Statistical analysis plan for the ‘Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2)’

Scutt, Polly; Appleton, Jason P.; Dixon, Mark; Woodhouse, Lisa J; Sprigg, Nikola; Wardlaw, Joanna M.; Montgomery, Alan; Pocock, Stuart J.; Bath, Philip M

doi:10.1177/2396987318756696

Cited by 11 publications

(16 citation statements)

References 42 publications

(60 reference statements)

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“…As far we are aware, RIGHT-2 is the first acute stroke trial to use a hierarchical approach to analysis in which the first analysis in the primary family was performed in the target population, with the potential for a subsequent primary analysis across the entire ITT population. We followed this predefined plan 17 since the high mimic rate had the potential to dilute any treatment effect. Although the non-positive result in the target population precluded testing the ITT population, this approach had the advantage that the primary analysis of the study directly addressed the core question of the biological benefit of drug administration in patients with the disease of interest.…”

Section: Discussionmentioning

confidence: 99%

“…Details of the trial design, statistical analysis plan, and baseline data have been published,16, 17, 18 and the design and protocol are summarised in the appendix. The study protocol is available online.…”

Section: Methodsmentioning

confidence: 99%

“…We required a total sample size of 850 participants (425 in each group) to detect a shift in mRS with a common odds ratio [OR] of 0·70, 17 assuming an overall significance level of 5%, 90% power, distribution of mRS scores as shown in the appendix, 10 3% loss to follow-up, mimic and transient ischaemic attack rate of 20%, and reduction for baseline covariate adjustment of 20% 23 . During the trial, we noted the non-stroke diagnosis rate exceeded 30%.…”

Section: Methodsmentioning

confidence: 99%

“…We assessed the primary outcome using ordinal logistic regression with adjustment for age, sex, premorbid mRS, FAST score, baseline systolic blood pressure, index event (intracerebral haemorrhage, ischaemic stroke, transient ischaemic attack, mimic), time to randomisation, and reperfusion treatment (thrombectomy, alteplase, none) 17 . We tested the assumption of proportional odds using the likelihood ratio test.…”

Section: Methodsmentioning

confidence: 99%

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Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Bath¹,

Scutt²,

Anderson³

et al. 2019

The Lancet

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Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UKbased ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Bath¹,

Scutt²,

Anderson³

et al. 2019

The Lancet

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147

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“…Analyses followed the statistical analysis plan for the overall trial. 22 The primary outcome (shift on 7-level mRS) was assessed using ordinal logistic regression with adjustment for age, sex, premorbid mRS, baseline FAST score, systolic BP, and time from the onset of symptoms to randomization. 22 The assumption of proportional odds was tested using the likelihood ratio test.…”

Section: Methodsmentioning

confidence: 99%

Prehospital Transdermal Glyceryl Trinitrate for Ultra-Acute Intracerebral Hemorrhage

Bath

Woodhouse

Krishnan

et al. 2019

Stroke

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Background and Purpose— Pilot trials suggest that glyceryl trinitrate (GTN; nitroglycerin) may improve outcome when administered early after stroke onset. Methods— We undertook a multicentre, paramedic-delivered, ambulance-based, prospective randomized, sham-controlled, blinded-end point trial in adults with presumed stroke within 4 hours of ictus. Participants received transdermal GTN (5 mg) or a sham dressing (1:1) in the ambulance and then daily for three days in hospital. The primary outcome was the 7-level modified Rankin Scale at 90 days assessed by central telephone treatment-blinded follow-up. This prespecified subgroup analysis focuses on participants with an intracerebral hemorrhage as their index event. Analyses are intention-to-treat. Results— Of 1149 participants with presumed stroke, 145 (13%; GTN, 74; sham, 71) had an intracerebral hemorrhage: time from onset to randomization median, 74 minutes (interquartile range, 45–110). By admission to hospital, blood pressure tended to be lower with GTN as compared with sham: mean, 4.4/3.5 mm Hg. The modified Rankin Scale score at 90 days was nonsignificantly higher in the GTN group: adjusted common odds ratio for poor outcome, 1.87 (95% CI, 0.98–3.57). A prespecified global analysis of 5 clinical outcomes (dependency, disability, cognition, quality of life, and mood) was worse with GTN; Mann-Whitney difference, 0.18 (95% CI, 0.01–0.35; Wei-Lachin test). GTN was associated with larger hematoma and growth, and more mass effect and midline shift on neuroimaging, and altered use of hospital resources. Death in hospital but not at day 90 was increased with GTN. There were no significant between-group differences in serious adverse events. Conclusions— Prehospital treatment with GTN worsened outcomes in patients with intracerebral hemorrhage. Since these results could relate to the play of chance, confounding, or a true effect of GTN, further randomized evidence on the use of vasodilators in ultra-acute intracerebral hemorrhage is needed. Clinical Trial Registration— URL: http://www.controlled-trials.com . Unique identifier: ISRCTN26986053.

