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The FRONTIER Trial – On The Frontier of Prehospital Stroke Treatment

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Jason E. Buick & Ian R. Drennan

Each year approximately 50,000 people in Canada suffer a stroke.That’s nearly one stroke every 10 minutes, leading to over 14,000 deaths and many others with permanent disabilities. Currently over 315,000 people in Canada live with disabilities from a stroke. Similar to rapid identification and treatment of acute myocardial infarctions, time is of the essence when treating an acute ischemic stroke (AIS).Each minute a patient will lose millions of brain cells, billions of synapses and kilometres of axonal fibers, with many strokes being fully completed within threehours of symptom onset.Furthermore, the likelihood of a positive outcome decreases 10 to 20 percent every half hour.1This leaves a very small time window when therapeutic interventions may be effective.

Emergency medical services (EMS) and paramedics play a crucial role in the care of patients suffering from AIS. However, usually the role of paramedics is limited to recognition of the signs and symptoms of a stroke and, if possible, rapid transport to a designated stroke centre. Although the implementation of systems of care for stroke patients, including prehospital bypass, has been shown to improve patient mortality and morbidity, beyond supportive care there is currently no treatment that paramedics can provide in the prehospital setting that will improve patient outcomes.

Currently the only drug approved for the in-hospital treatment of AIS is tissue plasminogen activator (tPA), which works by breaking down clots within the blood vessels of the brain.However, tPA is only effective within a small time frame from the onset of symptoms and there are many tests and procedures that need to be completed before administration. Once a patient has arrived at the specialized stroke centrethey must undergo a CT scan to ensure an ischemic stroke (as opposed to a hemorrhagic stroke).Then, if the patient doesn’t have any of the numerous contraindications, they are candidates for tPA.All of this must occur within 4.5 hours of when the symptoms began, however preferably much earlier.Unfortunately, only 8 per centof all patients receive tPA, with a large portion of the other 92 per centineligible due to time issues.2

Regardless of the intervention, early restoration of cerebral perfusion is important as irreversible ischemic damage likely begins shortly after onset and reaches a plateau within hours.The longer the delay to reperfusion therapy, the less salvageable the brain function will remain to benefit from treatments.That is where paramedics and NA-1 come into play. Paramedics in Toronto, Peel region and Vancouver are participating in a new research study called the FRONTIERTrial — Field Randomization of NA-1 Therapy in Early Responders.The objective of the study is simple.To see if administration of NA-1 can “buy time” and keep brain cells alive until a patient arrives at hospital, resulting in reduced global disability in patients with acute ischemic stroke.

NA-1 is a neuroprotectant (termed PSD95 inhibitor).Simply put, NA-1 prevents the formation of nitric oxide, a free radical toxin that combines with superoxides produced by the mitochondria to form a very potent neurotoxin.NA-1 does not target the actual blood clot causing the stroke, but instead limits the amount of damage that occurs in the ischemic but viable area of the brain, ultimately limiting the extent of damaged brain caused by the stroke and improving patient morbidity. It works by inhibiting PSD95, a protein found at neuronal cell synapses related to calcium channels.PSD95 links neurotransmitter receptors on the cell wall to intracellular enzymes such as nitric oxide synthase, which produces damaging free radicals.By inhibiting PSD95, the link between the receptors and radical production is broken without affecting the normal movement of calcium into the cell.

Initially developed by researchers out of the University of Toronto and University Health Network in Toronto, NA-1 has beenthoroughly studied in animal models and in human elective surgery trials.3It has shown with great successto significantly decrease infarct size when given up to threehours after symptom onset. An important note for prehospital administration of NA-1, these studies also showed that it was safe to administer in patients ultimately diagnosed with a hemorrhagic stroke.Furthermore NA-1 does not alter the effectiveness of tPA in treatment of AIS and in fact has been shown to even improve its effectiveness in reducing stroke damage if NA-1 is given 30 minutes prior to tPA.The FRONTIER trial will be the first study of NA-1 in patients suffering from AIS.

