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The Beneficial Failure of the FAST-MAG Trial
In 1997 a group of UCLA researchers led by Jeffrey Saver, MD, began training Los Angeles Fire Department paramedics on a new type of screening method to help identify strokes. Saver and his colleagues noticed that the accuracy of paramedics’ stroke diagnoses varied widely and that paramedics tended to overdiagnose stroke by failing to account for confounders such as stroke mimics and intoxicants.
They called their new screening tool the Los Angeles Prehospital Stroke Screen (LAPSS). Much like the more familiar Cincinnati Prehospital Stroke Scale, the LAPSS instructed paramedics to examine for unilateral weakness and facial asymmetry. It was more in-depth than the CPSS, however, and factored in conditions such as the patient’s age, past medical history and blood sugar. This gave it a greater ability to rule out conditions that could mimic true strokes.
Several academic papers were written regarding the LAPSS when L.A. paramedics put it into practice. In particular, researchers found that 93% of stroke patients were correctly identified using the tool. They also observed that if paramedics could be equipped with a drug that could treat the stroke at the time of identification in the field, then up to one hour and 50 minutes could be saved vs. administering the drug in the emergency department.1 The only problem was a lack of drugs suitable for field administration.
The Tease of Neuroprotectants
Neuroprotectants, drugs administered to protect the nervous system, have been an active area of stroke and brain injury research for over two decades. These drugs work via a number of mechanisms, ranging from reducing cerebral edema to mitochondrial stabilization to reducing excessive neurotransmitter stimulation. The concept of a single drug, or a cocktail of drugs, that could be easily administered to halt the progression of neurological damage could revolutionize not only stroke care, but also the care of traumatic brain injury, spinal injury and even chronic degenerative neurological disorders.
From the onset of neuroprotectant research, hundreds of laboratory, animal and clinical trials have been conducted. The measures tested often show remarkable promise in the lab, but they have failed to be proven successful in human trials. Explanations abound, yet there is no clear consensus as to why these drugs fail to translate into clinical practice.2
One of the hypotheses to explain the failure of neuroprotectants revolved around the relationship between the time of injury and time of drug administration. In animal studies neuroprotectants appeared most promising when they were administered as soon as possible after the injury occurred. It was thus surmised that the reason previous human trials failed was due to the time delay in administering the drug. Saver’s prehospital research appeared to be the perfect method of testing this idea.
In 1999 Saver and his colleagues submitted a proposal to the National Institutes of Health to fund a pilot trial studying prehospital administration of magnesium sulfate for acute stroke. Magnesium sulfate had previously shown promise in animal studies and human pilot trials. Additionally, a large, multicenter double-blinded randomized trial was underway in emergency departments across the United Kingdom to test its ability to improve stroke outcomes. Saver hypothesized that paramedics trained on the LAPSS would be able to administer magnesium sulfate in the field much faster than it could be administered in the hospital, and thus maximize a stroke patient’s chance at a good outcome.
The pilot trial was funded, and from May 2000 to April 2002, L.A. Fire paramedics enrolled 20 patients into the study and administered an IV dose of magnesium sulfate while en route to the hospital. Though the sample size was small, this study showed that prehospital administration of magnesium was safe and potentially beneficial. Of the enrolled patients, 60% showed good outcomes at three months (as defined by a modified Rankin score of less than or equal to 2), and the drug had a median administration time of only 100 minutes from the time symptoms began.3
Encouraged by the results, the investigators submitted a grant proposal to conduct a large Phase III clinical trial. This was the first study of its type to be conducted primarily in the field—double-blinded, multicenter randomized Phase III trials are normally conducted in the hospital setting. Despite its novelty, or perhaps because of it, the Field Administration of Stroke Therapy—Magnesium (FAST-MAG) trial received funding in 2003 and enrolled its first patient in January 2005. Conducting this type of research in the prehospital setting was not without its challenges, and the investigators had to pioneer methods of obtaining consent, randomizing and blinding both the patient and the paramedic.4
Paramedics enrolled 1,700 patients into the trial and started the drug in under an hour 74% of the time. There were 40 EMS agencies, 60 receiving hospitals and thousands of paramedics involved. The results were released this February at the International Stroke Conference in San Diego: There was no benefit shown to administering magnesium sulfate.
