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Aspirin Linked to Age-Related Eye Disorder
 
 
  Download the PDF here
 
Download the PDF here
 
previous published research on this issue
 
Aspirin Use Tied to Rare Eye Disorder - (12/20/12)
 
Taking aspirin for 10 years could double the risk of sight loss - (12/20/12)
 
Regular Aspirin Use May Boost Risk of Eye Problem - (12/20/12)
 
Aspirin Use Linked to Macular Degeneration
 
- full text commentary and study below
By Nancy Walsh, Staff Writer, MedPage Today
Published: January 21, 2013
 
http://www.medpagetoday.com/Ophthalmology/GeneralOphthalmology/36943?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&xid=NL_DHE_2013-01-22&eun=g92748d0r&userid=92748&email=julev@aol.com&mu_id=5092023
 
Regular aspirin use was associated with an elevated risk for neovascular age-related macular degeneration, an Australian study suggested, but actual causality remains uncertain.
 
Action Points
 
· In this study, regular aspirin use was associated with increased risk of incident neovascular age-related macular degeneration, independent of a history of cardiovascular disease and smoking.
 
· Note that the nonrandomized design of the study does not allow for determination of causality due to the potential for residual confounding.
 
After adjustment for age, sex, and history of smoking, the odds ratio for macular degeneration in aspirin users was 2.37 (95% CI 1.25 to 4.49), according to Jie Jin Wang, PhD, of the University of Sydney, and colleagues. With further adjustment for body mass index, systolic blood pressure, and history of cardiovascular disease (CVD), the association remained (OR 2.46, 95% CI 1.25 to 4.83), the researchers reported online in JAMA Internal Medicine. However, "the evidence is insufficient to adjudicate the relationship between aspirin and [age-related macular degeneration], thereby challenging causal inferences," Sanjay Kaul, MD, and George A. Diamond, MD, of Cedars-Sinai Medical Center in Los Angeles, wrote in an invited commentary.
 
A recent cross-sectional study suggested a possible link between neovascular age-related macular degeneration and routine aspirin use, but other studies have yielded conflicting findings.
 
To prospectively examine this potential link, Wang and colleagues analyzed data from the Blue Mountains Eye Study, which included 2,389 Australians ages 49 and older.
 
Retinal examinations were done every 5 years, and lesions classified as neovascular, or wet macular degeneration, or geographic atrophy, also known as dry macular degeneration.
 
Aspirin use was reported on a structured questionnaire, and information on relevant risk factors was obtained during physical examination and history reports.
 
According to the researchers, they did not collect information on aspirin dosage, but, they said, "most aspirin use in Australia is prescribed at 150 mg daily."
 
A total of 257 participants were regular aspirin users. Compared with nonusers, they were older and more often had conditions such as diabetes, cardiovascular disease, or elevated blood pressure.
 
During 15 years of follow-up, age-related wet macular degeneration was identified in 63 individuals.
 
Among regular users, the cumulative incidence was 1.9%, 7%, and 9.3% at years 5, 10, and 15, while the incidence among nonusers was 0.8%, 1.6%, and 3.7%, respectively.
 
The incidence of neovascular macular degeneration rose with more frequent aspirin use, increasing from 2.2% in those who never took aspirin, to 2.9% for those who used it only occasionally, and 5.8% for those who took aspirin routinely.
 
Aspirin use was not associated with risk for geographic atrophy. Additional secondary analyses found that the risk was four times higher in patients with a history of CVD (OR 4.36, 95% CI 1.24 to 15.32) and in those without a polymorphism on CFHY402H, a gene involved in the complement pathway that has been linked with macular degeneration (OR 4.17, 95% CI 1.05 to 16.49). The researchers also considered whether other medications often taken by aspirin users, such as acetaminophen and beta-blockers, might influence risk, and the results were negative.
 
These results create a quandary for the many patients using aspirin, particularly those taking the drug as secondary prevention of CVD, according to Wang's group.
 
"Aspirin is one of the most effective CVD treatments and reduces recurrent CVD events by one-fifth," they observed.
 
