Tirilazad for aneurysmal subarachnoid haemorrhage
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the safety and efficacy of tirilazad in aneurysmal subarachnoid haemorrhage (SAH).
Background
Stroke is the third leading cause of death and the leading cause of disability in contemporary society. Subarachnoid haemorrhage (SAH) accounts for approximately 6% to 8% of all strokes and 22% to 25% of cerebrovascular deaths (Ho 1997). In a meta‐analysis of relevant studies, the pooled incidence rate was 10.5 per 100,000 person years (Linn 1996). Despite considerable advances in the diagnosis and treatment of SAH, the outcome remains poor. Secondary cerebral ischaemia, as a major complication of SAH, has been demonstrated to be a significant predictor of adverse outcome and the leading potentially treatable cause of death and disability in patients with aneurysmal SAH (Kassell 1985; Kassell 1990).
Occurring initially for a short period (minutes to hours) at the onset of aneurysmal SAH, secondary cerebral ischaemia later peaks four to 10 days after the bleed date (Deitrich 2000; Grasso 2002). Vasospasm occurs in 70% of all patients who present with aneurysmal SAH and leads to symptomatic brain ischaemia or infarcts in 36% of all patients (Biller 1988). The presence of cerebral vasospasm has been correlated with a 1.5 to 3‐fold increase in mortality in the first two weeks after SAH. Recently the medical and surgical management of patients with aneurysmal SAH has improved, with wider use of calcium antagonists, replacing surgery with endovascular treatment of ruptured aneurysms, and improvements in general medical care. Despite the above management options, morbidity and mortality from secondary cerebral ischaemia remains high; 25% of patients allocated endovascular treatment were dead or dependent at two months (ISAT 2002).
Free‐radical‐induced lipid peroxidation has been identified as a potentially important contributor to both the arterial narrowing of vasospasm and the final cascade of ischaemic cell death (Hall 1988a; Treggiari‐Venzi 2001). Tirilazad mesylate is a non‐glucocorticoid 21‐aminosteroid, which has been developed for the acute treatment of SAH, traumatic brain injury (TBI), spinal cord injury (SCI), and ischaemic stroke, that exerts its anti‐lipid peroxidation action through cooperative mechanisms: a radical scavenging action (that is, a chemical antioxidant effect) and a physicochemical interaction with the cell membrane that serves to decrease membrane fluidity (that is, membrane stabilisation) (Hall 1988b). Tirilazad mesylate was neuroprotective in experimental models of TBI, SCI, and acute ischaemic stroke (Anderson 1988; Hall 1988a; Meden 1996). While human studies have not shown tirilazad to be effective in TBI (Marshall 1998) or in acute ischaemic stroke (TISC 2004), it improved outcome in two of four phase III studies of SAH (Clarke 1997; Kassell 1996; Lanzino 1999a; Lanzino 1999b) and is licensed for this indication in some countries. Indeed, in experimental models of SAH and focal cerebral ischaemia, tirilazad has been shown to ameliorate vasospasm and improve cerebral blood flow as well as reduce the size of cerebral infarction (Kanamaru 1990; Kanamaru 1991; Matsui 1994; Steinke 1989; Vollmer 1989; Zuccarello 1989).
In addition, preliminary studies with this drug have shown it to be safe and not associated with side effects such as hypotension, mental status changes or glucocorticoid toxicities (Fleishaker 1993a; Fleishaker 1993b; Fleishaker 1997). Local infusion‐related irritation and thrombophlebitis were the main adverse events, partially explained by the presence of citrate in the vehicle solution (Fleishaker 1993b).
A number of phase II and phase III trials have been undertaken in patients with aneurysmal SAH; this systematic review will assess these trials in the context of safety and efficacy.
Objectives
To assess the safety and efficacy of tirilazad in aneurysmal subarachnoid haemorrhage (SAH).
