In this large randomized trial, women assigned to alternate-day treatment with low-dose aspirin and followed for an average of 10 years had a non-significant 18% reduced risk of visually-significant AMD compared to women assigned to placebo. The 95% CI around this estimate could not rule out a possible beneficial effect as large as 36%, or a small harmful effect of 6% or less. Aspirin treatment appeared to have little effect on the endpoints of advanced AMD or all AMD cases with or without vision loss.
Evidence from observational studies on aspirin use and AMD is limited. A retrospective analysis of clinic patients with prevalent AMD showed that patients with choroidal neovascularization, compared to patients with dry AMD, were significantly less likely to use aspirin based on review of medication records (21
). Prospective observational data from the Age-Related Eye Disease Study (AREDS), comprised of patients at high risk of developing advanced AMD, showed no association between self-selected aspirin use at baseline and risk of neovascular AMD or geographic atrophy during 6.3 years of follow-up. However, the risk of geographic atrophy was inversely related to use of NSAIDS in that study (22
). In the Macular Photocoagulation Study, there was no significant difference between users and nonusers of aspirin in recurrence rate of AMD during 4 years of follow-up after initially successful laser treatment (23
). Three other prospective studies with mean follow-up of 4.8 to 6.5 years also reported no relation between use of aspirin or other NSAIDS and risk of early or late AMD (26
). Taken together, these observational studies provide little support for a benefit of aspirin treatment in AMD. Of note, however, these studies lacked detailed information on frequency, dosage, and duration of aspirin use, and thus had limited ability to assess the potential benefits of long-term aspirin treatment on AMD. Finally, several anecdotal reports of an increased risk of retinal hemorrhage in persons with AMD who used aspirin or other antiplatelet agents were limited by the absence of a comparison group and thus were impossible to interpret (35
Only one previous randomized trial has examined aspirin treatment in AMD. In Physicians’ Health Study I, men assigned to alternate-day low-dose aspirin (325 mg) had a non-significant 22% reduced risk of visually-significant AMD (HR, 0.78; CI, 0.46−1.32) during 5 years of follow-up (29
). However, the power of that trial to detect a benefit of aspirin treatment was limited by the early termination of the randomized aspirin component of PHS I (due primarily to a statistically extreme benefit of aspirin on first myocardial infarction [38
]) which resulted in a far lower number of incident cases of visually-significant AMD (n=57) than would have accrued without early termination. The present finding of a non-significant 18% reduced risk of visually-significant AMD in WHS is similar in magnitude to that reported for men in PHS I. When we combined data from the WHS and PHS I in a stratified proportional hazards model (with study as the strata), overall results indicate a possible, but statistically non-significant, 18% reduced risk of visually-significant AMD for those assigned to aspirin (HR, 0.82; 95% CI, 0.65−1.03). These combined data from women and men without a prior diagnosis of AMD tend to rule out a large beneficial effect for low-dose aspirin treatment on AMD occurrence, but are consistent with a modest benefit which, if confirmed in other trials of sufficient size and duration, would be of potential public health importance. Although most of the documented cases in the WHS and PHS I were characterized by a combination of drusen and RPE changes reflecting an early stage of AMD development, persons with early AMD are at increased risk of developing advanced AMD (4
), the leading cause of severe irreversible visual impairment in the US. Finally, the finding that the effect of aspirin on visually-significant AMD appeared to be modified by reported multivitamin use at baseline is intriguing and deserves further investigation. On the other hand, this could simply be a chance observation in view of the multiple comparisons.
There are several possible pathways through which aspirin could potentially exert a beneficial effect in AMD. At the dose tested in WHS (100 mg every other day), aspirin irreversibly inhibits platelet cyclooxygenase, resulting in a rapid and marked inhibition of platelet function and an immediate decrease in platelet aggregability and risk of thrombosis (39
). This mechanism of action is believed to underlie the protective effects of low-dose aspirin in CVD (42
), but seems unlikely to be an important mechanism in AMD. A more likely mechanism may involve the long-term effects of platelet inhibition on initiation and progression of atherosclerosis. Platelet inhibition may limit platelet adherence or aggregation on vascular endothelium and existing plaque, and may alter the chemotactic and adhesive properties of endothelial cells, which may be an important early pathophysiological event in atherogenesis (44
). At present, however, it remains unclear whether atherosclerosis is an important pathogenic mechanism in AMD (45
). Aspirin may also influence AMD development through pathways not dependent on platelet inhibition. For example, in the vascular endothelium aspirin has been shown to initiate production of 15-epi-lipoxin A4
which functions as a local endogenous antiinflammatory mediator (47
). Aspirin may also exert an antioxidant effect (49
) by protecting endothelial cells from the deleterious effects of hydrogen peroxide and other oxidative agents (50
), and perhaps by suppressing lipid peroxidation (53
Several possible limitations of the study need to be considered. Ascertainment of AMD cases was based on participant reports and thus some degree of underascertainment of AMD is plausible. Such underascertainment would likely reduce study power and also limit the comparison of incidence rates between this and other populations. However, underascertainment of disease is not associated with bias in randomized comparisons. Random misclassification of reported AMD, which would tend to shift the relative risk estimate toward the null, was reduced by the use of medical records to confirm the participant reports. Non-random or differential misclassification was unlikely since medical records were reviewed without knowledge of aspirin treatment assignment, and study participants and treating ophthalmologists and optometrists were unaware of aspirin treatment assignment. Confounding is unlikely in this large randomized trial since, as expected, baseline characteristics were equally distributed between the aspirin and placebo groups. This provides reassurance that other potential confounders, which were either unmeasured or unknown, were also likely to be evenly distributed between the two treatment groups.
In summary, these randomized trial data from a large population of healthy women indicate that 10 years of treatment with low-dose aspirin has no large beneficial effect in reducing risk of visually-significant AMD. However, a modest, but potentially important, beneficial effect on visually-significant AMD could not be ruled out and warrants continued examination in other populations of men and women.