Subject Retention in Prehospital Stroke Research Using a Telephone-Based Physician-Investigator Driven Enrollment Method.

Background and purposeSubject retention into clinical trials is vital, and prehospital enrollment may be associated with higher rates of subject withdrawal than more traditional methods of enrollment. We describe rates of subject retention in a prehospital trial of acute stroke therapy.MethodsAll subjects were enrolled into the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) phase 3 clinical trial. Paramedics screened eligible subjects and contacted the physician-investigator using a dedicated in-ambulance cellular phone. Physician-investigators obtained explicit informed consent from the subject or on-scene legally authorized representative (LAR) who reviewed and signed a consent form. Exception from informed consent (EFIC) was utilized in later stages of the study.ResultsThere were 1,700 subjects enrolled; 1,017 provided consent (60%), 662 were enrolled via LAR (39%), and 21 were enrolled via EFIC (1%). Of the 1,700 patients, 1,413 (83%) completed the 90-day visit, 265 (16%) died prior to the 90-day visit, and 22 (1.3%) withdrew from the study before completion. There were no differences in rates of withdrawal by method of study enrolment, i.e., self-consent (n = 14), 1.4%; LAR (n = 8), 1.2%; EFIC (n = 0) 0%.ConclusionThere was a high rate of retention when subjects were enrolled into prehospital stroke research using a phone-based method to obtain explicit consent

Marked Circadian Variation in Number and Type of Hyperacute Strokes During the 24 Hour Day-Night Cycle

Introduction: Circadian variations in stroke onset provide critical information for the allocation of pre-hospital and hospital resources in clinical care. Confining analysis to patients with defined onset in waking and clearly distinguished ischemic and hemorrhagic stroke subtypes, would substantial benefit our understanding of stroke etiology. Methods: We analyzed patients enrolled in the NIH FAST-MAG phase 3 trial of field-initiated neuroprotective agents in patients with hyperacute stroke within 2h of onset. Onset times were analyzed in 1h time blocks throughout the 24h day-night cycle. Patient demographic and clinical features, medical history, imaging characteristics, and stroke deficit severity were correlated with onset times. Results: Among 1632 patients, final diagnoses were acute cerebral ischemia in 76.2% and intracranial hemorrhage in 23.7%. Acute cerebral ischemia (ACI) had a unimodal distribution with peak onset at midday (12:00-12:59); intracerebral hemorrhage (ICH) a bimodal distribution with peaks at mid-morning (08:00-08:59) and early evening (18:00-18:59). Events were markedly reduced in early morning, with only 3.4% starting in the first 25% of the day. The proportion of hemorrhagic was higher in the first 8h of the day (00:00-07:59) than the remaining 16h, 33.3% vs 22.5%, p=0.006. ACI and ICH patients displayed fairly homogeneous vascular risk factors, presenting deficit severity, and initial brain imaging findings across all time periods. Discussion: There is marked, more than 10-fold, circadian variation in onset of acute cerebrovascular disease, and circadian variation in the ratio of ischemic to hemorrhagic neurovascular events. These findings can inform resource planning for regional systems of acute stroke care

Prehospital use of magnesium sulfate as neuroprotection in acute stroke

Background Magnesium sulfate is neuroprotective in preclinical models of stroke and has shown signals of potential efficacy with an acceptable safety profile when delivered early after stroke onset in humans. Delayed initiation of neuroprotective agents has hindered earlier phase 3 trials of neuroprotective agents. Methods: We randomly assigned patients with suspected stroke to receive either intravenous magnesium sulfate or placebo, beginning within 2 hours after symptom onset. A loading dose was initiated by paramedics before the patient arrived at the hospital, and a 24-hour maintenance infusion was started on the patient's arrival at the hospital. The primary outcome was the degree of disability at 90 days, as measured by scores on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability). Results: Among the 1700 enrolled patients (857 in the magnesium group and 843 in the placebo group), the mean (±SD) age was 69±13 years, 42.6% were women, and the mean pretreatment score on the Los Angeles Motor Scale of stroke severity (range, 0 to 10, with higher scores indicating greater motor deficits) was 3.7±1.3. The final diagnosis of the qualifying event was cerebral ischemia in 73.3% of patients, intracranial hemorrhage in 22.8%, and a stroke-mimicking condition in 3.9%. The median interval between the time the patient was last known to be free of stroke symptoms and the start of the study-drug infusion was 45 minutes (interquartile range, 35 to 62), and 74.3% of patients received the study-drug infusion within the first hour after symptom onset. There was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the magnesium group and those in the placebo group (P=0.28 by the Cochran–Mantel–Haenszel test); mean scores at 90 days did not differ between the magnesium group and the placebo group (2.7 in each group, P=1.00). No significant between-group differences were noted with respect to mortality (15.4% in the magnesium group and 15.5% in the placebo group, P=0.95) or all serious adverse events. Conclusions: Prehospital initiation of magnesium sulfate therapy was safe and allowed the start of therapy within 2 hours after the onset of stroke symptoms, but it did not improve disability outcomes at 90 days. (Funded by the National Institute of Neurological Disorders and Stroke; FAST-MAG ClinicalTrials.gov number, NCT00059332.)

