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Long-term Use of Aspirin and Age-related Macular Degeneration Beaver Dam Eye Study Klein and colleagues 19 examined the association between regular aspirin use and incident AMD in a longitudinal, population-based study of men and women aged 43 to 86 years in Wisconsin. A total of 3,206 participants with information on aspirin use and AMD status at baseline and at follow- up were included in analyses. Examinations were performed every 5  years over a 20-year period. Participants were asked at baseline and at each follow-up exam about possible AMD risk factors including aspirin use. Regular aspirin use was defined as use at least twice a week for more than 3 months. The presence and severity of lesions associated with AMD was assessed through review of retinal photographs taken at each examination and graded using the Wisconsin Age-Related Maculopathy Grading System. During a median duration of 15.9 years of follow-up, the investigators identified 512 incident cases of early AMD and 117 cases of late AMD, including 78 cases of neovascular AMD. The percentage of participants categorized as regular users of aspirin varied according to follow-up interval and AMD endpoint examined, but averaged between 42  % and 45  %. Specific information on the ways in which regular users of aspirin differed from nonregular users was not presented; however, analyses of early AMD included adjustment for age, sex, education level, ever heavy drinking, smoking, and history of arthritis, whereas analyses of late AMD included adjustment for age, sex, education, heavy drinking history, and smoking. Regular aspirin use 10 years prior to retinal examination was associated with an increased risk for late AMD (hazard ratio [HR], 1.63, 95 % CI 1.01–2.63). This increased risk was specific for neovascular AMD (HR 2.20, 95% CI 1.20–4.15); there was no significant association with pure geographic atrophy (HR 0.66, 95 % CI 0.25–1.95). Regular aspirin use 5 years prior to retinal examination was not associated with late AMD. Nor was there any association between incident early AMD and aspirin use 5 years (HR 0.86, 95 % CI 0.71–1.05) or 10 years (HR 0.86, 95 % CI 0.65–1.13) prior to retinal examination. Blue Mountains Eye Study Liew and colleagues examined the prospective relationship between long-term, low-dose aspirin use and risk for AMD in an Australian population-based cohort of 2,389 adult men and women aged 49 years or older. Participants completed a questionnaire at baseline providing information on a range of risk factors for AMD. Use of aspirin and other medications was ascertained during a structured interview at baseline using a standard questionnaire. Regular use of aspirin was defined as a reported frequency of one or more times per week in the past year, and occasional use as less than once per week in the past year. AMD status was assessed through review of retinal photographs obtained at baseline and at 5-year intervals over a 15-year follow-up period, and graded using an international AMD classification system. During the 15-year follow-up, 63 participants developed neovascular AMD. A total of 257 (10.8 %) of the 2,389 participants were classified as regular users of aspirin. Regular users were markedly older, and were more likely to report a personal history of stroke, heart disease, diabetes, and hypertension. Regular users of aspirin, compared with nonregular users (nonusers plus occasional users), had a two- to threefold increased risk for incident US Oph thal mic Revie w neovascular AMD (OR 2.37, 95 % CI 1.25–4.49) in analyses adjusted for age, sex, and smoking. The OR changed little after further adjustment for history of CVD, body mass index, and systolic blood pressure. Further adjustment for additional CVD risk factors including blood pressure, cholesterol level, diabetes, fish consumption, and inflammatory markers, reduced the OR and it was no longer significant (OR 2.05, 95 % CI 0.96–4.40). There was no significant association with geographic atrophy or early AMD. Commentary All three recently reported observational studies share several strengths including a well-characterized, population-based study sample, information on a range of risk factors for AMD, and the use of retinal photographs and a standardized classification scheme to assess AMD status. For the two prospective studies, 19,20 information on AMD risk factors was collected prior to the diagnosis of AMD, which is an additional strength. All three studies report a similar two- to threefold increased risk for neovascular AMD in regular users of aspirin. As noted in the Blue Mountain Eye Study report, 20 if these results reflect a true causal relationship, there are serious implications for the millions of people using aspirin therapy. However, these observational studies have several important limitations that need to be considered. An inherent limitation of all observational studies is the potential for uncontrolled, or uncontrollable, confounding. In all three studies, participants who chose to use aspirin regularly differed from nonregular users in important respects. They were markedly older, had more diabetes and hypertension, and were more likely to report a personal history of CVD. In assessing a possible causal connection with AMD, it seems particularly important to stress the magnitude of the difference in reported CVD (and CVD risk factors) between users and nonusers of aspirin in these studies. For example, in the European Eye Study, 38  % of daily aspirin users reported a history of CVD compared with 9 % of never users and 11 % of weekly users. In the Blue Mountains Eye Study, 40 % of regular aspirin users reported a history of heart disease compared with 11 % of nonregular users (occasional and never users). Because aspirin therapy is commonly recommended for persons with CVD, these differences are not surprising. However, AMD and CVD are postulated to share similar underlying mechanisms and risk factors, 21 and thus the potential for confounding, particularly confounding by indication, is great. All three studies attempted to account for these differences between users and nonusers by including terms for these factors in analyses. However, such factors as CVD and associated risk factors are difficult to measure and fully adjust for in analysis, leaving ample room for residual confounding. Moreover, regular users of aspirin may differ from nonregular users in ways that were not measured or, indeed, yet recognized which, if predictive of AMD occurrence, would raise further concern about uncontrolled confounding. Misclassification of aspirin use also seems a possibility. In the primary analyses for all three studies, aspirin exposure was based only on reported frequency of use, and participants were categorized into two to four broadly defined usage groups. Two studies collected no information on dosage 18,20 while the third study collected dosage information for secondary analyses. 19 145