Methods
Criteria for considering studies for this review
Types of studies
We seek to identify all unconfounded randomised clinical trials in patients with SAH comparing tirilazad with placebo or open control. We will exclude uncontrolled studies and quasi‐randomised controlled trials where allocation to treatment or control group was not concealed (e.g. allocation by alternation, open random number list, date of birth, day of the week or hospital number), since foreknowledge of treatment allocation might lead to biased treatment allocation (Schulz 1995).
Types of participants
We will include patients of any age and either gender with SAH documented by either computerised tomography (CT) scan or cerebrospinal fluid examination in the analysis. A ruptured cerebral aneurysm should be preferably proven by angiography, or at least be judged highly likely by the pattern of haemorrhage on CT. The patients could be any neurograde before the start of tirilazad treatment.
Types of interventions
Tirilazad mesylate versus control starting within 10 days of SAH onset. We will exclude trials where treatment was started only after onset of symptoms from secondary ischaemia.
Types of outcome measures
We will attempt to extract from each trial the outcome assessments at the end of follow up (at least 14 days after the haemorrhage) for all patients originally allocated to each treatment group, in order to provide an intention‐to‐treat analysis.
Primary outcome
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Death (any cause)
Secondary outcomes
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Poor outcome (death, vegetative state, or severe disability) (Glasgow Outcome Scale)
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Symptomatic vasospasm
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Cerebral infarction (CT‐documented)
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Adverse effects of the treatment (e.g. local infusion‐related irritation, thrombophlebitis, prolongation of Q‐T intervals, etc)
Search methods for identification of studies
See: 'Specialized register' section in Cochrane Stroke Group
We will search the Cochrane Stroke Group Trials Register. In addition, we will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue) (Appendix 1), MEDLINE (1966 to present) (Appendix 1) and EMBASE (1980 to present) (Appendix 2). We will search reference lists of relevant studies identified, and we also plan to contact the pharmaceutical company manufacturing tirilazad (UpJohn, Pfizer) to identify any relevant ongoing and unpublished studies.
We will also search relevant clinical trials and research databases including the Stroke Trials Directory (http://www.strokecenter.org/trials/), the National Center for Complementary and Alternative Medicine (http://www.nccam.nih.gov/clinicaltrials/), and the National Institute of Health Clinical Trials Database (http://www.clinicaltrials.gov/). We will handsearch the following 10 Chinese journals.
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Chinese Journal of Neurology (1995 to 2007)
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Journal of Apoplexy and Nervous Diseases (1995 to 2007)
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Stroke and Nervous Diseases (1995 to 2007)
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Journal of Brain and Nervous Diseases (1995 to 2007)
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Chinese Journal of Integrative Medicine (1995 to 2007)
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Journal of Emergency in Traditional Chinese (1995 to 2007)
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China Journal of Chinese Materia Medica (1995 to 2007)
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Chinese Journal of Information on Traditional Chinese Medicine (1995 to 2007)
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Chinese Traditional Patent Medicine (1995 to 2007)
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Research of Traditional Chinese Medicine (1995 to 2007)
Data collection and analysis
Study selection
To determine the studies to be assessed further, we will scan the titles, abstract sections and keywords of every record retrieved. We will only reject articles on initial screening if we can determine from the title and abstract that the article is not a report of a randomised controlled trial or the trial does not address the effect of intravenous tirilazad mesylate on the mortality and morbidity of SAH. If there is any doubt regarding these criteria from the information given in the title and abstract, we will retrieve the full article for clarification. We will develop an inclusion/exclusion form to assist with the selection of trials. Two review authors (Wang LC, Wu B) will independently assess the selection of studies, and any disagreements will be resolved by discussion; when necessary, in consultation with a third review author (Liu M). If it is not possible to resolve a disagreement, we will add the study to those awaiting assessment and we will contact the study authors for clarification.