Interhospital Transfer Before Thrombectomy Is Associated With Delayed Treatment and Worse Outcome in the STRATIS Registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke).

BACKGROUND: Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation. METHODS: STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0-2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass. RESULTS: A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients ( CONCLUSIONS: In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large-vessel occlusion and direct routing to endovascular-capable centers for patients with severe stroke may improve outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02239640

The Los Angeles Motor Scale (LAMS): a new measure to characterize stroke severity in the field.

OBJECTIVE: To develop and retrospectively analyze an instrument that rapidly characterizes pretreatment stroke severity for use in prehospital acute stroke clinical trials. METHODS: The Los Angeles Motor Scale (LAMS) was constructed by assigning point values to Los Angeles Prehospital Stroke Screen (LAPSS) items of facial weakness, arm strength, and grip to yield a total 0-5 scale. The concurrent, discriminant, and predictive validities of the LAMS were probed using data from 90 patients enrolled in acute stroke clinical trials. Predictive performance of the LAMS was compared with that of the initial full National Institutes of Health Stroke Scale (NIHSS) and the five-item shortened NIHSS (sNIHSS) in projecting long-term outcomes on standard functional end points. RESULTS: LAMS score at entry averaged mean 2.6, median 2. Entry LAMS scores correlated closely with entry NIHSS scores (r=0.75). LAMS score correlations with three-month functional outcome measures were robust. Receiver operator curve analyses (c statistic) for performance in predicting three-month outcomes were: three-month modified Rankin-LAMS 0.75, sNIHSS 0.69, NIHSS 0.74; three-month Barthel Index-LAMS 0.77, sNIHSS 0.76, NIHSS 0.82; three-month NIHSS-LAMS 0.76, sNIHSS 0.62, NIHSS 0.70; and three-month GOS-LAMS 0.55, sNIHSS 0.67, NIHSS 0.76. Considering dichotomized three-month measures, entry LAMS scores were markedly lower in patients destined for excellent outcome, e.g., three-month modified Rankin score CONCLUSIONS: A motor score derived from the LAPSS rapidly quantifies stroke severity in the field and predicts functional outcomes with accuracy comparable to that of the full NIHSS and the sNIHSS

Frameless stereotactic aspiration and thrombolysis of deep intracerebral hemorrhage is associated with reduction of hemorrhage volume and neurological improvement

Introduction: This ia a phase-2 safety trial to demonstrate the ability of frameless stereotactic aspiration and thrombolysis of ICH to safely remove blood. Methods: Patients with ICH in the deep basal ganglia and internal capsule of >5 cc volume were consented to undergo computed tomographic imaging for frameless stereotactic guidance registration. Using the frameless stereotactic (CT) guidance, a 4-mm diameter catheter was inserted into the body of the hematoma using a frontal burr hole approach. The catheter was aspirated and then flushed with saline and aspirated to remove unclotted blood. After a confirmatory CT scan to localize the catheter, 1 mg of recombinant tissue plasminogen activator (t-PA) was infused into the clot, permitted to bathe the clot for 30 minutes, and then drained into a closed circuit collection system. t-PA was infused every 8 hours for 48 hours. A follow up CT scan was obtained at 48 hours. Results: 28 patients with ICH (mean age 67.1) were admitted and underwent the procedure. Mean initial ICH volume was 54.6 cc ± 37.8. Mean time from onset to aspiration was 44 hours (range 7–180). Mean initial NIH Stroke scale (NIHSS) score was 24 (range 15–33). Compared with initial CT scan, there was a mean reduction of ICH volume by 77 ± 13% on final CT scan (p<0.0002). Compared with initial NIHSS, the discharge mean NIHSS (16 ± 6) was significantly improved (p<0.001). There were no infectious, hemodynamic or neurologic complications. There were no episodes of symptomatic hemorrhagic enlargement and one case of asymptomatic bleeding along the catheter tract. Conclusion: Frameless stereotactic aspiration and thrombolysis (FAST) of deep spontaneous intracerebral hemorrhage is a safe therapy that is associated with reduction in ICH volume, early improvement in NIHSS and potentially could be used to improve outcome