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Frequency, Predictors, and Outcomes of Prehospital and Early Postarrival Neurological Deterioration in Acute Stroke

et al. 2018

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IMPORTANCE Studies of neurological deterioration in stroke have focused on the subacute period, but stroke treatment is increasingly migrating to the prehospital setting, where the neurological course has not been well delineated. OBJECTIVE To describe the frequency, predictors, and outcomes of neurological deterioration among patients in the ultra-early period following ischemic stroke or intracranial hemorrhage. DESIGN, SETTINGS, AND PARTICIPANTS Exploratory analysis of the prehospital, randomized Field Administration of Stroke Therapy-Magnesium (FAST-MAG) Trial conducted from 2005 to 2013 within 315 ambulances and 60 stroke patient receiving hospitals in Southern California. Participants were consecutively enrolled patients with suspected acute stroke who were transported by ambulance within 2 hours of stroke onset. MAIN OUTCOMES AND MEASURES The main outcome was neurological deterioration, defined as a worsening of 2 or more points on the Glasgow Coma Scale (GCS), a level of consciousness scale ranging from 3 to 15, with higher scores indicating more alertness. Imaging outcomes were ischemic or hemorrhagic injury extent identified during the first brain imaging scan. Outcomes at 3 months included global disability level (assessed using the modified Rankin Scale [mRS]; range, 0-6, with higher numbers indicating greater disability) and mortality. RESULTS Among the 1690 patients (99.4%), the mean (SD) age was 69.4 (13.5) years, and 43% were female. Final diagnoses were acute cerebral ischemia in 1237 patients (73.2%), intracranial hemorrhage in 386 patients (22.8%), and neurovascular mimic in 67 patients (4.0%). The median (interquartile range [IQR]) minutes between the last well-known time and GCS assessments were 23 (14-42) minutes for prehospital, 58 (46-79) minutes for ED arrival, and 149 (120-180) minutes for early ED course assessments. From prehospital to early postarrival, ultra-early neurological deterioration (U-END) occurred in 200 of 1690 patients (11.8%), more often among patients with intracranial hemorrhage than among those with acute cerebral ischemia (119 of 386 [30.8%] vs 75 of 1237 [6.1%], P < .001). Patterns of U-END were prehospital U-END without early recovery in 30 of 965 patients (3.1%), stable prehospital course but early ED deterioration in 49 of 965 patients (5.1%), and continuous deterioration in both prehospital and early ED phases in 27 of 965 patients (2.8%). Ultra-early neurological deterioration was associated with worse 3-month outcomes, including increased global disability (mRS score, 4.6 vs 2.4; P < .001), reduced functional independence (mRS score 0-2, 32 of 200 [16.0%] vs 844 of 1490 [56.6%]; P < .001), and increased mortality (87 of 200 [43.5%] vs 176 of 1490 [11.8%]; P < .001). CONCLUSIONS AND RELEVANCE Ultra-early neurological deterioration occurs in 1 in 8 ambulance-transported patients with acute cerebrovascular disease, including 1 in 3 patients with intracranial hemorrhage and 1 in 16 patients with acute cerebral ischemia, and is associated with markedly reduced func...

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Statistical analysis plan for the ‘Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2)’

Cited by 11 publications

References 42 publications

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Prehospital Transdermal Glyceryl Trinitrate for Ultra-Acute Intracerebral Hemorrhage

Frequency, Predictors, and Outcomes of Prehospital and Early Postarrival Neurological Deterioration in Acute Stroke

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