Feasibility of an Ambulance-Based Stroke Trial, and Safety of Glyceryl Trinitrate in Ultra-Acute Stroke

Abstract

Background and Purpose— The practicalities of doing ambulance-based trials where paramedics perform all aspects of a clinical trial involving patients with ultra-acute stroke have not been assessed. Methods— We performed a randomized controlled trial with screening, consent, randomization, and treatment performed by paramedics prior to hospitalization. Patients with probable ultra-acute stroke (<4 hours) and systolic blood pressure (SBP) >140 mm Hg were randomized to transdermal glyceryl trinitrate (GTN; 5 mg/24 hours) or none (blinding under gauze dressing) for 7 days with the first dose given by paramedics. The primary outcome was SBP at 2 hours. Results— Of a planned 80 patients, 41 (25 GTN, 16 no GTN) were enrolled >22 months with median age [interquartile range] 79 [16] years; men 22 (54%); SBP 168 [46]; final diagnosis: stroke 33 (80%) and transient ischemic attack 3 (7%). Time to randomization was 55 [75] minutes. After treatment with GTN versus no GTN, SBP at 2 hours was 153 [31] versus 174 [27] mm Hg, respectively, with difference −18 [30] mm Hg ( P =0.030). GTN improved functional outcome with a shift in the modified Rankin Scale by 1 [3] point ( P =0.040). The rates of death, 4 (16%) versus 6 (38%; P =0.15), and serious adverse events, 14 (56%) versus 10 (63%; P =0.75), did not differ between GTN and no GTN. Conclusions— Paramedics can successfully enroll patients with ultra-acute stroke into an ambulance-based trial. GTN reduces SBP at 2 hours and seems to be safe in ultra-acute stroke. A larger trial is needed to assess whether GTN improves functional outcome. Clinical Trial Registration— URL: http://www.controlled-trials.com/ISRCTN66434824/66434824 . Unique identifier: 66434824.

Thomas Willis Lecture

“…Fortunately, innovations and improvements in hyper acute stroke care and trial methodology now allow us to put neuroprotection to the ultimate test in the golden hour. Several ongoing trials use randomization in the field and ultraacute treatment either by paramedics (FRONTIER [Field Randomization of NA-1 Therapy in Early Responders] trial, ClinicalTrials.gov Identifier: NCT02315443 33 ) or by dedicated mobile stroke units with specialist teams deployed to the home of the patient. 34 These approaches enable a 1-hour…”

Effect of waivers of consent on recruitment in acute stroke trials

“…) Among the 9 trials that did not require written consent, 7 of these sought consent but permitted waivers, 8,9,26,31,32,40,46 one did not seek consent at all, 28 and one permitted verbal consent. 37 Refusals of consent.…”

“…The 9 trials that did not require written informed consent prior to randomization (table 2) presented several rationales for using alternatives to written informed consent, including the permissibility of deferring consent, 8,26 approval by an Ethics Board, 28,32,46 the need for maximally rapid treatment, 31,37 the right of patients not to have tissue plasminogen activator (tPA) withheld, 9 and the ability of medical professionals to provide proxy consent. 40 One trial that, for the sake of analysis, was not grouped with the 9 trials that permitted waivers of consent required written informed consent at all 22 study sites except one, which was exempted "by the FDA and the institutional review board." 35 Many of these trials required later actions by patients to confirm consent.…”

“…9 In the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT), written informed consent was required by the patient or proxy at the hospital, after the first treatment dose had been given in the ambulance. 40 Efficacy and Safety of Continuous Intravenous Versus Usual Subcutaneous Insulin in Acute Ischemic Stroke (INSULINFARCT) stipulates that "consent was not immediately required" and Walter et al 8 alludes to "deferments," though neither specifies later steps required for full inclusion. 31 Outlier detection.…”

“…The prehospital interventions included 2 German trials of mobile stroke units with on-board imaging and thrombolysis capabilities (the only 2 cluster-randomized trials in this review), 8,9 a Swedish trial in which participants in the intervention arm were assigned a higher prehospital priority level by the emergency dispatch center, 28 and 3 trials with paramedic-initiated therapies: lisinopril (UK), 37 ischemic preconditioning (Finland), 39 and glycerol trinitrate (UK). 40 Of these prehospital trials, only one required written informed consent en route to the hospital. 39 When the 2 outlier trials were included in analysis (see above), the mean recruitment rate of trials that did not require written consent was nearly 6 times the rate of trials that required it (p 5 0.03).…”