Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke

Question: We wanted to evaluate the safety and effectiveness of GP IIb-IIIa inhibitors, alone or in combination with thrombolytic agents, in individuals with acute ischaemic stroke.

Background: Most strokes are due to a sudden blockage of an artery in the brain (this type of stroke is called an ischaemic stroke). In most ischaemic strokes, the blockage is caused by a blood clot. Clots form because platelets circulating in the blood in determined conditions aggregate. Glycoprotein (GP) IIb-IIIa inhibitors are potent, fast and selective blockers of the platelet aggregation and, thus, might help to dissolve blood clots, prevent new clots from forming, and so improve the blood supply to the brain. It is possible, if the drug is given within a few hours of the start of a stroke, that this would reduce brain damage and improve the chances of the individual making a good recovery. However, GP IIb-IIIa inhibitors can also cause bleeding in the brain, which are associated with poorer outcomes. This review aimed to evaluate whether GP IIb-IIIa inhibitors, administered within six hours from stroke onset, reduce the proportion of dead or dependent individuals.

Study characteristics: We identified four trials with a total of 1365 participants in searches conducted up to June 2013: three trials compared the intravenous GP IIb-IIIa inhibitor Abciximab with intravenous placebo and one trial compared the intravenous GP IIb-IIIa inhibitor Tirofiban with intravenous aspirin.

Key results: The results showed that GP IIb-IIIa inhibitors cause bleeding in the brain, and that this complication offset any benefits. Therefore, GP IIb-IIIa inhibitors should be avoided in people with acute ischaemic stroke.

Quality of the evidence: Overall, the studies were considered at low risk of bias.

Authors' conclusions: 

The available trial evidence showed that, for individuals with acute ischaemic stroke, GP IIb-IIIa inhibitors are associated with a significant risk of intracranial haemorrhage with no evidence of any reduction in death or disability in survivors. These data do not support their routine use in clinical practice. The conclusion is driven by trials of Abciximab, which contributed 89% of the total number of study participants considered.

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Background: 

Glycoprotein (GP) IIb-IIIa inhibitors are antiplatelet agents that act by antagonising GP IIb-IIIa receptors on the platelet surface and block the final common pathway to platelet aggregation by preventing the binding of fibrinogen molecules that form bridges between adjacent platelets. Thus, GP IIb-IIIa inhibitors could favour endogenous thrombolysis by reducing thrombus growth and preventing thrombus re-formation through competitive inhibition with fibrinogen and, due to their mechanism of action, are likely to have a more profound antiplatelet effect with more rapid onset than conventional antiplatelet agents, such as aspirin or clopidogrel. Currently used in clinical practice for the treatment of individuals with acute coronary syndromes and during coronary angioplasty, GP IIb-IIIa inhibitors could also be useful for the treatment of people with acute ischaemic stroke.

Objectives: 

To assess the use of GP IIb-IIIa inhibitors in people with acute ischaemic stroke to evaluate whether such treatments (1) reduce the proportion of patients who die or remain dependent, and (2) are sufficiently safe for general use. We wished to examine the effects GP IIb-IIIa inhibitors alone or in combination with thrombolytic agents.

Search strategy: 

We searched the Cochrane Stroke Group trials register (last searched 10 June 2013), MEDLINE (1966 to June 2013), EMBASE (1980 to June 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 5, 2013), and major ongoing clinical trials registers (June 2013). We also searched reference lists and contacted trial authors and pharmaceutical companies.

Selection criteria: 

We aimed to analyse unconfounded randomised controlled trials (RCTs) of GP IIb-IIIa inhibitors in the treatment of people with acute ischaemic stroke. Only individuals who started treatment within six hours of stroke onset were included.

Data collection and analysis: 

We independently selected trials for inclusion, assessed trial quality and extracted the data.

Main results: 

We included four trials involving 1365 participants. Three trials compared the intravenous GP IIb-IIIa inhibitor Abciximab with intravenous placebo (1215 participants) and one trial compared the intravenous GP IIb-IIIa inhibitor Tirofiban with intravenous aspirin (150 participants). Treatment with either of these GP IIb-IIIa inhibitors did not significantly reduce long-term death or dependency (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.77 to 1.22, for the comparison between Abciximab and placebo; OR 1.00, 95% CI 0.52 to 1.92, for the comparison between Tirofiban and aspirin) and had no effect on deaths from all causes (OR 1.08, 95% CI 0.77 to 1.53, for the comparison between Abciximab and placebo; OR 1.00, 95% CI 0.35 to 2.82, for the comparison between Tirofiban and aspirin). Abciximab was associated with a significant increase in symptomatic intracranial haemorrhage (OR 4.6, 95% CI 2.01 to 10.54) and with a non-significant increase in major extracranial haemorrhage (OR 1.81, 95% CI 0.96 to 3.41), whereas the only small trial comparing Tirofiban with aspirin showed no increased risk of bleeding complications with Tirofiban (OR 0.32, 95% CI 0.03 to 3.19, for symptomatic intracranial haemorrhage; OR 3.04, 95% CI 0.12 to 75.83, for major extracranial haemorrhages). There was no significant inconsistency across the studies.

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