However, significant adverse events can occur, such as cerebral and gastrointestinal bleeding.
 
"Our present study now raises the possibility that the risk of neovascular [age-related macular degeneration] may also need to be considered," they stated. Nonetheless, they conceded that the risk is small, at slightly under 4% over 15 years, and the evidence is thus far insufficient to support a change in practice away from widespread aspirin use, except for patients at very high risk for macular degeneration.
 
Any risk-benefit analysis also must consider the availability of effective -- but expensive -- treatments for neovascular age-related macular degeneration. "Any decision concerning whether to stop aspirin is thus complex and needs to be individualized," they wrote.
 
Limitations of the study included the possibility of confounding by indication and a lack of information on the reasons why participants were taking aspirin. In their invited commentary, Kaul and Diamond wrote, "These findings are, at best, hypothesis-generating that should await validation in prospective randomized studies before guiding clinical practice or patient behavior." They also advised that the choice of whether to use aspirin should focus on whether the indication is for secondary CVD prevention, "where the benefits of aspirin are indisputable and greatly exceed the risk," or for primary prevention, where the evidence is less clear, as well as the extent of the person's risk for macular degeneration and bleeding.
 
"In the final analysis, decisions about aspirin use are best made by balancing the risks against the benefits in the context of each individual's medical history and value judgments," they added.
 
Other experts, such as Shawn Wilker, MD, of University Hospitals Case Medical Center in Cleveland, agreed on the importance of individual risk.
 
"I think a reasonable circumstance when you could ask a patient not to take aspirin might be one in which there is a very low risk of mortality from cardiovascular disease or if that person is at very great risk of losing vision from macular degeneration," Wilker said in an interview.
 
Journal editor Kenneth E. Covinsky, MD, also weighed in in an editor's note, stating that "as with many good studies, the data are not definitive enough to suggest changes in clinical practice."
 
"Rather, we hope the study galvanizes more research on the relationship between aspirin and macular degeneration," Covinsky wrote.
 
------------------------------------
 
Invited Commentary | ONLINE FIRST
 
Relationship of Aspirin Use With Age-Related Macular DegenerationAssociation or Causation? Comment on "The Association of Aspirin Use With Age-Related Macular Degeneration"
 
Sanjay Kaul, MD; George A. Diamond, MD
 
In their prospective population-based cohort study of 2389 patients in the Blue Mountains region in Australia, Liew and colleagues1 report on the association of long-term use of low-dose aspirin and age-related macular degeneration (AMD), the leading cause of blindness in Western countries. The principal finding is that regular aspirin use is associated with an approximately 2.5-fold greater risk of incident AMD. This relationship is specific for late neovascular (wet) AMD but not geographic atrophy (dry AMD) and is independent of potential confounders, such as cardiovascular disease, smoking, age, sex, systolic blood pressure, and body mass index.
 
STRENGTH OF EVIDENCE
 
This study has important strengths and limitations. It provides evidence from the largest prospective cohort with more than 5 years of longitudinal evaluation reported to date using objective and standardized ascertainment of AMD. Additional strengths include the use of standardized protocols for determining medication use, the recording of detailed demographic and clinical information for risk adjustment, and appropriate methodologic approaches, such as multivariate logistic regression and propensity score adjustment, to minimize the impact of confounding.
 
The key limitation is the nonrandomized design of the study with its potential for residual (unmeasured or unobserved) confounding that cannot be mitigated by multivariate logistic regression or propensity score analysis. Limitations, such as the potential of recall and ascertainment bias, are addressed transparently, and reasonable arguments are offered to counter the effect of these biases on study results. Additional limitations that deserve attention include the modest strength of association (odds ratio, 2.0-2.5); incomplete data on other morbidities, such as arthritis, for which aspirin may be indicated; the potential for "overfitting" resulting in biased estimates because of the limited number of incident cases of AMD (n = 63) and 10 or more candidate predictor variables; and the issue of missing data (only 56% of the cohort eligible for follow-up at >15 years were assessed). All of these limitations can potentially undermine the interpretation and threaten the validity of trial results.
 
