Magnesium Fails to Benefit After Subarachnoid Bleed

Daniel M. Keller, PhD

June 05, 2012

June 6, 2012 (Lisbon, Portugal) — A large randomized trial appears to close the book on intravenous (IV) magnesium sulphate as a strategy to improve outcome after subarachnoid hemorrhage, finding no benefit with treatment compared with placebo.

Reporting results of the Magnesium for Aneurysmal Subarachnoid Hemorrhage trial (MASH-2), Sanne Dorhout Mees, MD, from the University Medical Center Utrecht, the Netherlands, showed that about one quarter of the patients in each group had a poor outcome.

The findings were presented here at the XXI European Stroke Conference (ECS) and published online simultaneously May 25 in the Lancet.

The investigators also performed a metaanalysis of 7 randomized trials involving more than 2000 patients, and that, too, showed no advantage for magnesium over placebo in reducing poor outcomes.

The investigators conclude that "on the basis of the results of MASH-2...and in combination with data from other trials, we do not recommend routine use of intravenous magnesium 64 mmol/day for the improvement of outcome after aneurysmal subarachnoid hemorrhage."

They also note that they found no subgroup of patients who might benefit from magnesium treatment.

Magnesium: No Benefit, No Harm

Magnesium is a neuroprotective agent and is beneficial for the treatment of eclampsia, which shares pathophysiological mechanisms with the delayed cerebral ischemia that occurs after aneurysmal subarachnoid hemorrhage (ASH), the authors noted.

The case fatality rate 1 month after ASH ranges from 27% to 44%, and 20% of survivors cannot live independently. The phase 3 MASH-2 therefore tested the effect of IV magnesium sulphate on outcomes after ASH.

Between April 2004 and September 2011, patients aged 18 years or older with an aneurysmal pattern of subarachnoid bleed on brain imaging within 4 days of the event were randomly assigned in a fully blinded manner to receive IV magnesium sulphate 64 mmol/day or saline placebo by continuous IV infusion for 20 days or until hospital discharge or death if it occurred sooner.

The primary endpoint was a poor outcome, as defined by a score of 4 to 5 on the modified Rankin Scale (denoting severe disability) 3 months after the hemorrhage, or death.

The magnesium and placebo groups were well matched for baseline characteristics, except that the magnesium group received the drug a median of 33 hours from symptom onset, and placebo was delivered at a median of 41 hours. Only 3 patients were lost to follow up in this intention-to-treat analysis.

There was no significant difference in the primary outcome between treatment and placebo groups.

Table. MASH-2: Primary Endpoint

Endpoint Magnesium Placebo RR (95% CI)
Modified Rankin Scale score of 4 or 5 (poor outcome) or death at 3 months, n (%) 158 (26.2) 151 (25.3) 1.03 (.85 - 1.25)

RR, risk ratio; CI, confidence interval

Further analysis revealed no differences in outcomes for any subgroup, which included groups determined on the basis of age, sex, severity grade of the stroke, or method of specific aneurysm treatment (or none).

Magnesium treatment was generally safe. There was 1 case of asymptomatic hypocalcemia, 2 cases of asymptomatic hypermagnesemia, and 1 case of symptomatic hypermagnesemia, all of which occurred in patients receiving magnesium.

The results of a metaanalysis of 7 randomized, controlled and blinded studies, including MASH-2, with a total of 2047 patients, were very much in agreement with MASH-2 findings. The overall risk ratio for magnesium vs placebo was .96 (95% CI, .86 - 1.08).

The End of Magnesium

Didier Leys, MD, PhD, professor and head of neurology at Lille University Hospital in Lille, France, and past president of the European Stroke Organization, agreed and told Medscape Medical News, "The results are completely neutral, so we have no proof of any efficacy and no proof of any safety concern with using magnesium in patients with subarachnoid hemorrhage, so we cannot recommend the use of this treatment."

When asked whether he thought MASH-2 was conclusive and should end any further debate on the role of magnesium after ASH, he replied, "Probably, because there were several studies before, and this one has finally confirmed the results with a good protocol, really well conducted, and it's probably the end of magnesium in this indication."

In an editorial accompanying the publication, Chethan P. Venkatasubba Rao, MBBS, and Jose I. Suarez, MD, from the Department of Neurology at Baylor College of Medicine, Houston, Texas, call the results "disappointing," but "are nonetheless very pertinent to the management of patients with aneurismal subarachnoid hemorrhage.

"We agree with the researchers, and previous findings, that routine intravenous magnesium sulphate infusion cannot be recommended for patients with aneurismal subarachnoid hemorrhage."

The study was funded by the Netherlands Heart Foundation and the UK Medical Research Council. The authors, the editorialists, and Dr. Leys have disclosed no relevant financial relationships.

Lancet. 2012; Published online May 25, 2012. Abstract

XXI European Stroke Conference (ESC). Large Clinical Trials. Presented May 25, 2012.

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