Pre-hospital transdermal glyceryl trinitrate for transient ischaemic attack: Data from the RIGHT-2 trial

doi:10.1111/ene.16502

Randomized Controlled Trial

. 2024 Dec;31(12):e16502.

doi: 10.1111/ene.16502. Epub 2024 Oct 11.

Pre-hospital transdermal glyceryl trinitrate for transient ischaemic attack: Data from the RIGHT-2 trial

Jason P Appleton^{1

2}, Mark Dixon^{2

3}, Lisa J Woodhouse², Craig S Anderson^{4

5

6}, Sandeep Ankolekar⁷, Lesley Cala⁸, Timothy J England², Peter J Godolphin⁹, Kailash Krishnan^{1

2}, Grant Mair¹⁰, Keith W Muir¹¹, John Potter¹², Chris I Price¹³, Marc Randall¹⁴, Thompson G Robinson¹⁵, Christine Roffe¹⁶, Peter M Rothwell¹⁷, Else Charlotte Sandset^{18

19}, Jeffrey L Saver²⁰, A Niroshan Siriwardena²¹, Joanna M Wardlaw¹⁰, Nikola Sprigg^{1

2}, Philip M Bath^{1

2}; RIGHT‐2 Investigators

Affiliations

¹ Stroke, Nottingham University Hospitals NHS Trust, Nottingham, UK.
² Stroke Trials Unit, School of Medicine, University of Nottingham, Nottingham, UK.
³ East Midlands Ambulance Service NHS Trust, Nottingham, UK.
⁴ George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
⁵ George Institute, Peking University Health Science Center, Beijing, China.
⁶ Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners, Sydney, New South Wales, Australia.
⁷ Department of Neurology, King's College Hospital London, London, UK.
⁸ Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia.
⁹ MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK.
¹⁰ Centre for Clinical Brain Sciences, Edinburgh Imaging and UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
¹¹ Institute of Neurology and Psychology, University of Glasgow, Glasgow, UK.
¹² Bob Champion Research and Education Building, University of East Anglia, Norwich, UK.
¹³ Population Health Sciences Institute, Newcastle University, Newcastle, UK.
¹⁴ Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹⁵ Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK.
¹⁶ Stroke Research in Stoke, School of Medicine, Keele University, Stoke-on-Trent, UK.
¹⁷ Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
¹⁸ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹⁹ Research and Development, Norwegian Air Ambulance Foundation, Oslo, Norway.
²⁰ Department of Neurology and Comprehensive Stroke Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²¹ Community and Health Research Unit, University of Lincoln, Lincoln, UK.

PMID: 39392040
PMCID: PMC11554870
DOI: 10.1111/ene.16502

Randomized Controlled Trial

Pre-hospital transdermal glyceryl trinitrate for transient ischaemic attack: Data from the RIGHT-2 trial

Jason P Appleton et al. Eur J Neurol. 2024 Dec.

. 2024 Dec;31(12):e16502.

doi: 10.1111/ene.16502. Epub 2024 Oct 11.

Authors

Affiliations

¹ Stroke, Nottingham University Hospitals NHS Trust, Nottingham, UK.
² Stroke Trials Unit, School of Medicine, University of Nottingham, Nottingham, UK.
³ East Midlands Ambulance Service NHS Trust, Nottingham, UK.
⁴ George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
⁵ George Institute, Peking University Health Science Center, Beijing, China.
⁶ Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners, Sydney, New South Wales, Australia.
⁷ Department of Neurology, King's College Hospital London, London, UK.
⁸ Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia.
⁹ MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK.
¹⁰ Centre for Clinical Brain Sciences, Edinburgh Imaging and UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
¹¹ Institute of Neurology and Psychology, University of Glasgow, Glasgow, UK.
¹² Bob Champion Research and Education Building, University of East Anglia, Norwich, UK.
¹³ Population Health Sciences Institute, Newcastle University, Newcastle, UK.
¹⁴ Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹⁵ Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK.
¹⁶ Stroke Research in Stoke, School of Medicine, Keele University, Stoke-on-Trent, UK.
¹⁷ Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
¹⁸ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹⁹ Research and Development, Norwegian Air Ambulance Foundation, Oslo, Norway.
²⁰ Department of Neurology and Comprehensive Stroke Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²¹ Community and Health Research Unit, University of Lincoln, Lincoln, UK.

PMID: 39392040
PMCID: PMC11554870
DOI: 10.1111/ene.16502

Abstract

Background and purpose: Ambulance trials assessing interventions in suspected stroke patients will recruit patients with currently active symptoms that will resolve into transient ischaemic attack (TIA). The safety and efficacy of glyceryl trinitrate (GTN) in the pre-specified subgroup of patients with TIA in the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial 2 (RIGHT-2) was assessed.

Methods: RIGHT-2 was a pre-hospital-initiated multicentre randomized sham-controlled blinded-endpoint trial that randomized patients with presumed ultra-acute stroke within 4 h of symptom onset to transdermal GTN or sham. Final diagnosis was determined by site investigators. The primary outcome was a shift in modified Rankin Scale (mRS) scores at 90 days analysed using ordinal logistic regression reported as adjusted common odds ratio with 95% confidence intervals (CIs). Secondary outcomes included death or dependence (mRS >2).

Results: In all, 109 of 1149 (9.5%) patients had a final diagnosis of TIA (GTN 57, sham 52) with mean age 73 (SD 13) years, 19 (17.4%) had pre-morbid mRS >2, and onset to randomization was 80 min (interquartile range 49, 105). GTN lowered blood pressure by 7.4/5.2 mmHg compared with sham by hospital arrival. At day 90, GTN had no effect on shift in mRS scores (common odds ratio for increased dependence 1.47, 95% CI 0.70-3.11) but was associated with increased death or dependence (mRS >2): GTN 29 (51.8%) versus sham 23 (46.9%), odds ratio 3.86 (95% CI 1.09-13.59).