IS THE ASSOCIATION CAUSAL?
 
The Hill criteria are useful and time-tested considerations for determining whether an association is causal.2 Application of these considerations to the current study yields instructive insights.
 
Strength of Association
 
A strong association is more likely to have a causal component than is a modest association. The association between regular aspirin exposure and the risk of AMD is modest, as reflected in the unadjusted odds ratio of 2.5 (P = .01) and the adjusted odds ratios of 2.05 (P = .06) to 2.31 (P = .03). Based on the data provided, we estimate the discriminant ability as measured by the area under the curve to be correspondingly low (c index of 0.66) and the positive predictive value to be only 6% given the very low prevalence of 2.6%.
 
Consistency
 
Relationships that are repeatedly observed by different investigators, in different places, circumstances, and times, are more likely to be causal. Previous nonrandomized studies linking aspirin use to AMD have yielded inconsistent results, ranging from a protective effect on geographic atrophy in 1 study3 to no association in 2 studies4 and a positive (harmful) association with early and late wet AMD in 1 study.5 Two prospective randomized trials6- 7 reported a nonsignificant protective effect of aspirin use on AMD. Several factors could potentially account for the conflicting results. These include differences in the patient population and their underlying risk of AMD (prevalence of AMD was 10 to 25 times lower in the randomized compared with the nonrandomized studies), methods of ascertainment and adjudication of AMD (self-reported and visually significant criterion used in randomized studies compared with the objective criterion used in the current study), duration of aspirin exposure, and the potential for bias in different study designs (case-control vs prospective cohort vs randomized studies). Thus, studies to date do not clearly demonstrate either a beneficial or harmful effect of low-dose aspirin use on the development or progression of AMD.
 
Temporality
 
The factor must precede the outcome it is assumed to affect. This is self-evident in a prospective cohort study. Further proof is provided by the observation that the association became evident only after 10 to 15 years of exposure.
 
Biological Gradient or Dose-Response Relationship
 
Responses that increase in frequency as exposure increases are more convincingly supportive of causality than are those that do not show this pattern. Although information regarding the exact aspirin dose is missing, the investigators observed a dose-response relationship, with more frequent aspirin use associated with greater risk.
 
Biological Plausibility
 
Associations that are consistent with the scientific understanding of the biology of the disease are more likely to be causal. Potential mechanisms by which aspirin can affect AMD include suppression of prostacyclin synthesis, leading to hypoxia and neovascularization; increased lipid oxidation; subretinal hemorrhages; and involvement of the complement pathway as evidenced by a potential pharmacogenetic interaction with aspirin and Y402H polymorphism reported in this study. Thus, the relationship appears to be biologically plausible, although prespecification of these mechanisms would have provided additional support.
 
Specificity
 
A factor influences specifically a particular outcome or population. Given the multifactorial causes of AMD and the multiple effects exerted by aspirin, this is difficult to establish.
 
Coherence
 
A causal conclusion should not fundamentally contradict present substantive knowledge. It is difficult to establish coherence given the current state of the knowledge regarding AMD and lack of supportive laboratory evidence.
 
Experiment
 
Causation is more likely if evidence is based on randomized experiments. The randomized studies yield directionally opposite results from the current observations, although differences in patient populations and ascertainment of AMD could potentially account for the discordant results.
 
Analogy
 
For analogous exposures and outcomes, an effect has already been shown. It is unclear whether other antiplatelet agents or nonsteroidal anti-inflammatory drugs exhibit a similar association with AMD.
 
Of these 9 criteria, only 3 less critical ones (temporality, dose-response, and plausibility) are fulfilled in the current study. Therefore, based on the totality of data, the evidence is insufficient to adjudicate the relationship between aspirin and AMD, thereby challenging causal inferences.
 
