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  • Relationship between nitrate headache and outcome in patients with acute stroke: results from the efficacy of nitric oxide in stroke (ENOS) trial

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Original research
Relationship between nitrate headache and outcome in patients with acute stroke: results from the efficacy of nitric oxide in stroke (ENOS) trial
  1. Lucy Beishon1,
  2. Lisa J Woodhouse1,
  3. Daniel Bereczki2,
  4. Hanne K Christensen3,
  5. Ronan Collins4,
  6. John Gommans5,
  7. Christina Kruuse6,
  8. George Ntaios7,
  9. Serefnur Ozturk8,
  10. Stephen Phillips9,
  11. Stuart Pocock10,
  12. Szabolcs Szatmari11,
  13. Joanna Wardlaw12,
  14. Nikola Sprigg1,13,
  15. Philip M Bath1,13
  16. for ENOS Investigators
  1. 1 Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK
  2. 2 Department of Neurology, Semmelweis University, Budapest, Hungary
  3. 3 Bispebjerg Hospital and University of Copenhagen, University of Copenhagen, Copenhagen, Denmark
  4. 4 Department of Geriatric and Stroke Medicine, Adelaide and Meath Hospital, Dublin, Ireland
  5. 5 Department of Medicine, Hawke's Bay Hospital, Camberley, New Zealand
  6. 6 Department of Neurology, Herlev Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
  7. 7 Department of Medicine, Larissa University Hospital, University of Thessaly, Volos, Greece
  8. 8 Department of Neurology, Selcuk University Medical Faculty, Konya, Turkey
  9. 9 Department of Neurology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
  10. 10 Medical Statistics Unit, London School of Hygiene & Tropical Medicine, London, UK
  11. 11 Department of Neurology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Targu Mures, Romania
  12. 12 Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
  13. 13 Stroke, Nottingham University Hospitals NHS Trust, Nottingham, UK
  1. Correspondence to Dr Lucy Beishon; lb330{at}le.ac.uk

Abstract

Introduction Nitrate-induced headache is common and may signify responsive cerebral vasculature. We assessed the relationship between nitrate headache and outcome in patients with acute stroke.

Materials and methods Patients were those randomised to glyceryl trinitrate (GTN) versus no GTN in the efficacy of nitric oxide in stroke trial. Development of headache by end of treatment (day 7), and functional outcome (modified Rankin Scale, primary outcome) at day 90, were assessed. Analyses are adjusted for baseline prognostic factors and give OR and mean difference (MD) with 95% CI.

Results In 4011 patients, headache was more common in GTN than control (360, 18.0% vs 170, 8.5%; p<0.001). Nitrate-related headache was associated with: younger age, female sex, higher diastolic blood pressure, non-total anterior circulation syndrome, milder stroke and absence of dysphasia (p<0.05). Nitrate headache was not associated with improved functional outcome (OR 0.90, 95% CI 0.73 to 1.10, p=0.30) or death (day 90) (HR 0.64, 95% CI 0.40 to 1.02, p=0.062), but reduced death or deterioration (day 7) (OR 0.45, 95% CI 0.25 to 0.82), death in hospital (OR 0.44, 95% CI 0.22 to 0.88) and improved activities of daily living (Barthel index, MD 3.7, 95% CI 0.3 to 7.1) and cognition (telephone interview cognitive screen, MD 2.0, 95% CI 0.7 to 3.3) (day 90). Non-nitrate headache was not associated with death, disability or cognition.

Discussion and conclusion Development of a nitrate headache by day 7 after stroke may be associated with improved activities of daily living and cognitive impairment at day 90, which was not seen with non-nitrate headache.

  • intervention
  • stroke
  • blood pressure

Data availability statement

Data are available on reasonable request. Individual participant data will be shared with the Virtual International Stroke Trials Archive (VISTA) collaboration. From 1 January 2022, the chief investigator and trial steering committee will consider other requests to share individual participant data via email at: enos@nottingham.ac.uk. We will require a protocol detailing hypothesis, aims, analyses and intended tables and figures. Where possible, we will perform the analyses; if not, deidentified data and a data dictionary will be supplied for the necessary variables for remote analysis. Any sharing will be subject to a signed data access agreement. Ultimately, the data will be published.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/svn-2020-000498

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    Data availability statement

    Data are available on reasonable request. Individual participant data will be shared with the Virtual International Stroke Trials Archive (VISTA) collaboration. From 1 January 2022, the chief investigator and trial steering committee will consider other requests to share individual participant data via email at: enos@nottingham.ac.uk. We will require a protocol detailing hypothesis, aims, analyses and intended tables and figures. Where possible, we will perform the analyses; if not, deidentified data and a data dictionary will be supplied for the necessary variables for remote analysis. Any sharing will be subject to a signed data access agreement. Ultimately, the data will be published.

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    Footnotes

    • Contributors LB conducted the analyses, drafted and revised the manuscript. LJW provided support and assistance with analyses and contributed to drafting the manuscript. PMB designed the ENOS trial, analysis plan for the manuscript and contributed to the draft and revision of the manuscript. All other authors contributed to the ENOS trial and the drafts and revision of the manuscript.

    • Funding ENOS was funded by the UK Medical Research Council (G0501797). JW was supported, in part, by the Scottish Funding Council through the SINAPSE Collaboration (www.sinapse.ac.uk/). PMB is Stroke Association Professor of Stroke Medicine and is an NIHR Senior Investigator. LB is currently a Dunhill Research Training Fellow (RTF1806\27) at the University of Leicester (all work was originally conducted at the Nottingham Trials Unit).

    • Competing interests None declared.

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