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. 2003;2003(3):CD001244.
doi: 10.1002/14651858.CD001244.

Excitatory amino acid antagonists for acute stroke

K W Muir  1 , K R Lees
Affiliations

Excitatory amino acid antagonists for acute stroke

K W Muir et al. Cochrane Database Syst Rev. 2003.

Abstract

Background: Focal cerebral ischaemia causes release of excitatory amino acid (EAA) neurotransmitters, principally glutamate, with resultant over-stimulation of EAA receptors and downstream pathways. Excess glutamate release is a pivotal event in the evolution of irreversible ischaemic damage in animal models of ischaemia, and drugs that modulate glutamate action either by inhibiting its release, or blocking post-synaptic receptors, are potent neuroprotective agents. Many clinical trials with EAA modulating drugs have been conducted, none individually demonstrating efficacy.

Objectives: To synthesise all the available data on all different classes of EAA modulators and to evaluate evidence of effects on outcome systematically.

Search strategy: Relevant trials were identified in the Specialised Register of Controlled Trials (last searched May 2001). In addition, MEDLINE and EMBASE online searches for the terms "neuroprotection" (and its variants), "neuroprotective agent", for all individual drugs and drug classes included in the review, hand searches of conference proceedings from European, International, American Heart Association and Princeton conferences on Stroke, American Neurological Association and American Academy of Neurology meetings from 1992-2001, and direct contact with individual investigators and pharmaceutical companies.

Selection criteria: Trials were included if they were randomised, controlled studies giving agents with pharmacological properties that included modification of release of EAAs, or blockade of EAA receptors, in stroke within 24h of onset. Efficacy analysis was restricted to trials with a parallel group design: dose escalation studies were excluded. Intention-to-treat analyses were performed on all data. Outcome had to be reported in terms of death or dependence 1-12 months after the acute event.

Data collection and analysis: Data were available for 36 of 41 relevant trials identified, involving 11,209 subjects. Data were unavailable for 632 participants (517 in trials fulfilling criteria for efficacy analysis). Seven trials did not report disability data, which were available for 29 trials involving 10,802 subjects. Twenty one of these trials, involving 10,342 subjects, were parallel group studies included in the primary efficacy analysis. Efficacy analysis included data derived from 9 trials not primarily designed to assess efficacy (1022 subjects). The primary (efficacy) end-point was the proportion of patients dead or disabled at final follow-up (defined by Barthel Index<60 at 3 months by preference). Mortality was a secondary end-point. Drugs were considered as individual agents, and also grouped principally into categories of ion channel modulators (glutamate release inhibition) and NMDA antagonists.

Main results: There was no significant heterogeneity of outcome amongst individual drugs, or of drug classes either for the primary efficacy analysis (death or dependence) or for mortality at final follow-up. For the primary efficacy analysis, odds of death or dependence were 1.03 [95% confidence interval 0.96-1.12], and for mortality 1.02 [0.92-1.12]. Neither ion channel modulators (death or dependence 1.02 [0.90-1.16]) nor NMDA antagonists (death or dependence 1.05 [0.95-1.16]) differed from the principal analysis including all compounds. Trends for increased mortality with three NMDA antagonists were seen - selfotel (OR 1.19 [0.81-1.74]), aptiganel (OR 1.32 [0.91-1.93]) and gavestinel (OR 1.12 [0.95-1.32]) - but this did not achieve significance for the NMDA antagonists considered as a class (1.09 [0.96-1.23]). Aptiganel was also associated with a trend towards worse functional outcome (OR 1.20 [0.88-1.65]) although this was not the case for either of the other two compounds. No statistically significant detriment of psychotomimetic NMDA antagonists was found, although a trend towards higher mortality in this sub-group was seen (OR 1.25 [0.96-1.64]).

Reviewer's conclusions: There was no evidence of significant benefit or harm from drugs modulating excitatory amino acid action. Reductio]).

Reviewer's conclusions: There was no evidence of significant benefit or harm from drugs modulating excitatory amino acid action. Reduction of death or dependence by 8% or more has been excluded for gavestinel and lubeluzole, which contribute most of the data for this review. However, mechanistic understanding of neuroprotection is too poor to extrapolate from these two failed development plans to all glutamate modulators. Further clinical trials of neuroprotective agents remain justified, since confidence limits around estimates of effect remain wide for most agents, and cannot reliably exclude benefit. Although numbers of patients are too small to confirm or refute a trend towards increased mortality with some NMDA antagonists, further commercial development of these agents is exceedingly unlikely.

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Conflict of interest statement

Prof Lees was principal investigator in GAIN‐International. Both authors are principal investigators in the Intravenous Magnesium Efficacy in Stroke trial, funded by the UK Medical Research Council. Both authors have received fees or expenses for speaking at symposia and / or consultancy on behalf of pharmaceutical companies in the neuroprotective field, including GlaxoWellcome, AstraZeneca, Boehringer Ingelheim, Pfizer, Janssen‐Cilag, Cambridge NeuroScience, and Roche. Both authors have received sponsorship for attendance at meetings and symposia organised by these companies and received payments for speaking at events related to neuroprotection.

Figures

1.1
1.1. Analysis
Comparison 1 Individual Drug Overview (True Randomised Trials), Outcome 1 Death or Dependence.
1.2
1.2. Analysis
Comparison 1 Individual Drug Overview (True Randomised Trials), Outcome 2 Death.
2.1
2.1. Analysis
Comparison 2 Drug Class Overview (True Randomised Trials), Outcome 1 Death or Dependence.
2.2
2.2. Analysis
Comparison 2 Drug Class Overview (True Randomised Trials), Outcome 2 Death.
3.1
3.1. Analysis
Comparison 3 NMDA Antagonists, Outcome 1 Death or Dependence.
3.2
3.2. Analysis
Comparison 3 NMDA Antagonists, Outcome 2 Death.
4.1
4.1. Analysis
Comparison 4 Individual Drug Overview (All Trials), Outcome 1 Death or Dependence.
4.2
4.2. Analysis
Comparison 4 Individual Drug Overview (All Trials), Outcome 2 Death.
4.3
4.3. Analysis
Comparison 4 Individual Drug Overview (All Trials), Outcome 3 Not fully recovered (BI < 95).
5.1
5.1. Analysis
Comparison 5 Ischaemic Stroke (All Trials), Outcome 1 Death or Dependence.
5.2
5.2. Analysis
Comparison 5 Ischaemic Stroke (All Trials), Outcome 2 Death.
See this image and copyright information in PMC

References

References to studies included in this review

AR‐R15896AR {published and unpublished data}
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GAIN ICH {published data only}
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IMAGES pilot {published data only}
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Lub‐Int 13 {published data only}
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Lub‐Int 9 {published data only}
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Muir 1998 {published data only}
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Remacemide phase 2 {unpublished data only}
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Selfotel IIa {published data only}
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Sipatrigine 137‐101 {published data only}
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Fosphenytoin phase 3 {published data only (unpublished sought but not used)}
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ZK‐200775 {published data only (unpublished sought but not used)}
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References to ongoing studies

ARTIST MRI {published and unpublished data}
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ARTIST+ {unpublished data only}
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