CLINICAL IMPLICATIONS
 
From a purely science-of-medicine perspective, the strength of evidence is not sufficiently robust to be clinically directive. These findings are, at best, hypothesis-generating that should await validation in prospective randomized studies before guiding clinical practice or patient behavior. However, from an art-of-medicine perspective, based on the limited amount of available evidence, there are some courses of action available to the thoughtful clinician. In the absence of definitive evidence regarding whether limiting aspirin exposure mitigates AMD risk, one obvious course of action is to maintain the status quo. This is currently the most prudent approach, especially in secondary prevention settings where the benefits of aspirin are indisputable and greatly exceed the risk.8 For primary prevention of cardiovascular disease, where the evidence is less certain,9 the decision to prescribe aspirin should be predicated on the balance of risks (bleeding and possibly AMD) and benefits (cardiovascular disease and possibly cancer). For guideline-eligible patients (the 10-year risk of myocardial infarction in men aged 45-79 years is >4%, and the 10-year risk of stroke in women aged 55-79 years is >3%, and in whom the bleeding risk is low),10 the presence or absence of strong risk factors for neovascular AMD might tilt treatment decisions in one direction or the other. For patients taking long-term aspirin for other indications (pain control), caution is warranted in light of these observations. In the final analysis, decisions about aspirin use are best made by balancing the risks against the benefits in the context of each individual's medical history and value judgments.
 
-----------------------------------
 
JAMA Intern Med. 2013 Gerald Liew, PhD; Paul Mitchell, PhD; Tien Yin Wong, PhD; Elena Rochtchina, MAppStat; Jie Jin Wang, PhD
 
The Association of Aspirin Use With Age-Related Macular Degeneration
 
ABSTRACT

 
Objective To determine whether regular aspirin use is associated with a higher risk for developing age-related macular degeneration (AMD) by using analyzed data from a 15-year prospective cohort.
 
Methods A prospective analysis was conducted of data from an Australian population-based cohort with 4 examinations during a 15-year period (1992-1994 to 2007-2009). Participants completed a detailed questionnaire at baseline assessing aspirin use, cardiovascular disease status, and AMD risk factors. Age-related macular degeneration was graded side-by-side from retinal photographs taken at each study visit to assess the incidence of neovascular (wet) AMD and geographic atrophy (dry AMD) according to the international AMD classification.
 
Results Of 2389 baseline participants with follow-up data available, 257 individuals (10.8%) were regular aspirin users and 63 of these (24.5%) developed neovascular AMD. Persons who were regular aspirin users were more likely to have incident neovascular AMD: the 15-year cumulative incidence was 9.3% in users and 3.7% in nonusers. After adjustment for age, sex, smoking, history of cardiovascular disease, systolic blood pressure, and body mass index, persons who were regular aspirin users had a higher risk of developing neovascular AMD (odds ratio [OR], 2.46; 95% CI, 1.25-4.83). The association showed a dose-response effect (multivariate-adjusted P = .01 for trend). Aspirin use was not associated with the incidence of geographic atrophy (multivariate-adjusted OR, 0.99; 95% CI, 0.59-1.65).
 
Conclusion Regular aspirin use is associated with increased risk of incident neovascular AMD, independent of a history of cardiovascular disease and smoking. Aspirin is one of the most widely used medications worldwide, with more than 100 billion tablets consumed each year.1 The benefits of aspirin in secondary prevention of recurrent cardiovascular disease (CVD), such as myocardial infarction and ischemic stroke, are well established and outweigh the increased risk for gastrointestinal and intracranial bleeding.2 Aspirin is also widely used for primary prevention of CVD, although its value in low-risk individuals is less certain3 and has been questioned.2,4 Recently, evidence has accumulated that aspirin may also reduce the incidence of cancer and cancer-related mortality.5
 
Age-related macular degeneration (AMD) is a leading cause of blindness in older persons.6 Until very recently, vision loss from AMD was largely irreversible. Despite extensive studies, cigarette smoking remains the only consistently reported preventable risk factor for AMD.7
 
Recently, a cross-sectional study8 of 4691 older individuals found that, controlling for age and cardiovascular risk factors, regular aspirin use was associated with AMD, particularly the more visually devastating neovascular (wet) form. This observation is of significant concern and has generated substantial publicity in the lay media.9- 11 If these results reflect a true causal relationship, there are serious implications for the millions of people using aspirin therapy. Notably, other studies12- 18 that have examined this relationship have reported inconsistent findings, ranging from no association to slightly increased risk and even to possibly beneficial effects with aspirin use. Few studies have investigated whether aspirin use is prospectively associated with incident AMD beyond 5 years' follow-up.
 
