Frank Pratt

Methodology of the Field Administration of Stroke Therapy – Magnesium (FAST‐MAG) phase 3 trial: Part 2 – prehospital study methods

Rationale In acute stroke, the volume of salvageable brain tissue is maximal at onset and declines rapidly with time. Prehospital start of clinical trial interventions would enable delivery of neuroprotective agents, such as magnesium sulfate, to stroke patients in the hyperacute period when they are potentially most effective. Aims A broad aim of the FAST-MAG study is to develop and validate techniques to perform pivotal trials of neuroprotective therapies for acute stroke in the prehospital setting. In tandem with an accompanying general trial design article, this manuscript provides a detailed overview of several novel prehospital study methods employed in the NIH FAST-MAG Trial. Design Multicenter, randomized, double-blinded, placebo-controlled, pivotal clinical trial. Special Prehospital Procedures Distinctive prehospital methods deployed in FAST-MAG include: identifying likely stroke patients using the Los Angeles Prehospital Stroke Screen; eliciting explicit informed consent from patients or on scene legally authorized representatives via cellphone discussion with off-scene physicians; paramedic rating of pretreatment stroke severity using the Los Angeles Motor Scale; assigning patients to a study arm using blinded, pre-encounter randomization; facilitating continuity of study infusion from the field to the ED by stocking ambulances with study kits including both field and hospital doses; and electronic fax consent signature documentation by geographically separated subjects and enrolling physicians. Discussion The suite of prehospital trial methods developed for the FAST-MAG Trial enable enrollment of patients in very early time windows, including the hyperacute, ‘golden hour’ period immediately after stroke onset.

Methodology of the Field Administration of Stroke Therapy – Magnesium (FAST-MAG) Phase 3 Trial: Part 1 – Rationale and General Methods:

Rationale Prehospital initiation by paramedics may enable delivery of neuroprotective therapies to stroke patients in the hyperacute period when they are most effective in preclinical studies. Magnesium is neuroprotective in experimental stroke models and has been shown to be safe with signals of potential efficacy when started early after onset of human cerebral ischemia. Aims (a) To demonstrate that paramedic initiation of the neuroprotective agent magnesium sulfate in the field is an efficacious and safe treatment for acute stroke; (b) To demonstrate that field enrollment of acute stroke patients is a practical and feasible strategy for phase 3 stroke trials, permitting enrollment of greater numbers of patients in hyperacute time windows. Design Multicenter, randomized, double-blinded, placebo-controlled, pivotal clinical trial. Study Procedures The study is enrolling 1700 patients (850 in each arm) with likely acute stroke, including both cerebral infarction and intracerebral hemorrhage patients. Inclusion criteria are: (a) likely stroke as identified by the modified Los Angeles Prehospital Stroke Screen (mLAPSS), (b) age 40–95, (c) symptom onset within 2 h of treatment initiation, and (d) deficit present ⩾15 min. Paramedics administer a loading dose of magnesium sulfate (Mg) or matched placebo in the field, 4 grams over 15 min. In the Emergency Department, a maintenance infusion follows, 16 grams Mg or matched placebo over 24 h. Outcomes The primary endpoint is the modified Rankin Scale measure of global disability, assessed using the Rankin Focused Assessment, 90 days after treatment. Secondary efficacy endpoints include the NIHSS (neurologic deficit), Barthel Index (activities of daily living), and the Stroke Impact Scale (quality of life).

Association Between Hyperacute Stage Blood Pressure Variability and Outcome in Patients With Spontaneous Intracerebral Hemorrhage

