Use of allopurinol did not reduce white matter hyperintensity (WMH) progression for patients with ischemic stroke or transient ischemic attack (TIA) in a randomized trial.
In the study, the difference in Rotterdam Progression Score (RPS) between patients who received allopurinol, a xanthine oxidase inhibitor, and those who received placebo was 0.17, a difference that was not statistically significant.
“We are surprised not to have seen a difference,” study author Jesse Dawson, MD, professor of stroke medicine at the University of Glasgow, Glasgow, United Kingdom, told Medscape Medical News. He cited small experimental studies in which allopurinol appeared to make small blood vessels within the brain more flexible.
“However, I think we recognize that WMHs probably have a number of other causes beyond simply brain blood vessel flexibility,” Dawson added. “A lack of effect is in keeping with the very complex pathophysiology of WMHs that we know exists.”
The findings were presented at the 13th World Stroke Congress (WSC) 2021, which was held online.
Uric Acid and Stroke
Previous research has shown that increasing serum uric acid levels are associated with risk for negative cardiovascular outcomes, including stroke. Xanthine oxidase inhibitors reduce blood uric acid levels and consequently might influence stroke risk.
A meta-analysis of small studies indicated that allopurinol lowers blood pressure to a modest extent and may reduce the risk for cardiovascular events in people with established cardiovascular disease.
On the basis of these findings, the current researchers conducted a study of whether allopurinol reduces WMH progression, a marker of stroke risk, and blood pressure following ischemic stroke or TIA. They enrolled patients aged 50 years or older at 22 sites in the United Kingdom.
After a 4-week run-in phase, the researchers randomly assigned participants to receive allopurinol 300 mg twice daily or placebo for 104 weeks. All underwent brain MRI at baseline and at week 104, as well as ambulatory blood pressure monitoring at baseline, week 4, and week 104.
The researchers chose WMH progression, measured using the RPS, as their primary outcome. MRIs were evaluated by raters who were blinded to treatment assignment. Secondary outcomes included mean daytime systolic blood pressure at week 4 and week 104.
No Significant Difference
The investigators enrolled 464 participants into the study and randomly assigned 232 participants to each treatment arm. The mean age at baseline was 66 years, and approximately two thirds of participants were men.
In all, 189 participants in the placebo group and 183 in the allopurinol group underwent MRI at week 104. The RPS was 1.33 in the allopurinol group and 1.51 among control patients. The between-group difference, -0.17, was not statistically significant.
The change in daytime systolic blood pressure at week 4 was -2.3 mm Hg with allopurinol and 0.8 mm Hg with placebo, yielding a between-group difference of -3.33 mm Hg (P = .0034). At week 104, there was significant loss to follow-up. At that time, the between-group difference in daytime systolic blood pressure was -2.95 mm Hg (P = .058).
The rates of adverse events generally were similar between groups, but rashes were more common with allopurinol (4.8%) than with placebo (1.3%).
In various meta-analyses of small studies of allopurinol, the magnitude of blood pressure reduction was equal to that observed in this study. “We weren’t surprised to see the blood pressure reduction that we saw, although we are a little bit disappointed, obviously, that it wasn’t larger,” said Dawson.
The results of the ALL-HEART study, which examined the effect of allopurinol in more than 5000 patients who had ischemic heart disease, may be published in the coming year. “We will wait and see what that study shows before we completely abandon the theory,” said Dawson.
The current focus is on identifying the patients who experienced the biggest blood pressure reductions with allopurinol, he added. “If we can identify people who have a 5- to 10-mm Hg reduction in their blood pressure due to allopurinol, that could be clinically important and clinically useful to us. I think that’s really the only avenue open to us at the moment following stroke.”
“Lots of Paradoxes”
The study “draws attention again to uric acid, but there are lots of paradoxes regarding uric acid,” said Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, Massachusetts, who commented on the findings for Medscape Medical News.
Epidemiologic studies have indicated that people with high uric acid levels are at increased risk for stroke. But other data have suggested that uric acid may have positive effects. A 2016 study showed that treatment with uric acid might prevent early ischemic worsening after acute stroke in patients who undergo thrombolysis.
“The whole story of uric acid is something that is evolving and is interesting,” said Caplan. “It just needs a lot more work, especially animal work.”
Also relevant is the lack of correlation between WMH and neurologic deficit, Caplan added. WMHs are not infarcts, and “it’s hard to know what the changes on the MRI really mean,” said Caplan.
The trial was funded by the UK Stroke Association and the British Heart Foundation. Dawson and Caplan have disclosed no relevant financial relationships.
13th World Stroke Congress (WSC) 2021: Abstract LB102. Presented October 28, 2021.
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