aspirin Use and Its Association With Age-Related Macular Degeneration
Source (Publication Year, Country) Design Study Period Population (Sample Size) Mean Age, y Follow- Up, y Aspirin Exposure Status AMD Classification AMD Definition and Grading Adjusted Variables Quality
Liew et al. 61 (2013, Australia) Cohort 1992–2010 Blue Mountains Eye Study, population based (N = 2,389) 64.1 15 Questionnaire confirmed by medicine lists and/or bottles
Regular: ≥once/wk
Occasional: <once/wk
Nonregular: none and occasional
Dosage: 150 mg/d, assumed from common Australian prescription
Early Geographic  atrophy
Neovascular
Stereoscopic retinal photograph
International AMD Classification
Age, sex, smoking, cardiovascular disease, systolic blood pressure, BMI 16
Klein et al. 37 (2012, US) Cohort 1988–2010 Beaver Dam Eye Study, population based (N = 4,926) 43–86 14.8 Self-report confirmed by medicine at every visit
Ever: ≥twice/wk for more than 3 mo
Never
Early
Late
Neovascular
Geographic  atrophy
Photographs of the retina Wisconsin ARM Grading System Age, sex 19
Rudnicka et al. 62 (2010, UK) Case-control 1996–2002 Clinic based (N = 158) ≥45 3 Questionnaire confirmed by medicine
Ever: any dosage
Never
Late Fundus photography; International ARM Epidemiological Study Group criteria Age, sex, smoking, blood pressure, BMI, total cholesterol 17
Christen et al. 59 (2009, US) RCT 1994–2004 Women's Health Study, volunteer health professionals, female only (N = 39,876) ≥45 10 Low-dose aspirin, 100 mg every other day
Placebo
Visually significant
Advanced: neovascular and geographic atrophy with or without vision loss
Self-report confirmed by medical records review
BCVA ≤ 20/30
Age, vitamin E, beta-carotene treatment 24
Douglas et al. 63 (2007, UK) Case-control 1987–2002 General Practice Research Database, population based (N = 104,176) ≥50 4 Medical records
Ever
Never
Any status Medical records confirmed by letters or reports Consultation rate 15
Clemons et al. 18 (2005, US) Cohort 1992–2004 Age-Related Eye Disease Study, clinic based (N = 4,757) 55–80 6.3 Questionnaires
Ever: ≥5 y
Never
Neovascular Geographic atrophy Stereoscopic color fundus photographs confirmed by annual visiting Age, sex, treatment assignment 17
DeAngelis et al. 64 (2004, US) Case-control 1998–2003 Clinic based (N = 136) ≥50 none Questionnaires
Ever
Never
Neovascular Fundus photography, fluorescein angiography, home examination None 15
Christen et al. 60 (2001, US) RCT 1982–1988 Physicians' Health Study I, volunteer health physicians, male only (N = 21,216) 40–84 7 Aspirin 325 mg every other day Placebo Without vision loss
With or without vision loss
Self-report confirmed by medical records BCVA ≤ 20/30 Age, beta-carotene treatment assignment 23
Blumenkranz et al. 26 (1986, US) Case-control 1986 Clinic based (N = 49) 75.7 none Questionnaires
Ever or current
Never
Neovascular Color fundus photograph None 15
Table 2
 
Subgroup Analyses of Aspirin Use and Age-Related Macular Degeneration
Table 2
 
Subgroup Analyses of Aspirin Use and Age-Related Macular Degeneration
Subgroups No. of Studies Summary Effect RR (95% CI) P Value Study Heterogeneity
I 2, % P Value
Study design
 RCT 2 0.93 (0.71–1.22) 0.62 52.30 0.15
 Cohort 3 1.02 (0.87–1.20) 0.78 0.00 0.49
 Case-control 4 1.00 (0.96–1.04) 0.98 0.00 0.59
Follow-up length
 Less than 10 years 3 0.99 (0.96–1.03) 0.77 0.00 0.46
 More than 10 years 6 1.05 (0.93–1.19) 0.41 0.00 0.92
Source of subjects
 Population based 3 1.00 (0.97–1.04) 0.86 0.00 0.70
 Clinic based 4 0.87 (0.66–1.15) 0.34 0.00 0.62
 Volunteer based 2 0.93 (0.71–1.22) 0.62 52.30 0.15
Adjusted for smoking
 Yes 2 0.99 (0.65–1.51) 0.96 23.90 0.25
 No 7 1.00 (0.96–1.04) 0.93 0.00 0.66
AMD stage
 Early 2 0.90 (0.69–1.16) 0.41 0.00 0.74
 Late 7 1.07 (0.84–1.37) 0.57 27.10 0.22
AMD subtype
 Neovascular 5 1.59 (1.09–2.31) 0.02 31.50 0.21
 Geographic atrophy 3 0.84 (0.58–1.22) 0.35 0.00 0.65
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