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 group of drugs, which includes diazepam and chlormethiazole, has been used as traditional sedatives for several decades, and have been found to be beneficial in stroke studies in animals. However, the sedative effect of GABA receptor agonists could be harmful for people with acute stroke.

Study characteristics: We identified five studies to May 2018 that met our inclusion criteria; they randomized 3838 participants (acute ischemic or hemorrhagic stroke patients) and analyzed 3758. The quality of all the studies was generally good, with a low risk of bias. One study tested the effects and safety of diazepam for acute stroke in 849 participants within 12 hours of stroke onset. Four studies tested the effects and safety of chlormethiazole in 2909 participants with acute stroke, within 12 hours of stroke onset; 95 participants had stroke caused by bleeding 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.

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.

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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 and 2016.

Objectives: 

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

Search strategy: 

We searched the Cochrane Stroke Group Trials Register (accessed May 2018), the Cochrane Central Register of Controlled Trials (CENTRAL) 2018, Issue 4 (accessed May 2018), MEDLINE (from 1949 to May 2018), Embase (from 1980 to May 2018), CINAHL (from 1982 to May 2018), AMED (from 1985 to May 2018), and 11 Chinese databases (accessed May 2018). In an effort to identify further published, unpublished, and ongoing trials we searched ongoing trial 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. We used the GRADE approach to assess the quality of the evidence.

Main results: 

We included five trials with 3838 participants (acute ischemic or hemorrhagic stroke patients, 3758 analyzed). Most of the participants recruited had acute ischaemic stroke, with limited data available from participants with other stroke subtypes, including total anterior circulation syndrome (TACS). The methodological quality of the included trials was generally good, with an unclear risk for selection bias only. For death and dependency at three months, pooled results did not find a significant difference for chlormethiazole versus placebo (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.96 to 1.11; four trials; 2909 participants; moderate-quality evidence) and for diazepam versus placebo (RR 0.94, 95% CI 0.82 to 1.07; one trial; 849 participants; moderate-quality evidence). The most frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95; two trials; 2527 participants; moderate-quality evidence) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46; two trials; 2527 participants; moderate-quality evidence).

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