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Ambulance magnesium failed to improve stroke outcomes
SAN DIEGO — Administration of magnesium in the ambulance for the treatment of stroke soon after the start of symptoms did not improve outcomes, according to research presented at the International Stroke Conference.
Despite this finding, Jeffrey L. Saver, MD, director of stroke neurology at the UCLA Stroke Center, said the Field Administration of Stroke Therapy – Magnesium (FAST-MAG) study is the first phase 3 trial of a stroke treatment within 1 hour of onset and has established a model for future research of agents for the treatment of stroke soon after symptom onset.
New trial paradigm
Jeffrey L. Saver
The primary aim of the FAST-MAG study was to “demonstrate that paramedic initiation of the neuroprotective agent magnesium sulfate in the field is an efficacious and safe treatment for stroke, but we also had a systems aim to demonstrate that field enrollment in acute stroke trials is a practical and feasible strategy,” Saver said at a press conference.
From 2005 to March 2013, FAST-MAG researchers enrolled 1,700 patients (mean age, 69 years; 42.6% women; 77.9% white) within 2 hours of stroke onset. The patients were randomly assigned to receive 4 g magnesium in the field followed by 16 g magnesium infusion during the next 24 hours (n=857) or placebo (n=843), Saver said.
The trial was conducted in California’s Los Angeles and Orange counties, and included 40 emergency medical service provider agencies (including 2,988 paramedics trained in study procedures) and 60 receiving hospitals.
“We had to do a number of novel techniques to enroll patients in the field,” Saver said, including physicians conducting review by cellphone to confirm diagnosis and obtain consent, administering the drug using a fixed lumen IV, and using the new Los Angeles Motor Scale tool to rate severity.
The primary endpoint was modified Rankin scale measure of global disability at 90 days.
Nearly all of the patients received magnesium or placebo within 2 hours of symptoms onset, including 74.3% within 1 hour. Mean onset-to-drug time was 45 minutes. There was no difference in serious adverse events between the two groups, according to Saver.
No difference in outcomes
At 90 days, modified Rankin scale distribution did not differ between the two groups (Cochran-Mantel-Haenszel test, P=.28). The magnesium group had excellent outcomes (modified Rankin Scale scores of 0 or 1) in 36.5% of patients, whereas the placebo group had excellent outcomes in 36.9% of patients. The neutral effect was observed across all subgroups, Saver said.
“It might not have worked because magnesium may traffic across the blood-brain barrier slowly, so it might not accumulate rapidly in the brain,” he said. “Magnesium as a single agent may not be enough to suppress the molecular ischemic cascade. Also, patient treatment with standard care got better during the course of the trial.”
Importantly, he said, FAST-MAG established a blueprint to test other therapies, particularly ones that showed promise in animals but were not effective in humans 3 hours after symptom onset, to determine whether they could be effective if administered within 2 hours of onset.
“Three [therapies] are currently being tested,” Saver said, noting that there is one study of remote ischemic preconditioning, two studies of glycerol trinitrate and another study about to be launched for NA-1. – by Erik Swain
For more information:
Saver JL. Abstract #214. Presented at: International Stroke Conference 2014; Feb. 12-14, 2014; San Diego.
Disclosure: Saver reports no relevant financial disclosures.
Perspective
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The study was designed to test two hypotheses. One was whether a prehospital randomized trial with obtaining informed consent is feasible. In that regard, it was a resounding success. It’s a fairly large study for stroke, regardless of location. This was a well-coordinated study that demonstrated that a platform could be built for prehospital stroke trials.
The second part of the study was a question of whether magnesium was ineffective as a neuroprotection agent because it was given too late. In my mind, this trial definitively answers the question. Magnesium is not effective in improving outcomes. We can’t give it before the stroke, and there’s no way we can give it any sooner than it was given in this trial, so this is a helpful trial in that it answers that question. You can put the drug back on the shelf and move on because there’s no future for magnesium as an acute neuroprotection agent in ischemic stroke.
The ideal agents to be studied in this format would meet certain criteria. No. 1, they would have good preclinical data showing a strong biological effect. No. 2, they would have a strong safety profile, so that risk for harm in the ambulance would be minimal. No. 3, there wouldn’t be a differential risk in patients with stroke mimics or brain hemorrhage, so they could be applied in the field with confidence. No. 4, the ideal agent would already be in the ambulance; it would already be a stocked item or could be easily added without the need for extra storage or refrigeration so it could be as widely distributed as possible. The biggest challenge of a study like this is equipping all the ambulances with the intervention. Even a mechanical intervention like tourniquets would be an exciting candidate.
Perspective
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The FAST-MAG study was born with the idea of treating patients as quickly as possible, ideally within 1 hour or less of stroke onset. The focus of this particular study was to apply a treatment that had been shown in animal models to act as a neuroprotectant and appeared to be safe to patients suffering from a stroke. The key for overall safety with magnesium is that it can be administered in the field before a CT scan is done and regardless of whether the stroke was an ischemic or hemorrhagic stroke. Overall, this trial was an absolutely heroic effort on behalf of the investigators, their collaborators and the EMS system — all of whom were able to conduct this trial successfully.
As a whole, this trial is a mixed success and failure. While the trial was very successful in doing what it set out to do, which was to test a candidate neuroprotective treatment very early after stroke onset, the magnesium itself was unsuccessful and did not demonstrate or hint at superior patient outcomes. FAST-MAG did not produce a new treatment option for reducing stroke severity, but it did prove that this kind of trial can be carried out and therapy can be administered in the field. Administration of a neuroprotectant agent by EMS personnel in the field is now established as a system that can be used not only to test future selected agents, but also to become standard of care for stroke treatment if we ever identify a successful therapy.
My hope is that we will see more trials like this and discover successful neuroprotectant treatments that are actually protective when given in this very early time frame. Going forward, it will be necessary to go through the FAST-MAG data carefully to see if there is any indication of subgroups of patients who benefitted or some other hint in the data that could help guide future trials. The other major task will be to identify other candidate treatments, potentially more biologically powerful than magnesium, that have the same property of being safe for both ischemic and hemorrhagic stroke so that they can be given without a CT scan.