Data extraction
Two review authors (Wang LC, Wu B) will independently extract and cross‐check data on patients, methods, interventions, outcomes and results. The following key information will be extracted.
(1) General information: published/unpublished, title, authors, reference/source, contact address, country, urban/rural, language of publication, year of publication, duplicate publications, sponsor, setting
(2) Trial characteristics: design, duration of follow up, method of randomisation, allocation concealment, blinding (patients, people administering treatment, outcome assessors)
(3) Intervention(s): intervention(s) (dose, route, timing), comparison intervention(s) (dose, route, timing), co‐medication(s) (dose, route, timing)
(4) Patients: exclusion criteria, total number and number in comparison groups, age (adults), baseline characteristics, diagnostic criteria, similarity of groups at baseline (including any co‐morbidity), assessment of compliance, withdrawals/losses to follow up (reasons/description), subgroups
(5) Outcomes: outcomes specified above, any other outcomes assessed, other events, length of follow up, quality of reporting of outcomes
Any inconsistency in the extracted data between the two review authors will be assessed and resolved by discussion; if no consensus can be reached between the two review authors, a third review author (Liu M) will be approached and her decision will be final. If there are patients excluded or lost to follow up after randomisation (trials with so‐called explanatory analysis) or if any of the above data is not available from the publication, we will seek further information by contacting the trialist. If the data about patients excluded or lost to follow up remains unavailable, all the review authors will decide whether to include this particular trial in the review or not.
Trial quality assessment
We will assess the quality of reporting of each trial based largely on the following factors as advised by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2006):
(1) Minimisation of selection bias: (a) was the randomisation procedure adequate? (b) was the allocation concealment adequate?
(2) Minimisation of performance bias: were the patients and people administering the treatment blind to the intervention?
(3) Minimisation of attrition bias: (a) were withdrawals and dropouts completely described? (b) was analysis by intention to treat?
(4) Minimisation of detection bias: were outcome assessors blind to the intervention?
Based on these criteria, we will broadly subdivide studies into the following three categories.
A ‐ all quality criteria met: low risk of bias
B ‐ one or more of the quality criteria only partly met: moderate risk of bias
C ‐ one or more criteria not met: high risk of bias
Two review authors (Wang LC, Wu B) will independently perform quality assessment, and any disagreements will be resolved by discussion or with a third review author (Liu M) if necessary.
Data analyses
We will use the I‐squared statistic to test for heterogeneity between trials results. The results will be reported as Peto odds ratios (OR) with corresponding 95% confidence interval (CI) for dichotomous data using the Peto fixed‐effect method (APT 1994). For continuous data, mean difference (MD) will be computed for outcomes measured on the same scale, and standardised mean difference (SMD) will be calculated when the same outcome measures are on different scales (for example, quality of life). Publication bias and other biases will be examined using a funnel plot . Effect size will be plotted against each study's sample size, resulting in graphical display, which will give some indication whether or not some studies with particular study and effect size combination have not been published or located.
Subgroup analyses
We hypothesise that different doses (e.g. 0.6 mg/kg/d, 2.0 mg/kg/d, 6.0 mg/kg/d) and gender (male and female) may have varying effects on the prognosis of SAH. We will base subgroup analysis on:
(1) comparing the efficacy of tirilazad therapy in males and females;
(2) comparing the efficacy of various doses of tirilazad;
(3) comparing the efficacy of tirilazad therapy by neurological severity.
Significant differences between two or more subgroups will be tested using the chi‐squared test, in which P‐value for Qint (Qint = Qall ‐ (Q1 + ... + Qm)) on m‐1 degrees of freedom will be computed using Excel software. Qall is the chi‐squared heterogeneity statistic for all included trials, Q1 to Qm are the chi‐squared heterogeneity statistics for each subgroup.
Sensitivity analyses
(1) Re‐analysing the data excluding studies with inadequate allocation concealment
(2) Re‐analysing the data excluding studies not using placebo or blinding
