Long-term aspirin use and neovascular age-related macular degeneration: association or causation?
- Correspondence to
: Dr William G Christen
Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue, 3rd floor, Boston, MA 02215, USA;
Aspirin is used by many for temporary pain relief, rheumatological conditions and where indicated, cardioprotection. However, recent findings from observational studies have raised the possibility that regular aspirin use may also increase the risk of some forms of age-related macular degeneration (AMD).
Liew and colleagues examined the relationship between long-term, low-dose aspirin use and risk of AMD in an Australian population-based cohort of 2389 adult men and women. Retinal photographs were obtained at baseline and at 5-year intervals over a 15-year follow-up period, and the AMD status was determined using an international AMD classification system. 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 administered at baseline using a standard questionnaire. Regular use of aspirin was defined as a reported frequency of once or more per week in the past year, and occasional use as less than once per week in the past year.
A total of 257 (10.8%) of the 2389 participants were classified as regular users of aspirin. During the 15-year follow-up, a total of 63 participants developed neovascular AMD. Regular users of aspirin, compared with non-regular users (non-users plus occasional users), were found to have a twofold to threefold increased risk of incident neovascular AMD (OR=2.37, 95% CI 1.25 to 4.49) in analyses that adjusted for age, sex and smoking. The OR changed little after further adjustment for history of cardiovascular disease (CVD), body mass index and systolic blood pressure. Subsequent additional adjustment for other CVD risk factors including: blood pressure, cholesterol level, diabetes mellitus, fish consumption and inflammatory markers, reduced OR and it was no longer significant (OR 2.05, 95% CI 0.96 to 4.40 p=0.06). There was no significant association with geographic atrophy or early AMD.
The study had several strengths that include a well-characterised population-based cohort, eye examinations at baseline and during follow-up, retinal photographs and a standardised classification scheme to assess the AMD status. The availability of prospectively collected information on a range of risk factors for AMD is an additional study strength. The finding of a twofold to threefold increased risk of neovascular AMD in regular users of aspirin is in accordance with the results of two recently reported observational studies,1 ,2 and the authors appropriately note that if their results reflect a true causal relationship, there are serious implications for the millions of people using aspirin therapy.
However, the study had several important limitations that need to be considered. An inherent limitation of all observational studies is the potential for uncontrolled, or uncontrollable, confounding. In this study, people who chose to use aspirin regularly differed from non-regular users in several important respects. They were markedly older, and were more likely to report a personal history of stroke, heart disease, diabetes and hypertension. The authors attempted to account for these differences by including terms for these factors in analyses, but such factors are difficult to measure and fully adjust for in analysis, leaving ample room for residual confounding. Perhaps more importantly, regular users of aspirin may differ from non-regular users in ways that were not measured or, indeed, yet recognised raising further concern about uncontrolled confounding.
Misclassification of aspirin use also seems a possibility. Aspirin use was ascertained once, at baseline, and the participants were classified into three broad categories based on reported frequency of use. No information on dosage was collected. Another concern is the small number of events. A total of 63 incident cases of neovascular AMD were observed, including only 15 cases among regular users of aspirin. The imprecise and unstable estimates of association are further weakened when attempting to control for multiple confounders.
Thus, while aspirin use may be causally associated with neovascular AMD, it is also possible that aspirin use is simply a marker for underlying factors or conditions (confounding by indication) more closely associated with the development or progression of AMD. Observational studies are unlikely to be able to distinguish between these and other possibilities.
Alternatively, most inherent limitations of observational studies are obviated in randomised trials in which a standard dosage of aspirin is randomly assigned to study participants. Two such trials, one conducted in men3 and the other in women,4 reported possible, but statistically non-significant, decreased risks of visually significant AMD in those assigned aspirin treatment. In one trial, there was a statistically non-significant 10% reduced risk of advanced AMD (neovascular AMD plus geographic atrophy) in the aspirin group, although the number of cases was small.4
The findings of Liew and colleagues have raised concern within the ophthalmic community and beyond, but warrant further study before concluding a causal connection between long-term aspirin use and neovascular AMD.