Conclusions: Pre-hospital ultra-acute transdermal GTN did not improve overall functional outcome in patients with investigator-diagnosed TIA compared with sham treatment.

Keywords: blood pressure; clinical trial; stroke; transient ischaemic attack.

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Conflict of interest statement

JPA is supported, in part, by a Nottingham University Hospitals Research and Innovation Award. PMB is Stroke Association Professor of Stroke Medicine and an Emeritus NIHR Senior Investigator. TGR is an NIHR Senior Investigator. GM is the Stroke Association Edith Murphy Foundation Senior Clinical Lecturer (SA L‐SMP 18\1000). JMW is supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. The remaining authors report no conflicts of interest.

Figures

**FIGURE 1**
Shift in modified Rankin Scale in 109 participants with a final diagnosis of transient ischaemic attack by treatment group—glyceryl trinitrate (GTN) versus sham. Comparison by ordinal logistic regression with adjustment for age, sex, pre‐morbid modified Rankin Scale, Face–Arm–Speech–Time test, pre‐treatment systolic blood pressure and time to randomization. The effect of treatment for GTN versus sham is shown as adjusted common odds ratio 1.47, 95% confidence interval 0.70–3.11, p = 0.31.

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References

1. Dixon M, Appleton JP, Siriwardena AN, Williams J, Bath PM. A systematic review of ambulance service‐based randomised controlled trials in stroke. Neurol Sci. 2023;44(12):4363‐4378. - PMC - PubMed
1. Right‐2 Investigators . Prehospital transdermal glyceryl trinitrate in patients with ultra‐acute presumed stroke (RIGHT‐2): an ambulance‐based, randomised, sham‐controlled, blinded, phase 3 trial. Lancet. 2019;393(10175):1009‐1020. - PMC - PubMed
1. Appleton JP, Scutt P, Dixon M, et al. Ambulance‐delivered transdermal glyceryl trinitrate versus sham for ultra‐acute stroke: rationale, design and protocol for the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial‐2 (RIGHT‐2) trial (ISRCTN26986053). Int J Stroke. 2019;14(2):191‐206. - PubMed
1. Scutt P, Appleton JP, Dixon M, et al. Statistical analysis plan for the ‘Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial‐2 (RIGHT‐2)’. Eur Stroke J. 2018;3(2):193‐196. - PMC - PubMed
1. Bath PM, Scutt P, Appleton JP, et al. Baseline characteristics of the 1149 patients recruited into the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial‐2 (RIGHT‐2) randomized controlled trial. Int J Stroke. 2019;14(3):298‐305. - PubMed

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[1] Dixon M, Appleton JP, Siriwardena AN, Williams J, Bath PM. A systematic review of ambulance service‐based randomised controlled trials in stroke. Neurol Sci. 2023;44(12):4363‐4378. - PMC - PubMed

[2] Dixon M, Appleton JP, Siriwardena AN, Williams J, Bath PM. A systematic review of ambulance service‐based randomised controlled trials in stroke. Neurol Sci. 2023;44(12):4363‐4378. - PMC - PubMed

[3] Right‐2 Investigators . Prehospital transdermal glyceryl trinitrate in patients with ultra‐acute presumed stroke (RIGHT‐2): an ambulance‐based, randomised, sham‐controlled, blinded, phase 3 trial. Lancet. 2019;393(10175):1009‐1020. - PMC - PubMed

[4] Right‐2 Investigators . Prehospital transdermal glyceryl trinitrate in patients with ultra‐acute presumed stroke (RIGHT‐2): an ambulance‐based, randomised, sham‐controlled, blinded, phase 3 trial. Lancet. 2019;393(10175):1009‐1020. - PMC - PubMed

[5] Appleton JP, Scutt P, Dixon M, et al. Ambulance‐delivered transdermal glyceryl trinitrate versus sham for ultra‐acute stroke: rationale, design and protocol for the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial‐2 (RIGHT‐2) trial (ISRCTN26986053). Int J Stroke. 2019;14(2):191‐206. - PubMed

[6] Appleton JP, Scutt P, Dixon M, et al. Ambulance‐delivered transdermal glyceryl trinitrate versus sham for ultra‐acute stroke: rationale, design and protocol for the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial‐2 (RIGHT‐2) trial (ISRCTN26986053). Int J Stroke. 2019;14(2):191‐206. - PubMed

[7] Scutt P, Appleton JP, Dixon M, et al. Statistical analysis plan for the ‘Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial‐2 (RIGHT‐2)’. Eur Stroke J. 2018;3(2):193‐196. - PMC - PubMed

[8] Scutt P, Appleton JP, Dixon M, et al. Statistical analysis plan for the ‘Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial‐2 (RIGHT‐2)’. Eur Stroke J. 2018;3(2):193‐196. - PMC - PubMed

[9] Bath PM, Scutt P, Appleton JP, et al. Baseline characteristics of the 1149 patients recruited into the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial‐2 (RIGHT‐2) randomized controlled trial. Int J Stroke. 2019;14(3):298‐305. - PubMed

[10] Bath PM, Scutt P, Appleton JP, et al. Baseline characteristics of the 1149 patients recruited into the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial‐2 (RIGHT‐2) randomized controlled trial. Int J Stroke. 2019;14(3):298‐305. - PubMed

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Pre-hospital transdermal glyceryl trinitrate for transient ischaemic attack: Data from the RIGHT-2 trial

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Pre-hospital transdermal glyceryl trinitrate for transient ischaemic attack: Data from the RIGHT-2 trial

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