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NEWS FROM THE INTERNATIONAL STROKE CONFERENCE: Magnesium Treatment for Stroke in the Ambulance Fails to Improve Outcomes

Susman, Ed

doi: 10.1097/01.NT.0000445558.78790.e2
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In a phase 3 trial, investigators reported that stroke patients who received magnesium sulfate in the ambulance before hospitalization did not have less disability three months later than those who didn't receive it.

SAN DIEGO—Treating stroke patients in the ambulance with the purported neuroprotective agent magnesium sulfate did not improve 90-day outcomes, researchers said here in February at the International Stroke Conference, sponsored by the American Stroke Association.

In the anxiously awaited FAST-MAG (Field Administration of Stroke Therapy–Magnesium) trial, the logistics of initiating therapy in the ambulance by paramedics allowed more than 75 percent of patients to undergo the magnesium therapy in the so-called ‘golden hour’ — 60 minutes from the time the patient last was reported well. Despite the feasibility success, however, there was not a positive shift in global disability at three months, as assessed with the modified Rankin Scale.

“FAST-MAG failed to confirm the primary hypothesis that pre-hospital magnesium sulfate is beneficial in likely stroke patients,” reported Jeffrey Saver, MD, professor of neurology and director of the Stroke Center at University of California, Los Angeles.

Dr. Saver said the research team decided to use magnesium sulfate as the treatment for the trial for a number of reasons: the knowledge that magnesium increases regional cerebral blood flow; it blocks calcium buildup in cells, and has been used clinically in pregnant women with eclampsia and other conditions for more than 75 years. The agent has a pretty good safety record, he noted, adding that magnesium is a generic agent.



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To perform the trial in Los Angeles and Orange counties in Southern California, researchers partnered with 40 emergency medical services agencies, including 315 rescue ambulances and 2988 paramedics. The program included 60 hospitals; 715 emergency medicine physicians; 210 neurologists; and 26 neurosurgeons, intensivists, and hospitalists. The study required 95 coordinators and research assistants.

When a suspected stroke occurred, the patient was assessed with the Los Angeles Prehospital Stroke Screen as one of the study entry criteria. The patients had to be between the ages of 40 and 95; were required to undergo treatment within two hours of the last known time of being well; and had to have presented with the stroke-caused deficit for at least 15 minutes.

The researchers excluded individuals who were comatose, who had major head trauma within the last 24 hours, who had severe comorbidities, or who were exhibiting rapid neurological improvement.

Once the paramedics arrived at the home — 97 percent of patients in the study had strokes in the home setting — they diagnosed the stroke, assessed its severity with standard instruments and with telephonic consults from a physician, and began therapy. Therapy consisted of a 4-gram dose of magnesium sulfate in the field, followed by a 16-gram maintenance dose for the next 214 hours. Randomization with either magnesium sulfate or placebo was determined before the patient encounter.

Dr. Saver said the researchers attempted to keep the stroke mimic level to less than 5 percent. The NIHSS stroke severity at admission to the hospital was 11.3: “These were fairly severe stroke patients,” he said.

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In the study, 21.7 percent of patients achieved a 0 score on the modified Rankin Scale — essentially no post-stroke disability compared with 20.9 percent of patients who were treated with magnesium in the ambulance; about 15.2 percent of stroke patients who were in the placebo group achieved a modified Rankin Scale score of 1 compared with 15.6 percent of patients treated with magnesium; 15.9 percent of patients in both groups had a 3-month modified Rankin Scale score of 2.

There were minimal differences in outcomes in the higher modified Rankin Scale scores — the categories measuring increasingly devastating functional deficits. Overall, the differences in the group failed to achieve statistical significance (p=0.28), Dr. Saver reported at a press briefing.



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Dr. Saver suggested several possibilities for why magnesium sulfate failed to make a difference in outcomes. Among them, he said, there was likely slow magnesium passage across the blood-brain barrier despite early systemic delivery, and magnesium as a single agent might have been insufficient to suppress the molecular ischemic cascade. Finally, he said, the improved standard of care reduced the opportunity to demonstrate a benefit — including better supportive care at primary stroke centers and the rapid and frequent use of tissue plasminogen activator.

Dr. Saver said that one of the major differences between FAST-MAG and other neuroprotective trials was that in this new study, 74.3 percent of patients were treated with magnesium within the golden hour. In the other trials, 0.2 percent of the population of some 5,345 patients was treated within in the golden hour. The search for a neuroprotective agent in the setting of stroke has been unproductive.

“We knew from a pilot trial that we could reduce the time to magnesium treatment by two hours by initiating treatment in the field,” Dr. Saver said. “We thought that the ambulance approach was the way to go. We thought we could begin treatment faster by using paramedics who are often the first point of contact with stroke patients.”

Of the 1700 patients in the trial, 1,253 were treated within the golden hour, Dr. Saver said. He said 25 percent of patients were treated within the one- to two-hour period. Getting patients from the scene of the stroke to the hospital door took an average of 33 minutes.

“This was the first acute — less than 3 hours — neuroprotective phase 3 study and the first stroke phase 3 trial of neuroprotection before recanalization,” Dr. Saver said.

Despite the trial's failure to show that magnesium sulfate could be used as a neuroprotective agent and influence outcomes, the results clearly showed that use of paramedics to assess and treat patients in the field was successful. Dr. Saver suggested that this finding will pave the way for future trials with other agents in stroke patients.

“This trial recognized the importance of time in stroke,” he said. “We know that for every minute that goes by in stroke without treatment, two million neural cells are lost. For every 10 minutes that go by before treatment with tissue plasminogen activator drugs, 1 per 100 fewer patients receive benefit of that treatment.”

“There were no differences in serious adverse events between the treatment and placebo arms of the trial,” Dr. Saver said. [See “More on the Study Participants.”]

The National Institute of Neurological Disorders and Stroke provided funding for the study.

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Commenting on the trial, Bruce Ovbiagele, MD, professor of neurology at the Medical University of South Carolina, said that the study results might not indicate further use of magnesium in the setting of acute stroke.

However, Dr. Ovbiagele, who moderated the press briefing suggested, “The trial does give us a whole new arena in which we can test promising new agents in this pre-hospital role. This is really, really important. While it was somewhat disappointing that magnesium wasn't efficacious, what is bigger than that is that it has been shown that this is feasible and that this can be done. That, more than anything else, is the redeeming message from this trial.”

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  • The average age of the patients in the study was 69 years.
  • 21.7 percent had been diagnosed with atrial fibrillation; 17.5 percent used tobacco; 38.5 percent used alcohol.
  • All the patients included in the study had a pre-stroke Rankin score of 0.
  • About 73 percent of patients were diagnosed with cerebral ischemia; 22.8 percent were diagnosed with intracranial hemorrhage; 3.9 percent of patients were diagnosed with stroke mimics.
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•. Backgrounder on the FAST-MAG trial:
    •. Neurology Today archive on stroke and neurovascular treatment:
      © 2014 American Academy of Neurology