Excitatory amino acid antagonists for acute stroke

Keith W Muir, Kennedy R Lees

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. To synthesise all the available data on all different classes of EAA modulators and to evaluate evidence of effects on outcome systematically. 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. 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 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. 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]). There was no evidence of significant benefit or harm from drugs modulating excitatory amino acid action. Reductio]). 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.