Brain bleeding 'caused by aspirin'

"The ‘wonder drug’ aspirin may cause bleeding in the brain", the_ Daily Express_ has reported. The story comes from research looking at brain scans from more than a thousand people, finding that those taking aspirin had a 70% higher chance of having microscopic bleeding in their brains. This research looked at a range of antithrombosis drugs, including aspirin, which prevent blood from clotting within blood vessels.

There are limitations to this research that should be taken into account when interpreting its findings. As these drugs are prescribed to those with an increased risk of cardiovascular disease (including heart disease and strokes) it is possible that the problems being treated are actually behind the increased bleeding risk. In addition, scans were only taken after people had used the drugs in question, so it is possible that bleeding had already occurred before the drugs were actually taken.

Anti-clotting drugs are known to increase the risk of bleeding. When prescribing them, clinicians should carefully consider the risks and benefits of treatment on an individual basis.

Where did the story come from?

This research was conducted by Dr Vernooij and colleagues of Erasmus MC University Medical Centre, Rotterdam, the Netherlands. The Rotterdam Study is supported by a number of organisations including Erasmus University Rotterdam, the Netherlands Organization for Scientific Research,the Dutch Ministry of Health, Welfare and Sports, and the European Commission (DG XII).

The study was published in the peer-reviewed medical journal, Archives of Neurology.

What kind of scientific study was this?

This was a cross-sectional study of an elderly population, investigating the relationship between the use of antithrombotic drugs such as aspirin and the presence of ‘microbleeds’ from small blood vessels in the brain lobes. Small vessel bleeds are believed to result from either hardening of the blood vessels (arteriosclerosis) or the formation of amyloid protein deposits in the blood vessel wall.

Participants were sourced from the previous Rotterdam Study, a large study that looked at a number of different risk factors for a range of health problems among the elderly. In this new study, the researchers selected 1062 members of the Rotterdam Study who had undergone MRI brain scans between 2005 and 2006.

To detect microbleeds the researchers examined participants’ MRI scans, looking for haemosiderin (iron deposits), which are a sign of bleeding. Presence, number and location of microbleeds in the brain were recorded by an experienced neuroradiologist, with location defined as:

lobar (grey and lobar white matter of the cerebral cortex),
deep (deep grey matter [basal ganglia and thalamus])
white matter of the internal or external capsule and corpus callosum (which connects the left and right hemisphere), and
infratentorial (brainstem and cerebellum).

Each participant’s antithrombotic drug use over the preceding 14 to 15 years was determined by pharmacy-filled prescriptions that included details of the drug, dose and date of prescription. Antithrombotic drugs were defined as those that prevent platelet aggregation (clumping of platelets within blood vessels), such as aspirin or anticoagulant drugs, including warfarin or heparin.

Antithrombotics are usually prescribed for people at risk or with a history of coronary heart disease or strokes and these conditions are also related to the risk of cerebral microbleeds. The researchers also assessed cardiovascular risk factors (through history, examination and lab results) and took them into account in their analyses. They also noted the presence of infarcts (markers of ischemic cerebrovascular disease, i.e. stroke) on MRI scans.

The researchers looked at the relationship between antithrombotic use and microbleeds, including further subanalysis according to antithrombotic drug used and site of microbleed within the brain.

What were the results of the study?

The average age of people in the study was 69.6 years, with equal numbers of men and women in the sample.

There were 363 people (34.2%) who had used some kind of antithrombotic drug in the years before their MRI. Within this group, 67% (245) had exclusively used the platelet aggregation inhibitors aspirin or carbasalate calcium, with the latter being used by the majority of people. Of the 363 people, 17% had used only anticoagulant drugs.

Cerebral microbleeds were more prevalent among users of antiplatelet drugs, with a 71% increased risk compared to those who did not use any antithrombotic therapy (odds ratio 1.71, 95% confidence interval 1.21 to 2.41). There was no statistically significant relationship between anticoagulant use and risk of microbleeds.

Of those taking antiplatelet drugs, microbleeds in the cerebral lobes of the brain were more common among those taking aspirin, with a more than double increased risk compared to non-users (OR 2.70, 95% CI 1.45 to 5.04). For carbasalate calcium, there was a non-significant risk increase in lobar bleeds compared to non-users.

What interpretations did the researchers draw from these results?

The researchers conclude that their analysis has shown that use of platelet aggregation inhibitors is associated with cerebral microbleeds. The two platelet aggregation inhibitors analysed, aspirin and carbasalate calcium, may differently affect risk of microbleeds in strictly lobar regions of the cerebral cortex.

What does the NHS Knowledge Service make of this study?

This large cross-sectional analysis had demonstrated the increased prevalence of microbleeds in the brains of middle-aged to elderly people who had been using antiplatelet drugs, aspirin in particular.

It should be noted that antiplatelet and anticoagulant drugs are taken because the person is considered to be at increased risk of cerebrovascular disease, e.g. clots in the blood vessels of the heart or brain, and both types of drug are known to increase the risk of bleeds in the brain. The physiological process that leads to a change in the structure of small blood vessels of the brain (and increase their tendency to bleed) may be related both to the processes of the cardiovascular disease being treated and to the antithrombotic drugs used. Therefore, it is difficult to attribute the increased risk of bleeding solely to antiplatelet use, although researchers did attempt to take this into account by adjusting for age, sex and subjects’ score on a scale of heart risk.

Some further points to note about this study:

Causation could be better assessed through a prospective study, that is, people examined by MRI prior to commencing antithrombotic treatment and then re-assessed at a later date to see whether microbleeds had developed. As the authors acknowledge, with their method of assessment, it is not possible to say when the bleed actually occurred, as iron deposits can remain in the brain for an undefined period. This means a bleed may have occurred before antithrombotics were used.
Aspirin was associated with increased risk of microbleed in lobar regions of the brain. However, the number of people exclusively using aspirin in this sample was relatively small (67), reducing the accuracy of any calculated risk estimate. A larger number used carbasalate calcium, which is not a prescribed antiplatelet drug in the UK.
Although anticoagulant drugs were not significantly associated with bleeds, fewer people exclusively used anticoagulants (61) compared to exclusive use of antiplatelets (245). This may not be a sufficiently large sample to find a difference if one exists.
Drug use in the preceding 15 years was determined by filled pharmacy prescriptions. However, from this it is not possible to assess whether the drugs were actually taken as prescribed.

When prescribing any antiplatelet or anticoagulant drug, clinicians should always carefully consider both the risks and benefits of treatment on an individual basis.