In this study, we prospectively examined the relationship of regular aspirin use to 15-year incidence of AMD, particularly neovascular AMD, in the Blue Mountains Eye Study (BMES), a population-based cohort of older participants designed to study the prevalence, incidence, and risk factors of eye disease.
 
RESULTS
 
Of 2389 participants at baseline, 257 individuals (10.8%) were regular aspirin users as confirmed by their medication lists and/or bottles. Regular users were older and more likely to have hypertension, CVD, and diabetes mellitus than were those who were not regular aspirin users (Table 1).
 
After the 15-year follow-up, 63 individuals (24.5%) developed incident neovascular AMD. The cumulative incidence of neovascular AMD among nonregular aspirin users was 0.8% at 5 years, 1.6% at 10 years, and 3.7% at 15 years; among regular aspirin users, the cumulative incidence was 1.9% at 5 years, 7.0% at 10 years, and 9.3% at 15 years, respectively (Figure 3). Regular aspirin use was significantly associated with an increased incidence of neovascular AMD (age-, sex-, and smoking-adjusted OR, 2.37; 95% CI, 1.25-4.49) (Table 2). The association remained unchanged after further adjustment for history of CVD, BMI, and systolic blood pressure (multivariate-adjusted OR, 2.46; 95% CI, 1.25-4.83). Regular aspirin use was not associated with an increased risk of geographic atrophy (multivariate-adjusted OR, 0.99; 95% CI, 0.59-1.65).
 
Incidence rates for neovascular AMD increased with increasing aspirin use, from 2.2% (nonusers) to 2.9% (occasional users) to 5.8% (regular users) (Table 2). Increasing frequency of aspirin use was associated with an increasing risk of neovascular AMD (multivariate-adjusted P = .01 for trend).
 
Baseline participants without follow-up data (n = 1082) were older (70.7 vs 64.3 years, P < .001) and were more likely to be female (57.9% vs 53.4%, P = .03), smokers (17.8% vs 12.9%, P < .001), and have a history of CVD (27.3% vs 16.2%, P < .001). The groups had similar rates of aspirin use (11.6 vs 10.7, P = .47). We also performed the secondary analyses (Table 3 and Table 4). First, in persons with a history of CVD, regular aspirin use was associated with a 4-fold increased risk of incident neovascular AMD after adjustment for AMD risk factors (OR, 4.36; 95% CI, 1.24-15.32) (Table 3). The association was weaker and not statistically significant in persons without a history of CVD (OR, 1.90; 95% CI, 0.84-4.34). Next, we stratified by CFHY402H polymorphism status (Table 4). The association of regular aspirin use with incident neovascular AMD was stronger in persons without the polymorphism (OR, 4.17; 95% CI, 1.05-16.49) and weaker in those with either homozygous or heterozygous genotypes of CFHY402H (OR, 1.74; 95% CI, 0.76-4.01). Geographic atrophy was not associated with aspirin use in persons with or without the CFHY402H polymorphism (OR, 0.80; 95% CI, 0.20-3.21 and OR, 1.89; 95% CI, 0.21-17.40, respectively). There was no significant interaction between a history of CVD or the CFHY402H polymorphism and aspirin use on the risk of neovascular AMD (P = .31 and P = .24, respectively). Finally, additional adjustment for other risk and protective factors, including regular fish consumption, white blood cell count, total cholesterol level, and presence of diabetes mellitus did not materially alter the association between regular aspirin use and incident neovascular AMD (OR, 2.05; 95% CI, 0.96-4.40; P = .06). Aspirin use was not associated with incident early AMD in our study. During the follow-up period, 37 regular aspirin users (17.8%) developed incident early AMD compared with 285 nonusers (15.6%) (age-, sex-, and smoking-adjusted OR, 0.94; 95% CI, 0.65-1.37; data not shown). The association of aspirin use and incident neovascular AMD was similar in persons with (OR, 1.87; 95% CI, 0.51-6.77) and without (OR, 2.38; 95% CI, 1.13-5.03) early AMD at baseline but was significant only in the latter group. There was no evidence that the existence of early AMD modified the association between aspirin use and incident neovascular AMD (P = .79 for interaction).
 
