Targeting the Brain: Neuroprotection and Neurorestoration in Ischemic Stroke

Jeffrey L. Saver, M.D., FAHA, FAAN

Disclosures

Pharmacotherapy. 2010;30(7):62S-69S. 

In This Article

The National Institutes of Health Fast-mag Trials

Prehospital trials of treatments for focal stroke face several design challenges, including accurate identification of patients with stroke, rating of pretreatment stroke severity, elicitation of informed consent in the field before hospital arrival, and randomization to appropriate treatment arm. The Field Administration of Stroke Therapy—Magnesium (FAST-MAG) investigators developed several novel methods to address these obstacles, first in a pilot, 20-patient feasibility trial,[14] and then in an ongoing, pivotal, 1700-patient phase III trial.

Stroke Identification

Paramedics identify patients with stroke using the Los Angeles Prehospital Stroke Screen (LAPSS), an 8-item diagnostic inventory that takes 1–2 minutes to perform, is well validated, and is a standard part of ambulance personnel training worldwide.[15]

Stroke Severity Rating

The Los Angeles Motor Scale (LAMS) is a 0–5-point rating of motor deficit severity that is derived directly from the face, arm, and grip weakness examination section of the LAPSS.[16] When performing the LAPSS, paramedics also automatically perform the LAMS. Although simple and rapid, the LAMS is a useful assessment of stroke deficit severity, correlating well with concurrently measured 13-item NIH Stroke Scale (NIHSS)[17] scores, and predicting final 3-month disability, activities of daily living, and neurologic deficit outcomes nearly as well as the full NIHSS.

Informed Consent Elicitation: Cellular Telemedicine

Most recent prehospital treatment trials have been conducted for conditions that render patients incompetent to provide consent, such as cardiac arrest, under regulations permitting waiver of explicit consent in emergency circumstances. In acute stroke, however, many patients retain decision-making capacity and require fully informed consent. Having paramedics elicit informed consent has the drawbacks of having non–stroke experts (the paramedics) answering the patient's queries about informed consent and of diverting paramedic attention from prehospital duties. In the cellular telemedicine enrollment system developed for FAST-MAG, rescue vehicles carry written informed consent forms and cellular phones that permit instant connection to on-call enrolling physician-investigators.[18] The physician-investigator discusses the trial by phone with patients or their legally authorized representatives while paramedics perform prehospital care duties unimpeded.

Preencounter Randomization

Keep it simple and straightforward (KISS) is an important principle in prehospital research. In the potentially chaotic prehospital setting, complex randomization schemes and multiple drug source bins have a high risk of leading to administration of unintended treatment regimens. To promote reliable and rapid administration of study agent, the randomized phase III FAST-MAG trial employs a preencounter randomization system. Each ambulance is stocked with only one blinded study kit at a time. When the study kit is used in a patient, the ambulance is restocked within 24 hours with the next kit in that ambulance's permuted block treatment schedule. When given approval to start study procedures by the enrolling physician-investigator, paramedics can quickly and unambiguously proceed with administering the sole, prerandomized kit available in the vehicle.

The FAST-mag Phase III Trial

Using these techniques, the FAST-MAG phase III trial has already enrolled more patients in the hyperacute, under 2-hour period than all previous acute stroke treatment trials combined. By the end of 2009, 911 patients had been enrolled, with a median time interval from when they were last known to be well to start of study infusion of 46 minutes.[19] Fully 656 patients (72%) were enrolled within the first hour after onset, and another 219 (24%) in the second hour. In this initial cohort, patient demographics are typical for the stroke population, with an average age of 70 years and 60% of the population male. Stroke-mimicking conditions have been enrolled at a low rate of 3%, below the 5% allotted in trial sample size projections. The enrolling event was acute cerebral ischemia in 73% of patients and intracerebral hemorrhage in 24%.

These preliminary findings indicate that the FAST-MAG trial is accomplishing several innovations in stroke clinical trials, including being the first prehospital randomized stroke trial; being the first treatment trial to enroll a substantial cohort of patients in first 60 minutes after onset (the "golden hour"); and being the first trial testing neuroprotective therapy delivery in advance of recanalization therapy, potentially permitting more brain tissue to still be salvageable when reperfusion is achieved.

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