Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial.

Background

People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA).

Methods

In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718.

Findings

Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference -0.17, 95% CI -0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group.

Interpretation

Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people.

Funding

The British Heart Foundation and the UK Stroke Association.

Informations de copyright

© 2023 The Authors.

Déclaration de conflit d'intérêts

JD has received honoraria from Pfizer, Daiichi Sankyo, Medtronic, Astra Zeneca, Bristol Myers Squibb, and Bayer unrelated to this trial. PMB is Stroke Association Professor of Stroke Medicine and an Emeritus NIHR Senior Investigator. He has received consulting fees from CoMInd, DiaMedica, Roche and Phagenesis. He is co-chair of the World Stroke Organisation Industry Committee. He has received equipment for research studies from Phagenesis. He reports stock options in DiaMedica and CoMind and was a member of the Data Safety Monitoring Committee for the European Carotid Surgery Trial-2. All reported declarations are unrelated to this research. KWM has received consulting fees from Boehringer Ingelheim, Biogen, Abbvie and honoraria from Boehringer Ingelheim unrelated to the trial; trial support from Boehringer Ingelheim, the NIHR, the Stroke Association, Innovate UK and the British Heart Foundation unrelated to the trial. He was a member of the data monitoring committee for the ARREST trial, unrelated to this research. AC has received research grants from 10.13039/100004319Pfizer and honoraria from BMS, Pfizer, AstraZeneca and Boeheringer Ingelheim unrelated to this trial. MK has received honoraria from Astra Zeneca and research funding from the 10.13039/501100000274British Heart Foundation unrelated to this research. AS holds a patent for the use of xanthine oxidase inhibition for the treatment of angina pectoris. KD has received conference support from 10.13039/100004336Novartis and honoraria from Allegan unrelated to this research. DD received payment for image analysis in this study and has received payment for image analysis from MicroTransponder Inc unrelated to this research. LS is a member of the executive committee of the British and Irish Association of Stroke Physicians. She is a member of stroke specialist advisory committee of the Joint Royal College and Training Board in the UK. DW has received consulting fees and honoraria from Bayer, Alnylam, Portola and NovoNordisk unrelated to this research. He is chair of the IDMC for the OXHARP trial. He is president-elect of British and Irish Association of Stroke Physicians. He is Chair of Association of British Neurologists Stroke Advisory Group. He serves on the Editorial Board of Practical Neurology, European Journal of Neurology and International Journal of Stroke. He is Chair of UK Stroke Forum. He is member of NICE AI in Stroke Diagnosis Guideline Committee. He is Chief Investigator for the OPTIMAS and Prohibit-ICH trials. He serves on the steering committee and co-investigator for LACI-2, TICH-3, RECAST-3. He serves on the steering committee and is co-investigator for RESTART, TICH-2. The other authors declare they have no competing interests.