UMEM Educational Pearls

 

Magnesium, another failed neuroprotectant?

Stroke is a leading cause of adult disability and the second leading cause of death worldwide.  Currently available therapies for acute ischemic stroke are based on restoring perfusion to the ischemic penumbra. However, they are only moderately effective.

A series of pathological cascades leading to neuronal death are triggered in acute ischemia.  Thus it may be logical to suggest that if one can interrupt the propagation of these cascades, perhaps part of the brain tissue can be protected and salvaged.

Magnesium has been shown in various animal models to have pluripotent neuroprotective properties.  It is also widely available, simple to administer, and has a favorable risk profile.  A prior study of magnesium in acute ischemic stroke (IMAGES) did not show a benefit when the agent was administered a median 7.4 hours after symptom onset.  However, a subgroup of patients treated within 3 hours of symptom onset showed possible benefit.

 

The Field Administration of Stroke Therapy - Magnesium (FAST-MAG) trial, funded by the NIH, looked at magnesium administered within 2 hours after symptom onset on the degree of disability at 90 days after stroke as measured by the modified Rankin scale.

• A total of 1700 patients were included in the study.
• 73.3% of patients had a final diagnosis of ischemic stroke, compared with 22.8% with intracranial hemorrhage and 3.9% with stroke-mimicking condition.
• Of the patients with ischemic stroke, 52.4% were treated with tPA.

Magnesium was not found to have any benefit in functional outcome at 90 days.

 

This study was unique in several ways:

• It examined the use of a neuroprotective agent in the hyperacute window of 2 hours, as a common criticism of prior neuroprotective studies is that those agents may not have been administered within the optimal therapeutic window
• Administration of the neuroprotective agent began in the prehospital setting.  Logistically, this was done with a pre-randomized study kit containing the initial bolus dose to be administered by EMS and the maintenance dose to be given to the receiving hospital for administration in the ED.
• Despite the short window for enrollment and drug administration, patients were screened using a previously validated prehospital stroke scale and 98.7% of patients were enrolled after explicit written informed consent from the patient or a legally authorized representative.

However, despite this study being very well executed, demonstrating the feasibility of conducting a phase 3 trial with targeted intervention within the hyperacute window, it is another neuroprotective agent that failed to translate from the laboratory bench to the clinical realm.

Potential explanations for the discrepancies between preclinical and clinical outcomes of neuroprotective agents thus far include discrepancies on outcome measures, functional assessments, pre-morbid conditions, therapeutic windows, and drug-dosing schedules between animal studies and clinical trials.

 

Take Home Point: Magnesium does not have any clear benefit in acute ischemic stroke at this time.

References

Muir KW, Lees KR, Ford I, et al. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): a randomised controlled trial. Lancet. 2004;363(9407):439-445.

Saver JL, Starkman S, Eckstein M, et al. Prehospital use of magnesium as neuroprotection in acute stroke. N Engl J Med. 2015;372(6):528-536.

Cheng YD, Al-Khoury L, Zivin JA. Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx. 2004;1(1):36-45.

 

Follow me on Twitter @EM_NCC