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

Jesse Dawson; Michele Robertson; David Alexander Dickie; Phillip Bath; Kirsten Forbes; Terence Quinn; Niall M. Broomfield; Krishna Dani; Alex Doney; Graeme Houston; Kennedy R. Lees; Keith W. Muir; Allan Struthers; Matthew Walters; Mark Barber; Ajay Bhalla; Alan Cameron; Alexander Dyker; Paul Guyler; Ahamad Hassan; Mark T. Kearney; Breffni Keegan; Sekaran Lakshmanan; Mary Joan Macleod; Marc Randall; Louise Shaw; Ganesh Subramanian; David Werring; Alex McConnachie

doi:10.1016/j.eclinm.2023.101863

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

Jesse Dawson^* (Corresponding Author), Michele Robertson, David Alexander Dickie, Phillip Bath, Kirsten Forbes, Terence Quinn, Niall M. Broomfield, Krishna Dani, Alex Doney, Graeme Houston, Kennedy R. Lees, Keith W. Muir, Allan Struthers, Matthew Walters, Mark Barber, Ajay Bhalla, Alan Cameron, Alexander Dyker, Paul Guyler, Ahamad HassanMark T. Kearney, Breffni Keegan, Sekaran Lakshmanan, Mary Joan Macleod, Marc Randall, Louise Shaw, Ganesh Subramanian, David Werring, Alex McConnachie

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Summary 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.

Original language	English
Article number	101863
Number of pages	10
Journal	EClinicalMedicine
Volume	57
Early online date	16 Feb 2023
DOIs	https://doi.org/10.1016/j.eclinm.2023.101863
Publication status	Published - 1 Mar 2023

Bibliographical note

Acknowledgments
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. We would like to thank Christine McAlpine, Ruth Graham, Glasgow Royal Infirmary, UK; Lauren Pearce, Royal United Hospital, UK; Caroline Fornolles, Louise Tate, Frances Justin, Luton and Dunstable University Hospital, UK; Dean Waugh, Leeds Teaching Hospitals NHS Trust, UK; Donal Concannon, Altnagelvin Hospital, UK; Sharon Tysoe, Nina Francia, Nisha Menon, Raji Prabakaran, Southend University Hospital, UK; Amy Ashton, Caroline Watchurst, Marilena Marinescu, Sabaa Obarey, Scheherazade Feerick, University College London NHS Foundation Trust, UK; and Janice Irvine, Sandra Williams, and German Guzman Gutierrez, Aberdeen Royal Infirmary, UK; Caroline Fox and Joanne Topliffe, Broomfield Hospital, Essex, UK.

Data Availability Statement

Data sharing statement
Study data, including brain MRI will be shared with the Virtual International Stroke Trials Archive after publication of the primary manuscript. Study data including anonymized individual level participant data will be shared with academic investigators or health care professionals following review and approval of a proposal and subject to a data sharing agreement (contact jesse.dawson@glasgow.ac.uk).

Keywords

Stroke
Allopurinol
Hypertension
White matter hyperintensities

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Dawson, J., Robertson, M., Dickie, D. A., Bath, P., Forbes, K., Quinn, T., Broomfield, N. M., Dani, K., Doney, A., Houston, G., Lees, K. R., Muir, K. W., Struthers, A., Walters, M., Barber, M., Bhalla, A., Cameron, A., Dyker, A., Guyler, P., ... McConnachie, A. (2023). 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. EClinicalMedicine, 57, Article 101863. https://doi.org/10.1016/j.eclinm.2023.101863

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. / Dawson, Jesse (Corresponding Author); Robertson, Michele; Dickie, David Alexander et al.
In: EClinicalMedicine, Vol. 57, 101863, 01.03.2023.

Research output: Contribution to journal › Article › peer-review

Dawson, J, Robertson, M, Dickie, DA, Bath, P, Forbes, K, Quinn, T, Broomfield, NM, Dani, K, Doney, A, Houston, G, Lees, KR, Muir, KW, Struthers, A, Walters, M, Barber, M, Bhalla, A, Cameron, A, Dyker, A, Guyler, P, Hassan, A, Kearney, MT, Keegan, B, Lakshmanan, S, Macleod, MJ, Randall, M, Shaw, L, Subramanian, G, Werring, D & McConnachie, A 2023, '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', EClinicalMedicine, vol. 57, 101863. https://doi.org/10.1016/j.eclinm.2023.101863

