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Original research
Prehospital transdermal glyceryl trinitrate for ultra-acute ischaemic stroke: data from the RIGHT-2 randomised sham-controlled ambulance trial
  1. Jason Philip Appleton1,2,
  2. Lisa J Woodhouse3,
  3. Craig S Anderson4,5,6,
  4. Sandeep Ankolekar7,
  5. Lesley Cala8,
  6. Mark Dixon3,9,
  7. Timothy J England3,
  8. Kailash Krishnan10,
  9. Grant Mair11,
  10. Keith W Muir12,
  11. John Potter13,
  12. Christopher I Price14,
  13. Marc Randall15,
  14. Thompson G Robinson16,
  15. Christine Roffe17,
  16. Else C Sandset18,19,
  17. Jeffrey L Saver20,
  18. Angela Shone21,
  19. Aloysius Niroshan Siriwardena9,22,
  20. Joanna M Wardlaw11,
  21. Nikola Sprigg3,10,
  22. Philip M Bath3,10
  23. On behalf of the RIGHT-2 Investigators
  1. 1 Stroke, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
  2. 2 Institute of Applied Health Research, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
  3. 3 Stroke Trials Unit, Mental Health and Clinical Neurosciences, University of Nottingham, Nottingham, UK
  4. 4 Faculty of Medicine, The George Institute for Global Health, Sydney, New South Wales, Australia
  5. 5 The George Institute China at Peking University Health Science Center, Beijing, China
  6. 6 Neurology, Royal Prince Alfred Hospital, Sydney Health Partners, Sydney, New South Wales, Australia
  7. 7 Department of Neurology, King's College Hospital NHS Foundation Trust, London, UK
  8. 8 Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Western Australia, Australia
  9. 9 East Midlands Ambulance Service NHS Trust, Nottingham, UK
  10. 10 Stroke, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
  11. 11 Centre for Clinical Brain Sciences, Dementia Research Institute, Univeristy of Edinburgh, Edinburgh, UK
  12. 12 Institute of Neurology and Psychology, University of Glasgow, Glasgow, UK
  13. 13 Bob Champion Research and Education Building, University of East Anglia, Norwich, UK
  14. 14 Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
  15. 15 Department of Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  16. 16 Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK
  17. 17 Stroke Research in Stoke, Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent, UK
  18. 18 Department of Neurology, Oslo University Hospital, Oslo, Norway
  19. 19 Research and Development, Norwegian Air Ambulance Foundation, Oslo, Norway
  20. 20 Department of Neurology and Comprehensive Stroke Center, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
  21. 21 Research and Graduate Services, University of Nottingham, Nottingham, UK
  22. 22 Community and Health Research Unit, University of Lincoln, Lincoln, UK
  1. Correspondence to Professor Philip M Bath; philip.bath{at}nottingham.ac.uk

Abstract

Background The effect of transdermal glyceryl trinitrate (GTN, a nitrovasodilator) on clinical outcome when administered before hospital admission in suspected stroke patients is unclear. Here, we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2).

Methods RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4 hours of onset. The primary outcome was a shift in scores on the modified Rankin scale (mRS) at day 90. Secondary outcomes included death; a global analysis (Wei-Lachin test) containing Barthel Index, EuroQol-5D, mRS, telephone interview for cognitive status-modified and Zung depression scale; and neuroimaging-determined ‘brain frailty’ markers. Data were reported as n (%), mean (SD), median [IQR], adjusted common OR (acOR), mean difference or Mann-Whitney difference (MWD) with 95% CI.

Results 597 of 1149 (52%) patients had a final diagnosis of ischaemic stroke; age 75 (12) years, premorbid mRS>2 107 (18%), Glasgow Coma Scale 14 (2) and time from onset to randomisation 67 [45, 108] min. Neuroimaging ‘brain frailty’ was common: median score 2 [2, 3] (range 0–3). At day 90, GTN did not influence the primary outcome (acOR for increased disability 1.15, 95% CI 0.85 to 1.54), death or global analysis (MWD 0.00, 95% CI −0.10 to 0.09). In subgroup analyses, there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1 hour of symptom onset and in those with more severe stroke.

Conclusions In patients who had an ischaemic stroke, ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.

  • Stroke
  • Blood Pressure
  • Cerebral Infarction
  • Clinical Trial

Data availability statement

Data are available on reasonable request. Data are available on reasonable request to the corresponding author.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/svn-2022-001634

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    Data availability statement

    Data are available on reasonable request. Data are available on reasonable request to the corresponding author.

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    Footnotes

    • Twitter @JPAppleton, @not applicable, @nsiriwardena

    • JPA and LJW contributed equally.

    • Contributors LJW performed the analyses. JPA interpreted the data and wrote the first draft. All authors edited the manuscript. PMB is corresponding author and guarantor for the study.

    • Funding British Heart Foundation (grant number CS/14/4/30972). JPA is supported by an NIHR Health and Care Research Scholarship. PMB is Stroke Association Professor of Stroke Medicine and an NIHR Senior Investigator. TR is an NIHR Senior Investigator. GM is the Stroke Association Edith Murphy Foundation Senior Clinical Lecturer (SA L-SMP 18\1000). JW is supported by the UK Dementia Research Institute which receives its funding from DRI, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK.

    • Competing interests JPA is supported by an NIHR Health and Care Research Scholarship. PMB is Stroke Association Professor of Stroke Medicine and an NIHR Senior Investigator. TR is a NIHR Senior Investigator. GM is the Stroke Association Edith Murphy Foundation Senior Clinical Lecturer (SA L-SMP 18\1000). JW is supported by the UK Dementia Research Institute which receives its funding from DRI, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. The remaining authors report no declarations of interest.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.