Background and Purpose— Increased blood pressure (BP) variability, in addition to high BP, may contribute to adverse outcome in intracerebral hemorrhage. However, degree and association with outcome of BP variability (BPV) in the hyperacute period, 15 minutes to 5 hours after onset, have not been delineated. Methods— Among consecutive patients with intracerebral hemorrhage enrolled in the FAST-MAG trial (Field Administration of Stroke Therapy-Magnesium), BPs were recorded by paramedics in the field and during the first 24 hours of hospital course. BP was analyzed in the hyperacute period, from 0 to 4–6 hours, and in the acute period, from 0 to 24–26 hours after onset. BPV was analyzed by SD, coefficient of variation, and successive variation. Results— Among 386 patients with intracerebral hemorrhage, first systolic BP at median 23 minutes (interquartile range, 14–38.5) after onset was median 176 mm Hg, second systolic BP on emergency department arrival at 57 minutes (interquartile range, 45–75) after onset was 178 mm Hg, and systolic BP 24 hours after arrival was 138 mm Hg. Unfavorable outcome at 3 months (modified Rankin Scale, 3–6) occurred in 270 (69.9%). Neither mean nor maximum systolic BP was associated with outcome in multivariable analysis. However, all 3 parameters of BPV, in both the hyperacute and the acute stages, were associated with poor outcome. In the hyperacute phase, BPV was associated with poor outcome with adjusted odds ratios of 3.73 for the highest quintile of SD, 4.78 for the highest quintile of coefficient of variation, and 3.39 for the highest quintile of successive variation. Conclusions— BPV during the hyperacute first minutes and hours after onset in patients with intracerebral hemorrhage was independently associated with poor functional outcome. Stabilization of BPV during this vulnerable period, in the pre-hospital and early emergency department course, is a potential therapeutic target for future clinical trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.

Field Validation of the Los Angeles Motor Scale as a Tool for Paramedic Assessment of Stroke Severity

Background and Purpose— The Los Angeles Motor Scale (LAMS) is a 3-item, 0- to 10-point motor stroke-deficit scale developed for prehospital use. We assessed the convergent, divergent, and predictive validity of the LAMS when performed by paramedics in the field at multiple sites in a large and diverse geographic region. Methods— We analyzed early assessment and outcome data prospectively gathered in the FAST-MAG trial (Field Administration of Stroke Therapy–Magnesium phase 3) among patients with acute cerebrovascular disease (cerebral ischemia and intracranial hemorrhage) within 2 hours of onset, transported by 315 ambulances to 60 receiving hospitals. Results— Among 1632 acute cerebrovascular disease patients (age 70±13 years, male 57.5%), time from onset to prehospital LAMS was median 30 minutes (interquartile range 20–50), onset to early postarrival (EPA) LAMS was 145 minutes (interquartile range 119–180), and onset to EPA National Institutes of Health Stroke Scale was 150 minutes (interquartile range 120–180). Between the prehospital and EPA assessments, LAMS scores were stable in 40.5%, improved in 37.6%, and worsened in 21.9%. In tests of convergent validity, against the EPA National Institutes of Health Stroke Scale, correlations were r=0.49 for the prehospital LAMS and r=0.89 for the EPA LAMS. Prehospital LAMS scores did diverge from the prehospital Glasgow Coma Scale, r=−0.22. Predictive accuracy (adjusted C statistics) for nondisabled 3-month outcome was as follows: prehospital LAMS, 0.76 (95% confidence interval 0.74–0.78); EPA LAMS, 0.85 (95% confidence interval 0.83–0.87); and EPA National Institutes of Health Stroke Scale, 0.87 (95% confidence interval 0.85–0.88). Conclusions— In this multicenter, prospective, prehospital study, the LAMS showed good to excellent convergent, divergent, and predictive validity, further establishing it as a validated instrument to characterize stroke severity in the field.

Intercontinental elicitation of informed consent for enrollment in stroke research.

Physician-elicited explicit informed consent via cell phone is a method of prehospital enrollment into clinical trials which maximizes the autonomy of research subjects [1,2]. Commercialized Voice over Internet Protocol (VoIP) phone simultaneous ring systems [3], internet-based faxing systems and internet-based enrollment tools allow for safe enrollment of prehospital acute stroke patients into the NIH-funded Field Administration of Stroke Therapy – Magnesium (FAST-MAG) clinical trial from remote locations [4,5].

Enrollment Yield and Reasons for Screen Failure in a Large Prehospital Stroke Trial

