Stroke - XILO-FIST

The clinical question

A stroke happens when the blood flow to part of your brain is cut off, preventing brain cells from getting the oxygen they need. If the stroke is caused by a blood clot in an artery supplying blood to the brain, this is called an ischaemic stroke. If the brain’s blood flow is interrupted for a short period of time, this is called a transient ischaemic attack (TIA) or ‘mini-stroke’. Both strokes and TIAs can cause sudden symptoms such as problems with speech or vision, but TIAs usually resolve on their own after a few minutes. 

Previous research has suggested a link between the amount of a molecule called uric acid in the blood and the risk of having an ischaemic stroke, and with having worse outcomes from a stroke. Uric acid is produced by the body as a ‘waste product’ and is the cause of gout (where small crystals of uric acid build up in the joints, causing pain and swelling). High levels of uric acid in the blood are also linked to increased blood pressure – an important risk factor for stroke.

Allopurinol is a medication commonly used to treat gout, which helps reduce the amount of uric acid the body produces and also has anti-inflammatory effects. A team of researchers led by Professor Jesse Dawson at the University of Glasgow carried out a clinical trial, called XILO-FIST, to test whether taking allopurinol could benefit people who have had a stroke or TIA. The trial was jointly funded by the British Heart Foundation and the Stroke Association.

What did the study involve?

XILO-FIST recruited participants aged over 50 who had recently (in the previous 4 weeks) had an ischaemic stroke or TIA, from 22 UK hospitals. All participants attended an initial study visit, which included having an MRI scan of their brain, their blood pressure measured, and an assessment of their brain function. 

The MRI scan was to look for markers of damage in the brain’s white matter (the deepest tissues of the brain), called ‘white matter hyperintensities’ (WMH). Previous research found that WMH are present in up to 90% of people who have experienced an ischaemic stroke, and that people who have more WMH (or develop more WMH over time) are more likely to experience another stroke or have a decline in their cognitive (brain) function. The researchers wanted to find out whether taking allopurinol could help to prevent more WMH developing over time, potentially reducing the risk of another stroke.

After the initial visit, participants were randomly assigned to take one of the following for the next two years:

• Daily allopurinol tablets (300-600mg)
• Daily placebo tablets (inactive ‘dummy’ pills) 

464 people (232 per group) were randomised, and had regular follow up visits over the two-year period. This allowed the trial team to monitor if their medication dose needed changing, collect information on any side effects experienced or decline in their brain function, and measure their blood pressure. At the final study visit (two years after starting the medication), participants had another MRI scan of their brain. This allowed the researchers to see how their level of WMH had changed over time. 372 participants completed the final trial visit.

What did the study show?

• Taking allopurinol did not affect the level of WMH present in the brain. People in both the placebo and allopurinol groups experienced a similar level of ‘progression’ (increase) in WMH between the initial and two-year MRI scans.
• At 4 weeks, there was a slight blood pressure-reducing effect of taking allopurinol - particularly in people who had high levels of uric acid in their blood at their initial visit.
• Allopurinol can have side effects, such as serious rashes, so these were closely monitored in the trial. The researchers found that the level of side effects reported was similar to previous trials of allopurinol. 

Why is the study important?

Around 1.4 million people living in the UK have survived a stroke or TIA, and are at increased risk of another stroke and decline in their (cognitive) brain function. Finding ways to reduce the risk of recurrent stroke (called ‘secondary prevention’) has been identified as a priority area for research by the Stroke Priority Setting Partnership. Previous research had suggested allopurinol could help to reduce the risk of ‘cardiovascular events’ such as heart attack or stroke in people at high risk - so it was important to explore whether this cheap, readily available medication could help people who had experienced a stroke or TIA.

While the results of XILO-FIST suggest that allopurinol is unlikely to help reduce the risk of recurrent stroke in people who have experienced a stroke or TIA, the study confirmed that allopurinol can have a slight blood pressure-lowering effect in this group – particularly in people with high levels of uric acid in their blood.

Professor Dawson said: “White matter hyperintensity is a marker of disease in small blood vessels deep in the brain, and the risk of recurrent stroke. In XILO-FIST, we did not see an effect of allopurinol on this marker. However, we also know that high blood pressure is an important risk factor for both primary and recurrent strokes.

Study details

Publication details