Xanthine Oxidase Inhibition And White Matter Hyperintensity Progression Following Ischaemic Stroke and Transient Ischaemic Attack; The XILO-FIST 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.  Methods: In this multicentre, prospective, randomised, blinded, placebo-controlled trial we assigned participants within 30-days of ischaemic stroke or TIA to receive allopurinol 300mg twice daily or placebo for 104 weeks (registration number NCT02122718).  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). Secondary outcomes included change in day-time systolic BP (SBP). Analyses were by intention to treat.  Findings: We randomised 464 participants (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 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. The change in daytime SBP at week 4 was greater with allopurinol than placebo, between group difference -3.33, 95% CI -5.55 to -1.11, p=0.0034. Interpretation: Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA. Allopurinol lowered SBP at 4 weeks by approximately 3 mmHg.  Funding: The trial was funded by The British Heart Foundation and the UK Stroke Association. Trial Registration Details: The trial is registered in clinicaltrials.gov (registration number NCT02122718). Funding Information: This work was supported by the Stroke Association and British Heart Foundation [grant number TSA BHF 2013/01] The work of Dr David Dickie and Dr Terry Quinn is funded by the Stroke Association. Declaration of Interests: JD has received honoraria from Pfizer, Daiichi Sankyo, Medtronic, Boehringer Ingelheim, 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 honoraria from DiaMedica, Moleac and Phagenesis. KWM has received honoraria from Boehringer Ingelheim, Biogen, Abbvie, unrelated to the trial; trial support from Boehringer Ingelheim unrelated to the trial. AC has received research grants from Pfizer and honoraria from BMS, Pfizer, AstraZeneca and Boeheringer Ingelheim unrelated to this trial. DW reports honoraria from Bayer, Alnylam, Portola, Alexion, and NovoNordisk. The other authors declare they have no competing interests. Ethics Approval Statement: The study was approved by the NHS Research Ethics Committee (REC number 14/WS/0113) and by the UK MHRA. was adopted by the UK National Institute of Health Stroke Research Network and the Scottish Stroke Research Network. Written informed consent was obtained from all participants. The study was conducted according to the Declaration of Helsinki 2013. Study reporting followed CONSORT guidance.