Elsevier

The Lancet

Volume 363, Issue 9407, 7 February 2004, Pages 439-445
The Lancet

Articles
Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial

https://doi.org/10.1016/S0140-6736(04)15490-1Get rights and content

Summary

Background

Magnesium is neuroprotective in animal models of stroke, and findings of small clinical pilot trials suggest potential benefit in people. We aimed to test whether intravenous magnesium sulphate, given within 12 h of stroke onset, reduces death or disability at 90 days.

Methods

2589 patients were randomised within 12 h of acute stroke to receive 16 mmol MgSO4 intravenously over 15 min and then 65 mmol over 24 h, or matching placebo. Primary outcome was a global endpoint statistic expressed as the common odds ratio for death or disability at day 90. Secondary outcomes were mortality and death or disability, variously defined as Barthel score less than 95, Barthel score less than 60, and modified Rankin scale more than 1. Predefined subgroup analyses were for the primary endpoint in patients in whom treatment commenced within 6 h versus after 6 h, ischaemic versus non-ischaemic strokes, and cortical stroke syndromes versus non-cortical strokes. Intention-to-treat and efficacy analyses were done.

Findings

The efficacy dataset included 2386 patients. Primary outcome was not improved by magnesium (odds ratio 0·95, 95% CI 0·80–1·13, p=0·59). Mortality was slightly higher in the magnesium-treated group than in the placebo group (hazard ratio 1·18, 95% CI 0·97–1·42, p=0·098). Secondary outcomes did not show any treatment effect. Planned subgroup analyses showed benefit of magnesium in noncortical strokes (p=0·011) whereas greater benefit had been expected in the cortical group.

Interpretation

Magnesium given within 12 h of acute stroke does not reduce the chances of death or disability significantly, although it may be of benefit in lacunar strokes.

Introduction

Acute stroke is the third leading cause of mortality in developed countries and the largest single cause of disability. Treatment options in the immediate hours after stroke are limited. Recombinant tissue plasminogen activator (rtPA) greatly improves chances of full recovery if given intravenously within 3 h of stroke onset1 but the short time window and bleeding risks restrict rtPA to a few stroke patients. Aspirin has a small absolute benefit (about 1% reduction in death or disability) if started within 48 h of stroke, but absence of evidence of a time-dependent effect suggests its probable mode of action to be prevention of early recurrent stroke.2

Results of imaging studies and animal models of stroke have given rise to the notion of the ischaemic penumbra, a region of hypoperfused tissue surrounding the infarct core in which blood flow is between the thresholds of cell viability and functional activity. Metabolic and neurochemical events within the penumbra lead to cell death unless reperfusion takes place. In animal models, pharmacological modulation of various aspects of penumbral pathophysiology reduces infarct volume and improves outcome. Such neuroprotective treatments are attractive since they promise benefit without the potential bleeding risk of thrombolysis. However, no neuroprotective agent has yet been translated successfully from animal models into clinical practice.3 Some agents have been associated with important toxic effects and worsening of clinical outcomes.

Magnesium is neuroprotective in various animal models. It is a potentially safe and inexpensive treatment. In permanent or transient middle cerebral artery occlusion (MCAO) models in rodents, systemically administered magnesium reduces infarct volume.4, 5 Serum concentrations of magnesium as low as 1·49 mmol/L are associated with maximum infarct volume reduction.5 In embolic MCAO, magnesium significantly reduced infarct volume even when given 6 h after onset of ischaemia, a time window considerably longer than for other neuroprotective agents.6 The mechanism of neuroprotection by magnesium remains uncertain: increasing magnesium concentration reduces presynaptic release of the neurotransmitter glutamate,7 blocks glutamatergic N-methyl-D-aspartate receptors,8 potentiates adenosine action, improves mitochondrial calcium buffering, and blocks calcium entry via voltage-gated channels. Furthermore, it has cardiovascular effects, notably enhanced cerebral perfusion after MCAO9 and raised cardiac output. Antiplatelet actions are not relevant in clinical use.10

Workers on several small pilot trials in stroke have reported reduced proportions of magnesium-treated patients being dead or disabled at 3–6 months.11, 12, 13, 14, 15 The odds ratio for death or disability in a systematic review of these pilot trials was 0·73, but with a wide 95% CI (0·38–1·41).16 Potential neuroprotective effects have been identified in preterm perinatal hypoxic injury.17

We aimed to test whether intravenous magnesium sulphate, given within 12 h of stroke onset, reduces death or disability at 90 days.

Section snippets

Participants

Between October, 1997, and April, 2003, we enrolled and randomised patients in the Intravenous Magnesium Efficacy in Stroke (IMAGES) trial. This study was an international, multicentre, double-blind, placebocontrolled, parallel group study. Trial entry was based on a clinical diagnosis of stroke with treatment to begin within 12 h of the time the participant was last known to be well. Patients had to be conscious, aged 18 years or older, and previously independent (estimated premorbid modified

Results

Of 2589 patients randomised, 2543 (98%) received at least part of the trial infusion. Of the 46 participants who received no trial treatment, the reason was most usually because of clinical deterioration between randomisation and planned commencement of infusions. These individuals were excluded a priori from the efficacy analysis. Nine participants (0·3%) were lost to follow-up (figure 1). Three people received treatment that differed from that allocated (none of those allocated magnesium).

Discussion

Despite promising findings of animal studies and preliminary clinical trials that provided a solid rationale for our trial, intravenous magnesium sulphate did not reduce death or disability at 90 days when given within 12 h of clinically diagnosed stroke. Prespecified hypotheses that treatment within 6 h would be better than treatment within 6–12 h, that ischaemic stroke would benefit rather than intracerebral haemorrhage, and that cortical strokes would benefit more than lacunes were not

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