Tirilazad for aneurysmal subarachnoid haemorrhage

Subarachnoid haemorrhage (SAH) is a life-threatening type of stroke caused when a small blood vessel near the surface of the brain bursts. The bleeding usually comes from an aneurysm (a weakness in the blood vessel wall). The blood enters the fluid-filled space around the brain called the subarachnoid space, which lies between the outer surface of the brain and the inner surface of the skull. Thus, the condition is called aneurysmal SAH. Approximately one-third of patients develop a complication of the bleeding in which narrowing of the blood vessels occurs. In turn, this may cause the blood supply to parts of the brain to be reduced or stopped. The resulting brain damage is called delayed cerebral ischaemia. It happens most often four to 10 days after SAH, and it can cause disability or even death. In animal studies, the drug tirilazad appeared to reduce brain damage after SAH. We reviewed the evidence from randomised controlled trials of tirilazad in patients with SAH to see if it could reduce the risk of death or disability. The review did not show any evidence of benefit from tirilazad in patients with aneurysmal SAH.

Authors' conclusions: 

There is no evidence that tirilazad, in addition to nimodipine, reduces mortality or improves poor outcome in patients with aneurysmal SAH.

Read the full abstract...
Background: 

Delayed cerebral ischaemia is a significant contributor to poor outcome (death or disability) in patients with aneurysmal subarachnoid haemorrhage (SAH). Tirilazad is considered to have neuroprotective properties in animal models of acute cerebral ischaemia.

Objectives: 

To assess the efficacy and safety of tirilazad in patients with aneurysmal SAH.

Search strategy: 

We searched the Cochrane Stroke Group Trials Register (last searched October 2009); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2009); MEDLINE (1966 to October 2009); EMBASE (1980 to October 2009); and the Stroke Trials Directory, the National Center for Complementary and Alternative Medicine, and the National Institute of Health Clinical Trials Database (searched October 2009). We handsearched 10 Chinese journals, searched the reference lists of relevant publications, and contacted the manufacturers of tirilazad.

Selection criteria: 

Randomised trials of tirilazad started within four days of SAH onset, compared with placebo or open control in patients with aneurysmal SAH documented by angiography and computerised tomography (CT) scan or cerebrospinal fluid examination, or both.

Data collection and analysis: 

We extracted data relating to case fatality, poor outcome (death, vegetative state, or severe disability), delayed cerebral ischaemia (or symptomatic vasospasm), cerebral infarction and adverse events of treatments. We pooled the data using the Peto fixed-effect method for dichotomous data.

Main results: 

We included five double-blind, placebo-controlled trials involving 3821 patients; there was no significant heterogeneity. Oral or intravenous nimodipine was used routinely as a background treatment in both groups in all trials. There was no significant difference between the two groups at the end of follow up for the primary outcome, death (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.74 to 1.06), or in poor outcome (death, vegetative state or severe disability) (OR 1.04, 95% CI 0.90 to 1.21). During the treatment period, fewer patients developed delayed cerebral ischaemia in the tirilazad group than in the control group (OR 0.80, 95% CI 0.69 to 0.93). Subgroup analyses did not demonstrate any significant difference in effects of tirilazad on clinical outcomes. Leukocytosis and prolongation of Q-T interval occurred significantly more frequently in the treatment group in only one trial evaluating tirilazad at high dose. There was no significant difference in infusion site disorders or other laboratory parameters between the two groups.

Share/Save