Does aspirin increase the risk of age-related macular degeneration?

Abstract

This commentary on the review by Christen and Chew discusses the controversy surrounding aspirin use and its association with age-related macular degeneration (AMD). We address the strength of evidence between low-dose aspirin use and AMD and also discuss the risks and benefits of aspirin use in primary versus secondary prevention of cardiovascular diseases in these cases. We also highlight an ongoing randomized controlled trial in this area.

Keywords::

• age-related macular degeneration
• aspirin
• epidemiology
• randomized controlled trial

1. Commentary

The review by Christen and Chew [1] is timely as recently there has been much discussion and increased concern in the community about the use of long-term low-dose aspirin. The recent publication of results from two studies linked aspirin use with the development of age-related macular degeneration (AMD), the leading cause of irreversible severe vision loss in the developed world. These reports were based on two large prospective cohort studies from the USA [2] and Australia [3] and showed a 2 – 3 fold increased risk of incident neovascular AMD in persons on aspirin. How should we interpret this new information in light of current recommendations [4] for the use of low-dose aspirin for secondary prevention of cardiovascular diseases (CVDs), for example, acute myocardial infarct or stroke, to decrease the risk of further cardiovascular events, all of which can lead to significant morbidity and mortality? Given both AMD and CVD are common in the elderly, clinicians will often be faced with competing risks and benefits. While most would not have issues with long-term, low-dose aspirin prophylaxis if there was a clear and present danger of stroke or heart disease, the decision becomes more difficult when the potential risks are not well known or are small. Should patients be placed prophylactically on aspirin if there is no strong suggestion of increased risk of cardiovascular events and what should one do when a person with AMD presents a significant risk of CVD?

Although this review by Christen and Chew is not a systematic review, the authors have discussed the main studies evaluating aspirin use and its associations with AMD. They discussed two cross-sectional studies [5,6], two prospective cohort studies [2,3] and the two randomized controlled trials (RCT) [7,8] on this subject. They nicely showed the biases inherently present in epidemiological non-randomized studies where people on aspirin, not surprisingly, tended to be older and have more CVD risk factors. Residual confounding is still likely to be present, despite adjusting for CVD risk factors in statistical models; hence, results from these observational studies need to be validated in RCTs. The cross-sectional studies reported an association with early AMD, while this was not found in the cohort studies. The cohort studies found an association with only neovascular AMD (a form of late AMD, which results in bleeds in the macula, also known as wet AMD), with no associations with early AMD or geographic atrophy (the other form of late AMD where the macula atrophies and degenerates, also known as dry AMD). There is sound biological plausibility in this finding as aspirin is an anti-thrombotic, which can lead to more symptomatic bleeding in neovascular AMD, and this demands further study. There are two separate questions to answer with regard to neovascular AMD: first, does aspirin truly lead to a higher incidence of neovascular AMD (this complication can only be accurately diagnosed on fluorescein angiogram) and second, if neovascular AMD already exists, will aspirin cause ongoing, potentially larger more symptomatic bleeds, which would be more readily diagnosed in studies and would likely lead to a worse prognosis. Results from the two RCTs, where persons were equally randomized into both the aspirin and placebo groups, showed no increased risk of any AMD, and in contrast, it was in the direction of being protective for visually significant AMD, although not statistically significant. The undisputable strength of RCTs is the elimination of confounding by age, CVD risk factors or other unmeasured confounders. However, the AMD end points in these RCTs were defined differently to the observational studies, and in general, these RCTs had a younger cohort (majority younger than 65 years) and a shorter follow-up time (5 – 10 year difference) compared with the cohort studies, resulting in only a small number of cases with late AMD.

Christen and Chew [1] concluded in their review that there was insufficient evidence to warrant any change from current clinical practice in those who had already suffered a cardiovascular event; as the benefits of regular aspirin use in prevention of recurrent vascular events in those at high risk (secondary prevention) are well established [4]. However, the use of low-dose aspirin for the large majority of persons at low-to-moderate risk of CVD (primary prevention) may be questionable.

Currently, the best advice for ophthalmologists with patients who have existing neovascular AMD would be to consult the patient's primary physician to evaluate if cessation of aspirin would be a reasonable option, where aspirin was started for primary CVD prevention. We agree with Christen and Chew [1] that additional observational data are unlikely to further clarify causality and data from RCTs of sufficient size and duration are required to evaluate aspirin's effect in the early stages of the disease as well as in late AMD. It is important to clarify the risk/benefit of regular aspirin use in the large majority of individuals at low-to-moderate CVD risk. This is particularly important as aspirin is one of the most commonly used, most cost-effective medications in the world.

The ASPirin in Reducing Events in the Elderly (ASPREE) study (ISRCTN83772183) is the largest primary prevention aspirin study undertaken in the healthy elderly [9,10]. It is funded by the National Institutes of Health, including the National Institute on Aging and the National Cancer Institute (USA), the National Health and Medical Research Council of Australia and the Victorian Cancer Agency (Australia). ASPREE is a randomized double-blind placebo-controlled trial of 100 mg enteric-coated aspirin tablets daily over an average of 5 years, in 19,000 older aged men and women in Australia (16,500) and the USA (2500) who do not have overt CVD. The ASPREE-AMD^# ancillary study (ACTRN12613000755730) plans to enroll up to 6000 ASPREE participants aged 70+ years in Australia. These participants will undergo retinal photography and assessment for AMD prior to enrolment and after 3 and 5 years on treatment. ASPREE-AMD, projected to be fully recruited by the end of 2014, should provide some answers about AMD-related safety and efficacy of the use of low-dose aspirin for primary prevention in older persons. Until then, discussion between ophthalmologist and physician on each individual patient's situation appears the most prudent advice.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgement

RH Guymer and LD Robman are investigators on the ASPREE-AMD study.