Because aspirin use is strongly associated with painful conditions and CVD, we examined whether other medications associated with these conditions had a similar association with neovascular AMD. At baseline, acetaminophen was used by 5.8% of participants and ß-blockers were used by 15.2%. None of these medications was significantly associated with neovascular AMD, and including them in our multivariate model with age, sex, smoking, history of CVD, systolic blood pressure, and BMI did not change our findings. We also performed analyses using age, sex, smoking, history of CVD, systolic blood pressure, BMI, diabetes mellitus, regular fish consumption, total cholesterol level, and white blood cell count to calculate a propensity score. When used in the model instead of the same set of covariates, these factors resulted in slightly stronger findings when adjusted for propensity score (OR, 2.31; 95% CI, 1.11-4.82; P = .03) and when multivariate adjusted (OR, 2.05; 95% CI, 0.96-4.40; P = .06).
 
COMMENT
 
Age-related macular degeneration is responsible for blindness in up to 500 000 Americans,6 with a prevalence of approximately 1.5% in Americans older than 55 years, 1.8% in Australians, and 1.6% in Europeans of similar age.28 Surveys suggest that people fear blindness from AMD more than they do stroke and myocardial infarction.29 In this study we found that regular aspirin use was associated with risk of neovascular AMD during a 15-year follow-up period, independent of history of CVD, smoking, and other potential AMD risk factors. Our results therefore confirm the findings from the European cross-sectional survey that reported a 2-fold increased prevalence of neovascular AMD (OR, 2.22; 95% CI, 1.61-3.05) among regular aspirin users.8 Other studies have provided conflicting results, with a small number of case-control studies13 reporting increased frequency of subretinal and vitreous hemorrhage with aspirin use in persons with AMD and 2 large randomized clinical trials, the Physicians' Health Study14 and the Women's Health Study,15 reporting no increased AMD risk during 7 to 10 years among aspirin users. However, these studies relied mainly on self-reported AMD diagnosis or used AMD definitions that have been criticized30 and, importantly, did not examine neovascular AMD and geographic atrophy separately. In contrast, the case-controlled Age-Related Eye Disease Study18 (AREDS) reported that the use of anti-inflammatory medications, including aspirin, had a protective effect on geographic atrophy. An earlier report from the BMES,16 the Beaver Dam Eye Study,17 and pooled findings from the BMES and Beaver Dam Eye Study plus the Rotterdam Study12 reported no association of aspirin use at baseline with the 5-year incidence of any AMD, although there was a suggestion of increased risk for late AMD (ie, combined neovascular AMD and geographic atrophy) in the earlier report.16
 
Several findings from our study warrant further discussion. The increased risk of neovascular AMD was detected only after 10 or 15 years, suggesting that cumulative dosage is important in pathogenesis. This long lead time may explain why previous studies, including the earlier report,16 failed to detect this association. The CFHY402H polymorphism is a strong risk factor for all forms of AMD and codes for a CFH regulatory protein with impaired ability to inhibit complement pathway activation.31 We speculate that aspirin, which is known to increase complement activation in vitro and in vivo, partly through inhibition of the C1 inactivator,32 may also be associated with incident AMD via complement pathways. Other proposed mechanisms include disruption of prostacyclin synthesis and increased lipid metabolism.8
 