Dawson J, Robertson M, Dickie DA, Bath P, Forbes K, Quinn T et al. 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. EClinicalMedicine. 2023 Mar 1;57:101863. Epub 2023 Feb 16. doi: 10.1016/j.eclinm.2023.101863

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abstract = "Summary 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.",

keywords = "Stroke, Allopurinol, Hypertension, White matter hyperintensities",

author = "Jesse Dawson and Michele Robertson and Dickie, {David Alexander} and Phillip Bath and Kirsten Forbes and Terence Quinn and Broomfield, {Niall M.} and Krishna Dani and Alex Doney and Graeme Houston and Lees, {Kennedy R.} and Muir, {Keith W.} and Allan Struthers and Matthew Walters and Mark Barber and Ajay Bhalla and Alan Cameron and Alexander Dyker and Paul Guyler and Ahamad Hassan and Kearney, {Mark T.} and Breffni Keegan and Sekaran Lakshmanan and Macleod, {Mary Joan} and Marc Randall and Louise Shaw and Ganesh Subramanian and David Werring and Alex McConnachie",

note = "Acknowledgments 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. We would like to thank Christine McAlpine, Ruth Graham, Glasgow Royal Infirmary, UK; Lauren Pearce, Royal United Hospital, UK; Caroline Fornolles, Louise Tate, Frances Justin, Luton and Dunstable University Hospital, UK; Dean Waugh, Leeds Teaching Hospitals NHS Trust, UK; Donal Concannon, Altnagelvin Hospital, UK; Sharon Tysoe, Nina Francia, Nisha Menon, Raji Prabakaran, Southend University Hospital, UK; Amy Ashton, Caroline Watchurst, Marilena Marinescu, Sabaa Obarey, Scheherazade Feerick, University College London NHS Foundation Trust, UK; and Janice Irvine, Sandra Williams, and German Guzman Gutierrez, Aberdeen Royal Infirmary, UK; Caroline Fox and Joanne Topliffe, Broomfield Hospital, Essex, UK.",

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TY - JOUR

T1 - 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

AU - Dawson, Jesse

AU - Robertson, Michele

AU - Dickie, David Alexander

AU - Bath, Phillip

AU - Forbes, Kirsten

AU - Quinn, Terence

AU - Broomfield, Niall M.

AU - Dani, Krishna

AU - Doney, Alex

AU - Houston, Graeme

AU - Lees, Kennedy R.

AU - Muir, Keith W.

AU - Struthers, Allan

AU - Walters, Matthew

AU - Barber, Mark

AU - Bhalla, Ajay

AU - Cameron, Alan

AU - Dyker, Alexander

AU - Guyler, Paul

AU - Hassan, Ahamad

AU - Kearney, Mark T.

AU - Keegan, Breffni

AU - Lakshmanan, Sekaran

AU - Macleod, Mary Joan

AU - Randall, Marc

AU - Shaw, Louise

AU - Subramanian, Ganesh

AU - Werring, David

AU - McConnachie, Alex

N1 - Acknowledgments 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. We would like to thank Christine McAlpine, Ruth Graham, Glasgow Royal Infirmary, UK; Lauren Pearce, Royal United Hospital, UK; Caroline Fornolles, Louise Tate, Frances Justin, Luton and Dunstable University Hospital, UK; Dean Waugh, Leeds Teaching Hospitals NHS Trust, UK; Donal Concannon, Altnagelvin Hospital, UK; Sharon Tysoe, Nina Francia, Nisha Menon, Raji Prabakaran, Southend University Hospital, UK; Amy Ashton, Caroline Watchurst, Marilena Marinescu, Sabaa Obarey, Scheherazade Feerick, University College London NHS Foundation Trust, UK; and Janice Irvine, Sandra Williams, and German Guzman Gutierrez, Aberdeen Royal Infirmary, UK; Caroline Fox and Joanne Topliffe, Broomfield Hospital, Essex, UK.

PY - 2023/3/1

Y1 - 2023/3/1

N2 - Summary 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.

AB - Summary 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.

KW - Stroke

KW - Allopurinol

KW - Hypertension

KW - White matter hyperintensities

U2 - 10.1016/j.eclinm.2023.101863

DO - 10.1016/j.eclinm.2023.101863

M3 - Article

C2 - 36864979

SN - 2589-5370

VL - 57

JO - EClinicalMedicine

JF - EClinicalMedicine

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