The Silver Lining
Despite the failure of the trial, Saver saw some benefit: “The study has really opened up opportunities to treat patients in the prehospital setting in the earliest minutes after symptoms appear,” he said. Sam Stratton, MD, co-investigator and medical director of Orange County EMS in California, echoed Saver: “FAST-MAG has raised the bar for future development of EMS and has been a study that all EMS and emergency medicine providers should be proud of as being representative of the profession. For the future, FAST-MAG will serve as the ultimate example for scientific exploration in medicine.5
Criticism has been raised, however, in regards to investigating drugs in the field as opposed to the hospital and the associated costs. Establishing new methods of conducting research and coordinating with fire chiefs, EMS administrators and paramedics wasn’t easy and required substantial government funding. Richard Bukata, MD, editor of Emergency Medical Abstracts and clinical instructor at the University of Southern California, recently criticized the FAST-MAG trial, saying, “The idea of creating an infrastructure to potentially give drugs in the field that have not been proven to work is the issue…FAST-MAG should have been done as a pilot in the ED.6
Despite the $16 million price tag of FAST-MAG and the negative results of magnesium, one must acknowledge that the experience and lessons learned by conducting the study could potentially benefit future trials. FAST-MAG created a template researchers can use for clinical trial design. Neuroprotectants are still at the forefront of stroke research, and if one is ever found successful, it will certainly find its way into the prehospital setting.
The naturally occurring hormone progesterone is currently being studied as a potential treatment for traumatic brain injury and, if successful, might one day be carried on ambulances. A chemical compound called NA-1 is currently in Phase II clinical research for the treatment of stroke. Of NA-1, Michael Hill, MD, of the University of Calgary said, “After two decades of negative human trials in the neuroprotection area, this in the first one with serious promise to show a true effect in human ischemic stroke.7
The next step for NA-1 is a large Phase III trial, which may involve prehospital providers. Even if paramedics are not involved directly in the investigation of the drug, they could find it in their drug boxes down the road if it works. Up to 70% of all stroke patients in the United States are first cared for by paramedics, and ambulance transport is widely considered to be the optimal method of delivering stroke patients to the hospital. EMS plays a vital role in providing stroke care, and the greatest benefit of neuroprotectant therapy, should one be proven successful, may come from prehospital administration.
Conclusion
In order to celebrate the successes of scientific research, we must also embrace its many failures and apply the lessons learned. Each failed trial is a brick in the road to success. As we discovered that prehospital magnesium administration failed to work, we also found that paramedics could successfully identify strokes, minimize errors in clinical research data collection, and initiate investigational drug therapy in the field. To paraphrase Thomas Edison, the FAST-MAG researchers didn’t fail, they simply found another way that didn’t work. Despite the failure of FAST-MAG, the next time paramedics assist with investigational drug research could successfully revolutionize stroke care.
References
1. Kidwell CS, Saver JL, Schubert GB, Eckstrin M, Starkman S. Design and retrospective analysis of the Los Angeles Prehospital Stroke Screen. Prehosp Emerg Care, 1998 Oct–Dec; 2(4): 267–73.
2. Cheng YD, al-Khoury L, Zivin JA. Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx, 2004 Jan; 1(1): 36–45.
3. Saver JL, Kidwell C, Eckstein M, Starkman S; FAST-MAG pilot trial investigators. Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy—Magnesium (FAST-MAG) pilot trial. Stroke, 2004 May; 35(5): e106–8.
4. Saver JL, Starkman S, Eckstein M, et al.; FAST-MAG Investigators and Coordinators. Methodology of the Field Administration of Stroke Therapy—Magnesium (FAST-MAG) phase 3 trial: Part 2—prehospital study methods. Int J Stroke, 2014 Feb; 9(2): 220–5.
5. E-mail conversation with Drs. Stratton and Saver, March 2014.
6. E-mail conversation with Dr. Bukata, March 2014.
7. Brooks M. Novel neuroprotectant reduces stroke during aneurysm repair. Medscape, www.medscape.com/viewarticle/772305.
Stephen Hatez, BS, NREMT-P, has been a paramedic for nearly a decade in a variety of roles including critical care transport, tactical EMS and fire-based EMS. He has also been an EMS instructor for many years. In addition to teaching and writing, he works on stroke and brain injury clinical trials at the Emory University School of Medicine.