There have been over 200 previous trials that have examined the use of other neuroprotectants in ischemic stroke. To date, none have been able to find a benefit in administration ofneuroprotectants, however each has suffered from limitations. In-hospital trials examining the use of neuroprotectants have all administered the medication at a mean time of more than four hours after symptom onset, much too late to positively affect patient outcomes from AIS.

Administration of NA-1 is ideal for the prehospital setting for a number of reasons. As NA-1 targets specific receptor sites in the brain it is very safe to administer, with few side effects. It is also safe and perhaps even beneficial in both AIS and hemorrhagic strokes, something that is difficult to differentiate in the prehospital setting.In the field, paramedics will identify potential stroke patients through use of the provincial stroke card and components of the modified Los Angeles Motor Scale (LAMS), which was used by paramedics in Los Angeles to randomize stroke patients in a trial comparing magnesium versus saline.The trial failed to show any advantage with magnesium but it demonstrated the LAMS scores identified very sick stroke patients, which are the target for enrolment in the FRONTIERTrial.4Paramedics will discuss the patient’s presentation with the on-call investigator (either an EMS medical director, emergency room physician or neurologist), and if deemed eligible the patient will be enrolled into the trial to receive either an infusion of NA-1 or a placebo.Patients are then transported to a designated stroke centere and will receive the current standard of care.This is an incredible opportunity for paramedics to be involved in a ground-breaking study that may have global implications for patients suffering from a stroke.

Training of paramedics and outfitting of the ambulances with the required equipment has already been completedand the trial began enrolling patients in March 2015.NA-1 is very receptive to changes in temperature, so fridges were installed in all ambulances to ensure proper storage of the drug.Additionally, paramedics are now using infusion pumps to deliver NA-1, as opposed to a traditional bolus.The trial is scheduled to run for approximately twoyears until the 558 required patients are recruited.For many, the study can’t be completed soon enough.If successful, NA-1 represents the first advancement in stroke treatment in years.Paramedics will be right at the frontier of stroke treatment.

The FRONTIER Trial has been registered on clinicaltrials.gov: https://clinicaltrials.gov/ct2/show/NCT02315443

More information can be accessed at the Rescu website: www.rescu.ca

About The Authors

Jason Buick is a paramedic in York and Halton Regions.He completed his graduate training at the Institute of Health Policy, Management and Evaluation at the University of Toronto and with the Rescu research program at St. Michael’s Hospital.His research interests include prehospital resuscitation of life-threatening emergencies and evidence based clinical practice and decision rules.Jason can be reached at BuickJ@smh.ca.

Ian Drennan is an advanced care paramedic in York Region and a PhD(c) in the Institute of Medical Science, Department of Medicine, at the University of Toronto and Rescu, Li Ka Shing Knowledge Institute at St. Michael’s Hospital.His research interests include resuscitation and other critical illness in the prehospital setting as well as the integration of community paramedicine into clinical practice.Ian is also a faculty member in the paramedic program at Georgian College.Ian can be reached at DrennanI@smh.ca.

References

1. Saver JL. Time is brain–quantified. Stroke. 2006;37(1):263-266.

2. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB. Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29-322.

3. Hill MD, Martin RH, Mikulis D, Wong JH, Silver FL, Terbrugge KG, Milot G, Clark WM, Macdonald RL, Kelly ME, Boulton M, Fleetwood I, McDougall C, Gunnarsson T, Chow M, Lum C, Dodd R, Poublanc J, Krings T, Demchuk AM, Goyal M, Anderson R, Bishop J, Garman D, Tymianski M. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2012;11(11):942-950.

4. Saver JL, Starkman S, Eckstein M, Stratton SJ, Pratt FD, Hamilton S, Conwit R, Liebeskind DS, Sung G, Kramer I, Moreau G, Goldweber R, Sanossian N. Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N Engl J Med. 2015;372(6):528-536.

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