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Gamma aminobutyric acid (GABA) receptor agonists for acute stroke

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Abstract

Background

Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal models of cerebrovascular disease. However, the sedative effects of GABA receptor agonists have limited their wider application in people with acute stroke, due to the potential risk of stupor. This is an update of a Cochrane review first published in 2013, and previously updated in 2014.

Objectives

To determine the efficacy and safety of GABA receptor agonists in the treatment of acute stroke.

Search methods

We searched the Cochrane Stroke Group Trials Register (accessed March 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) 2016, Issue 3, part of the Cochrane Library (accessed March 2016), MEDLINE (from 1949 to March 2016), Embase (from 1980 to March 2016), CINAHL (from 1982 to March 2016), AMED (from 1985 to March 2016), and 11 Chinese databases (accessed March 2016). In an effort to identify further published, unpublished, and ongoing trials we searched ongoing trials registers, reference lists, and relevant conference proceedings, and contacted authors and pharmaceutical companies.

Selection criteria

We included randomized controlled trials (RCTs) investigating GABA receptor agonists versus placebo for people with acute stroke (within 12 hours after stroke onset), with the primary outcomes of efficacy and safety.

Data collection and analysis

Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross‐checked the data for accuracy, and assessed the risk of bias.

Main results

We included five trials with 3838 participants (3758 analyzed). The methodological quality of the included trials was generally good, with an unclear risk for selection bias only. Four trials (N = 2909) measured death and dependency at three months for chlormethiazole versus placebo; pooled results did not find a significant difference (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.96 to 1.11). One trial (N = 849) measured this outcome for diazepam versus placebo (RR 0.94, 95% CI 0.82 to 1.07). The most frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95; two trials; N = 2527) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46; two trials; N = 2527).

Authors' conclusions

This review provides moderate‐quality evidence that fails to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of people with acute stroke. More well‐designed RCTs with large samples of participants with total anterior circulation syndrome are required to determine if there are benefits for this subgroup. Somnolence and rhinitis are frequent adverse events related to chlormethiazole.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Plain language summary

Gamma aminobutyric acid (GABA) receptor agonists for acute stroke

Question: Are GABA receptor agonist drugs effective and safe in the treatment of acute stroke?

Background: GABA receptor agonists are a type of drug that may help protect the brain in acute stroke. This class of drugs, which includes diazepam and chlormethiazole, have been used as traditional sedatives for several decades, and have been found to be beneficial in animal models of stroke. However, the sedative effect of GABA receptor agonists could be harmful for people with acute stroke.

Study characteristics: We identified five studies to March 2016 that met our inclusion criteria; they randomized 3838 participants and analyzed 3758. The quality of all the studies was generally good, with a low risk of bias. One study evaluated the efficacy and safety of diazepam for acute stroke in 849 participants within 12 hours of stroke onset. Four studies evaluated the efficacy and safety of chlormethiazole in 2909 participants with acute stroke, within 12 hours of stroke onset; 95 participants had hemorrhagic stroke and were analyzed separately.

Key results: All five trials reported death and dependency at three months. There was no significant difference between the chlormethiazole and placebo groups or between the diazepam and placebo groups. The most frequent side effects caused by chlormethiazole were drowsiness and nasal irritation.

Quality of the evidence: In conclusion, moderate‐quality evidence did not support the use of GABA receptor agonists for the treatment of people with acute stroke. The most frequently reported side effects of chlormethiazole were drowsiness and nasal irritation.