Background and Purpose— The enrollment yield and reasons for screen failure in prehospital stroke trials have not been well delineated. Methods— The Field Administration of Stroke Therapy–Magnesium (FAST-MAG) trial identified patients for enrollment using a 2 stage screening process—paramedics in person followed by physician-investigators by cell phone. Outcomes of consecutive screening calls from paramedics to enrolling physician-investigators were prospectively recorded. Results— From 2005 to 2012, 4458 phone calls were made by paramedics to physician-investigators, an average of 1 call per vehicle every 135.7 days. A total of 1700 (38.1%) calls resulted in enrollments. The rate of enrollment of stroke mimics was 3.9%. Among the 2758 patients not enrolled, 3140 reasons for screen failure were documented. The most common reasons for nonenrollment were >2 hours from last known well (17.2%), having a prestroke condition causing disability (16.1%), and absence of a consent provider (9.5%). Novel barriers for phone informed consent specific to the prehospital setting were infrequent, but included: cell phone connection difficulties (3.2%), patient being hard of hearing (1.4%), insufficient time to complete consent (1.3%), or severely dysarthric (1.3%). Conclusions— In this large, multicenter prehospital trial, nearly 40% of every calls from the field to physician-investigators resulted in trial enrollments. The most common reasons for nonenrollment were out of window last known well time, prestroke confounding medical condition, and absence of a consent provider. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.

Characteristics and Outcomes of Very Elderly Enrolled in a Prehospital Stroke Research Study

Background and Purpose— Greater numbers of individuals aged ≥80 years enjoy a high quality of life, yet historically stroke trials have excluded this population. We aimed to describe a population of very elderly successfully enrolled into an acute stroke trial and compare their characteristics and outcomes with the younger cohort. Methods— We analyzed consecutive patients enrolled <2 hours of symptom onset in a prehospital stroke treatment trial, the FAST-MAG clinical trial (Field Administration of Stroke Therapy-Magnesium). We gathered demographic, treatment, and outcome data for nonelderly (<80 years old), very elderly (≥80 years old), and extreme elderly (≥90 years old). We describe key differences in the population of elderly and the impact of their inclusion on the clinical trial. Results— Of 1700 participants in FAST-MAG, there were 1210 nonelderly, 490 very elderly, and 60 extreme elderly subjects. Very elderly stroke patients successfully enrolled in a research study were more likely to be women, white, and have an ischemic mechanism rather than an intracerebral hemorrhage. Although the very elderly had generally poorer outcomes, 4 in 10 were functionally independent at 90 days. Conclusions— Inclusion of the very elderly population in acute stroke clinical trials would both significantly increase study participation and generalizability of future acute stroke clinical trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.

Paramedic Initiation of Neuroprotective Agent Infusions: Successful Achievement of Target Blood Levels and Attained Level Effect on Clinical Outcomes in the FAST-MAG Pivotal Trial (Field Administration of Stroke Therapy – Magnesium)

Background and Purpose— Paramedic use of fixed-size lumen, gravity-controlled tubing to initiate intravenous infusions in the field may allow rapid start of neuroprotective therapy for acute stroke. In a large, multicenter trial, we evaluated its efficacy in attaining target serum levels of candidate neuroprotective agent magnesium sulfate and the relation of achieved magnesium levels to outcome. Methods— The FAST-MAG phase 3 trial (Field Administration of Stroke Therapy – Magnesium) randomized 1700 patients within 2 hours of onset to paramedic-initiated, a 15-minute loading intravenous infusion of magnesium or placebo followed by a 24-hour maintenance dose. The drug delivery strategy included fixed-size lumen, gravity-controlled tubing for field drug administration, and a shrink-wrapped ambulance kit containing both the randomized field loading and hospital maintenance doses for seamless continuation. Results— Among patient randomized to active treatment, magnesium levels in the first 72 hours were assessed 987 times in 572 patients. Mean patient age was 70 years (SD±14 years), and 45% were women. During the 24-hour period of active infusion, mean achieved serum level was 3.91 (±0.8), consistent with trial target. Mg levels were increased by older age, female sex, lower weight, height, body mass index, and estimated glomerular filtration rate, and higher blood urea nitrogen, hemoglobin, and higher hematocrit. Adjusted odds for clinical outcomes did not differ by achieved Mg level, including disability at 90 days, symptomatic hemorrhage, or death. Conclusions— Paramedic infusion initiation using gravity-controlled tubing permits rapid achievement of target serum levels of potential neuroprotective agents. The absence of association of clinical outcomes with achieved magnesium levels provides further evidence that magnesium is not biologically neuroprotective in acute stroke.

Frequency, Predictors, and Outcomes of Prehospital and Early Postarrival Neurological Deterioration in Acute Stroke: Exploratory Analysis of the FAST-MAG Randomized Clinical Trial

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 functional independence and increased mortality. Averting U-END may be a target for future prehospital therapeutics. Trial Registration ClinicalTrials.gov Identifier: NCT00059332