Given the widespread use of aspirin, any increased risk of disabling conditions and morbidity will be significant and affect many people. Although aspirin is one of the most effective CVD treatments and reduces recurrent CVD events by one-fifth,2 some meta-analyses2 have called into question the efficacy of aspirin use in CVD primary prevention and highlighted the significant adverse effects, such as increased gastrointestinal, intracerebral, and extracranial hemorrhage. Our present study now raises the possibility that the risk of neovascular AMD may also need to be considered. This potential risk appears small (3.7% after 15 years) and should be balanced with the significant morbidity and mortality of suboptimally treated CVD. Another factor to consider is that there are now effective but costly treatments for neovascular AMD comprising regular injections of antiŠvascular endothelial growth factor, which may need to be accounted for in cost-benefit studies of aspirin efficacy. Any decision concerning whether to stop aspirin therapy is thus complex and needs to be individualized. Currently, there is insufficient evidence to recommend changing clinical practice, except perhaps in patients with strong risk factors for neovascular AMD (eg, existing late AMD in the fellow eye) in whom it may be appropriate to raise the potentially small risk of incident neovascular AMD with long-term aspirin therapy.
 
Strengths of our study include its population-based, prospective design with long-term follow-up and careful ascertainment of aspirin use, AMD subtypes, and major confounders. Major limitations include, first, the possibility of residual confounding, such as by indication, whereby CVD rather than aspirin use contributes to the increased AMD risk. We note that, after adjustment for additional CVD risk factors (BMI, blood pressure, blood total cholesterol level, diabetes mellitus, fish consumption, inflammatory markers), our findings became marginally nonsignificant (OR, 2.05; 95% CI, 0.96-4.40; P = .06), likely because of reduced power from additional covariates in the model. To address this, we performed propensity score analysis. This incorporates the same variables as an indicator variable represented by the propensity score, and adjusting for this score in the model to replace several covariables resulted in slightly stronger findings, supporting a persistent association. Furthermore, other medications associated with painful conditions and CVD (acetaminophen and ß-blockers) were not associated with incident wet AMD, and adjusting for them in the multivariate model did not change our findings. Second, aspirin use was determined only at baseline and was not updated. If participants started taking aspirin after the baseline assessment, they would have been classified as nonregular users. This would bias our findings toward the null, that is, reduce the magnitude of any associations of aspirin use with incident AMD, if any association existed. Including aspirin users with less than 10 years' duration in our analyses could dilute our findings to a large extent, since our a priori hypothesis was that long-term (>10 years) aspirin use is associated with incident AMD. Our findings appear to bear this out, as shown in Figure 3, where the association became evident only after 10 to 15 years of follow-up. Cessation of aspirin use during follow-up would tend to bias toward the null as well, but since most persons with regular aspirin use continue it for life, we believe that this is unlikely to cause a large bias. Third, we have no data on the indications for aspirin use in our cohort and are unable to adjust for all possible indications (eg, rheumatologic conditions). Nonetheless, acetaminophen was not significantly associated with neovascular AMD, with a multivariate-adjusted OR of 1.04 (95% CI, 0.61-1.79). Fourth, our ascertainment of aspirin use was through questionnaire (with confirmation using medication bottles brought to follow-up examinations by participants), the assessment of geographic atrophy did not use fundus autofluorescence, the study design was observational, and the participants were mostly a homogeneous white population. Our results should thus be viewed as potentially influenced by ascertainment bias (ie, underreporting of regular aspirin use and underdetection of geographic atrophy) and nonrandom allocation of aspirin use and may not be applicable to nonwhite populations with different risk profiles for CVD and AMD. However, we anticipate the ascertainment bias from aspirin use to be nondifferential and occur equally in the groups who developed and did not develop incident AMD and thus to dilute the observed association toward the null. Our results may be influenced by the low proportion of participants who attended 15-year follow-up examinations. Participants with CVD were less likely to be followed up because of higher mortality and were more likely be regular aspirin users and develop incident AMD.7 We could have missed persons who were using aspirin and would have gone on to develop incident AMD had they lived longer. This would, however, tend to attenuate the association and bias our findings toward the null. In summary, we report from this prospective population-based cohort that regular aspirin use is associated with a 2-fold increase in risk of neovascular AMD during a 15-year period. These findings appear to be independent of CVD, smoking, and other risk factors.
 
 
 
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