Magnesium and ICH: More Work to Be Done

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Magnesium and ICH: More Work to Be Done

• Paul M. Wechsler, MD @wechsler_paul

Originally published April 19, 2024 10.1161/blog.20240418.316697

Liotta EM, Maas MB, Prabhakaran S, Shkirkova K, Sanossian N, Liebeskind DS, Sharma L, Stratton S, Conwit R, Saver JL, and for the FAST-MAG Investigators and Coordinators. Magnesium and Hematoma Expansion in Intracerebral Hemorrhage: A FAST-MAG Randomized Trial Analysis. Stroke. 2024;55:463–466.

Studies have suggested a hemostatic role for magnesium in patients with intracerebral hemorrhage (ICH). A secondary analysis of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial did not show an association between treatment with magnesium and hematoma expansion (HE) or functional outcomes in patients with ICH. This analysis was confounded by imbalances in available data between the treatment and placebo groups and did not consider the effect of serum magnesium levels. Liotta et al. aimed to identify the associations between serum magnesium level and outcomes in patients with ICH in the FAST-MAG trial, while accounting for imbalances in data availability.

This was an ancillary analysis of the FAST-MAG trial, a pragmatic prehospital clinical trial that investigated the neuroprotective effects of magnesium sulfate versus placebo administered in the field for patients with suspected acute stroke within 2 hours of symptom onset. Supplemental data elements, including magnesium levels and serial neuroimaging, were not required due to the trial’s pragmatic design. Patients diagnosed with spontaneous ICH with available data on both magnesium levels and serial neuroimaging were included in this analysis. The primary outcome was HE within 24 hours of hospital arrival, defined as an increase in hematoma volume ≥ 3mL. The secondary outcome was early neurological deterioration (END), defined as a decrease ≥ 1 in the Glasgow Coma Score (GCS) from hospital arrival to day 4. The associations between magnesium levels and outcomes were assessed by adjusted logistic regression. Analyses were stratified by treatment group (magnesium sulfate and placebo) to account for imbalance in data availability between groups.

Among 1700 patients enrolled in the FAST-MAG trial, 381 (22.4%) were diagnosed with ICH. Serum magnesium levels were available in 143 (74.1%) magnesium- and 131 (69.7%) placebo-treated patients. Placebo patients had significantly fewer serial neuroimaging available (65.4% vs. 75.1%, p=0.038). Among all ICH patients, 189 patients (104 magnesium- and 85 placebo-treated) had the available data (magnesium levels and serial neuroimaging) for the current analysis. There were no differences in NIHSS scores, GCS, or initial hematoma volumes between the two groups. Serum magnesium levels were significantly higher in the magnesium-treated patients (3.70 mg/dL vs. 2.00 mg/dL). In magnesium-treated patients (n=104), higher magnesium level was independently associated with lower odds of HE (aOR 0.64 per mg/dL, 95% CI 0.42-0.93, p=0.024) and lower odds of END (aOR 0.54 per mg/dL, 95% CI 0.33-0.82, p=0.007). In the placebo group (n=85), there was no association between magnesium level and HE (aOR 1.80 per mg/dL, 95% CI 0.37-9.26) or END (Spearman correlation, 0.05; p=0.68). A threshold magnesium serum level of ≥4.3 mg/dL maximized the negative predictive value for HE and END.

This study found an association between higher magnesium levels and lower odds of HE and END in magnesium-treated patients but not in placebo-treated patients with ICH enrolled in the FAST-MAG trial. The authors propose a multitude of reasons for these findings. From a clinical perspective, there may be a threshold effect of magnesium to achieve hemostatic effects. This could explain why there was an association only in the magnesium group, as this group achieved higher levels of serum magnesium compared to placebo. From a statistical standpoint, there may be type 1 error, as post hoc analyses are prone to, and unmeasured confounders that influence HE may exist that influenced investigators to obtain supplemental data in this pragmatic trial.

This was a creative study design in an attempt to account for imbalances in neuroimaging data that may have affected results in previous analyses of the FAST-MAG trial investigating the therapeutic effect of magnesium in ICH. Given the placebo group had less serial neuroimaging available, observational bias may have affected previous analyses. As pragmatic trials may proliferate given their cost and efficiency advantages over traditional randomized controlled trials, analyses such as this one by Liotta et al. could serve as a blueprint for sound ancillary analyses of pragmatic trials in the future. It also highlights that future work is needed to determine the optimal method of handling missing data and potential observational bias in pragmatic trials.

Although no firm conclusions or cause and effect can be drawn from this study, it supports the notion that we are only in the prologue for the story of magnesium and ICH. Equipoise remains, and clinical trials specifically designed to test the effect of magnesium levels on ICH outcomes may be worthwhile.