Long-term aspirin use 'increases blindness risk'

The Daily Telegraph reports that using aspirin regularly could triple the risk of developing one of the commonest forms of blindness; “wet” age-related macular degeneration (AMD) – which causes progressive loss of central vision.

This story is based on a relatively large, long-term study which looked at whether and how often middle-aged and elderly people took aspirin, and their subsequent vision or sight loss. The study found that about 4% of occasional or non-users of aspirin developed wet AMD, compared with about 9% regular users of aspirin.

However, the study method used means that the groups of people being compared may differ in ways other than their aspirin use, and these other factors may be influencing the results. For example, cardiovascular disease (CVD) and wet AMD share some common risk factors, such as smoking. So it is not possible to say for certain – based on a single study of this type – whether aspirin definitely increases risk of wet AMD.

Two very large randomised controlled trials (RCTs) – one reported in Behind the Headlines in 2009, found that taking aspirin for seven to ten years did not increase risk of AMD. Evidence from RCTs is likely to carry more weight than evidence from the type of study used in this latest research. However, these older RCTs have their own limitations, such as relying mainly on participants to self-report whether they had AMD.

Ideally, a systematic review would be needed to summarise all of the available research evidence to determine whether it looks like aspirin could be contributing to AMD risk.

Where did the story come from?

The study was carried out by researchers from the Universities of Sydney and Melbourne and the National University of Singapore.

It was funded by the National Health and Medical Research Council, Australia.

The study was published in the peer-reviewed Journal of the American Medical Association – Internal Medicine.

In general, the BBC, The Daily Telegraph, and the Daily Mail covered the story well – emphasising the important point that the potential risk of aspirin-associated AMD had to be balanced against the drug’s protective effect against heart disease and stroke.

However, the Mail and the Telegraph could not agree whether there was a two-fold or three-fold increase in risk detected by the study – the precise figure from the main analysis was 2.46, so it’s a case whether you choose to round up or down.

What kind of research was this?

This was a prospective cohort study looking at whether aspirin use was linked with risk of developing age-related macular degeneration (AMD). AMD is a common cause of blindness in older people, and comes in two forms – “wet” AMD and “dry” AMD.

The macula is the area of the light sensitive covering on the inside of the eye that is responsible for the central part of our vision. In dry AMD, the cells of the macula gradually become damaged, affecting vision. In wet AMD, new blood vessels grow underneath the macula in the eye and disrupt vision. In some cases, symptoms of dry AMD (which tend to be less severe) are then followed by symptoms of wet AMD (which usually causes a greater disruption to normal vision). The only known preventable risk factor for AMD is smoking. Some studies have suggested that aspirin use may be a risk factor for AMD, while others not have found a link.

A cohort study is a good way to look at links between a long-term real-life exposure (in this case aspirin use) and a particular outcome (in this case AMD), particularly if a randomised controlled trial would not be feasible.

However, as people in this study were deciding for themselves whether to take aspirin, they may have characteristics that differ from those who take aspirin less frequently, and this could affect results (known as confounding).

Long-term RCTs of aspirin have been carried out, and the results of these trials should not be affected by confounding, so from this perspective their results would be seen as more robust. However, the RCTs would not have set out to look specifically at AMD, and this means they would not have done specific examinations of people’s eyes as part of the study. Therefore, researchers would have to rely on people reporting their condition or it being recorded in their medical notes. So, the current study has the advantage of setting out to assess the effect of aspirin on AMD, and therefore included thorough eye examinations to look specifically for the condition.

What did the research involve?

The study recruited Australians aged 49 and over, living in urban areas, between 1992 and 1994, following them up for 15 years. The participants were assessed four times during this period, initially filling out questionnaires assessing their aspirin use, whether they had cardiovascular disease, or risk factors for AMD. Participants also provided a list of all the medications they had taken in the last month, and were asked to show the researchers all the medicine bottles of the medicines they used.

This allowed researchers to check their aspirin use, although the dose was not recorded.

At the start of the study, participants also had pictures taken of the retinas in both eyes to ensure they did not have any signs of AMD. These pictures were taken every five years during the 15-year study, and each time the researchers looked for signs of wet or dry AMD (defined by an international standard).

The researchers had complete data for 2,389 people for their analyses. Aspirin use was classified as:

regular – one or more per week in the last year
occasional – less than once per week in the last year
non-users

They compared the risk of AMD in aspirin users with non-users. In some analyses occasional and non-users were grouped into “non-regular users”.

The researchers took into account potential confounding factors that could affect outcomes, including:

age
gender
smoking
history of cardiovascular disease
blood pressure
body mass index (BMI)
fish consumption
cholesterol level
markers of inflammation in blood tests

What were the basic results?

The researchers found that 10.8% of participants regularly used aspirin (257 people), this group were older, more likely to have high blood pressure, cardiovascular disease and diabetes than non-regular users.

Almost a quarter of participants (24.5%, 63 people) developed wet AMD during the study. When classified by aspirin use, 9.3% of aspirin users developed wet AMD during the 15-year study, compared with 3.7% of people who did not regularly use aspirin.

The researchers took into account the age, BMI, systolic blood pressure, gender, smoking, and cardiovascular disease of the participants when analysing their results. They found that those who used aspirin had about two and a half times the odds of developing wet AMD as those who did not take aspirin (odds ratio [OR] 2.46, 95% confidence interval [CI] 1.25 to 4.83).

Taking into account additional cardiovascular risk factors (blood total cholesterol level, diabetes mellitus, fish consumption, and markers of inflammation in blood tests) made the results become just non-statistically significant (OR 2.05, 95% CI 0.96 to 4.40).

There was no difference between aspirin users and non-users in the risk of developing dry AMD.

How did the researchers interpret the results?

The researchers concluded that “regular aspirin use is associated with increased risk of [developing wet] AMD, independent of a history of cardiovascular disease and smoking”.

Conclusion

This cohort study has suggested that there may be a link between aspirin use and risk of developing wet AMD. The main strengths of this study are that it followed people up over a long time, collected data prospectively and carried out thorough eye examinations for AMD. This means that cases of AMD were not likely to be missed. However, it should be noted that:

The study’s main weakness was that, as a cohort study, its results may be affected by confounding, although the researchers did try to take into account factors that could be having an effect. Confounding ‘by indication’ is a possibility; this is where the reason for taking the aspirin may be influencing the results, rather than the aspirin itself. The researchers controlled for this by taking into account cardiovascular disease, and this led to a reduction in the association. This suggests that cardiovascular disease could be contributing to the increased AMD risk.
The authors note that two large RCTs (which should not be affected by confounding) found no increase in risk of AMD in people taking aspirin for seven to 10 years. However, they note that these RCTs mainly relied on self-reported AMD diagnosis or used definitions of AMD that have been criticised, and did not analyse the wet and dry forms of AMD separately.
Aspirin use in the past year was assessed only at the start of the study, and may have differed either before or after this.

Overall, the inherent limitations to this type of study, the fact that RCTs have not found a link with AMD as a whole, and that taking into account certain factors makes the link non-significant, mean that it is not possible to conclusively say whether aspirin increases wet AMD risk.

If your doctor has prescribed you aspirin for a specific purpose, for example to reduce your risk of blood clots, it is likely that the benefits of taking it will outweigh the unconfirmed potential increase in risk of developing wet AMD in the long term.

In general, you, you should always see your GP or your optometrist as soon as possible if you notice any deterioration to your vision.