Fibrinogen depleting agents for acute ischaemic stroke
Zilong Hao
Ming Liu
Carl Counsell
Joanna M Wardlaw
Sen Lin
Xiaoling Zhao
Corresponding author.
Collection date 2012 Mar.
Abstract
Background
Fibrinogen depleting agents reduce fibrinogen in blood plasma, reduce blood viscosity and hence increase blood flow. This may help remove the blood clot blocking the artery and re‐establish blood flow to the affected area of the brain after an ischaemic stroke. The risk of haemorrhage may be less than with thrombolytic agents. This is an update of a Cochrane review first published in 1997 and last updated in 2003.
Objectives
To assess the effect of fibrinogen depleting agents in patients with acute ischaemic stroke.
Search methods
We searched the Cochrane Stroke Group Trials Register (July 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 7), the Chinese Stroke Trials Register (September 2011), MEDLINE (1950 to July 2011), EMBASE (1980 to July 2011) and Web of Science Conference Proceedings (1990 to July 2011). In addition, we searched six Chinese databases, four ongoing trials registers (July 2011) and relevant reference lists. For previous versions of the review, we handsearched journals and contacted researchers in China and Japan and relevant drug companies.
Selection criteria
Randomised trials of fibrinogen depleting agents started within 14 days of stroke onset, compared with control in patients with definite or possible ischaemic stroke.
Data collection and analysis
Two review authors independently selected trials, assessed trial quality and extracted the data. We resolved disagreement by discussion.
Main results
We included eight trials involving 5701 patients. Six trials tested ancrod and two trials tested defibrase (patients were treated for less than three hours to less than 48 hours). Allocation concealment was adequate in seven trials. Fibrinogen depleting agents marginally reduced the proportion of patients who were dead or disabled at the end of follow‐up (risk ratio (RR) 0.95, 95% confidence Interval (CI) 0.90 to 0.99, 2P = 0.02). There was no statistically significant difference in death from all causes during the scheduled treatment or follow‐up period. There were fewer stroke recurrences in the treatment group than in the control group (RR 0.67, 95% CI 0.49 to 0.92, 2P = 0.01). However, symptomatic intracranial haemorrhage was about twice as common in the treatment group compared with the control group (RR 2.42, 95% CI 1.65 to 3.56, 2P < 0.00001).
Authors' conclusions
The current evidence is promising but not yet sufficiently robust to support the routine use of fibrinogen depleting agents for the treatment of acute ischaemic stroke. Further trials are needed to determine whether there is worthwhile benefit, and if so, which categories of patients are most likely to benefit.
Keywords: Humans, Ancrod, Ancrod/adverse effects, Ancrod/therapeutic use, Batroxobin, Batroxobin/adverse effects, Batroxobin/therapeutic use, Brain Ischemia, Brain Ischemia/drug therapy, Fibrinolytic Agents, Fibrinolytic Agents/adverse effects, Fibrinolytic Agents/therapeutic use, Intracranial Hemorrhages, Intracranial Hemorrhages/chemically induced, Randomized Controlled Trials as Topic, Stroke, Stroke/drug therapy, Stroke/mortality
Plain language summary
Fibrinogen depleting agents may help to remove blood clots in acute ischaemic stroke
Fibrinogen depleting agents are promising but unproven for acute ischaemic stroke. Most strokes are due to a blood clot blocking an artery in the brain. Fibrinogen depleting agents may help remove the blood clot to restore the blood supply to the brain and so improve the chance of making a recovery from the stroke. Fibrinogen depleting agents also reduce blood thickness (or viscosity), which also helps to improve blood flow to the brain. However, these agents can also cause serious bleeding in the brain. Evidence from this updated review, which includes eight trials involving 5701 participants, indicates that there is currently not sufficient evidence to support the routine use of fibrinogen depleting agents for the treatment of acute ischaemic stroke. Further trials are needed to determine reliably whether there is worthwhile benefit, and if so, which categories of patients are most likely to benefit.
Background
Description of the condition
Stroke is a leading cause of death and disability in the world. Despite improvements in prevention (Collins 1990;ATT 2002;Cina 2002;SPARCL 2006), little progress has been made in treating stroke with specific interventions once it has occurred. At present, stroke unit care, intravenous tissue plasminogen activator within three to four‐and‐a‐half hours or aspirin within 48 hours of stroke onset, and decompressive surgery for supratentorial malignant hemispheric cerebral infarction are proven beneficial (Donnan 2008;Hacke 2008). But the short therapeutic time window (less than three to four‐and‐a‐half hours) (Donnan 2008;Hacke 2008) and increased intracranial haemorrhage (Wardlaw 2009) limits the use of thrombolysis. New effective therapeutic strategies should be investigated further.
Description of the intervention
Several extracts from the venom of pit vipers have been shown to cleave circulating fibrinogen (e.g. ancrod, batroxobin) rather than fibrin. These agents, referred to as fibrinogen depleting agents, may be beneficial in patients with acute ischaemic stroke and indeed they are used to treat such patients in some countries (Chen 1997).
How the intervention might work
Reduction of plasma fibrinogen leads to reduced blood viscosity and hence increased blood flow and may prevent clot formation or extension (Hossmann 1983). These drugs also appear to promote the release of endogenous tissue plasminogen activator and therefore have some indirect thrombolytic activity (Pollack 1990). Moreover, the risk of haemorrhage may be less than with conventional thrombolytic agents.
Why it is important to do this review
Ancrod has been used in a variety of conditions for a number of years and the risk of major haemorrhage appears to be small (Latallo 1983;Pollack 1990). However, before routine use of these agents in stroke patients can be recommended, their efficacy and safety (especially the risk of major intracranial and extracranial haemorrhage) needs to be confirmed in randomised controlled trials (RCTs). We therefore undertook this to review systematically all such RCTs of fibrinogen depleting agents in patients with acute ischaemic stroke. In a previous version of this Cochrane review (Liu 2003), five trials including 2926 patients were analysed. Ancrod appeared to be promising, but the evidence base was too small to draw any reliable conclusions. Since then a further three trials of fibrinogen depleting agents for acute ischaemic stroke have been published (RDTCI‐2 2005;ESTAT 2006;ASP 2009). Therefore, the aim of this version is to update the current randomised evidence to see if there is enough reliable evidence to recommend wider use of fibrinogen depleting agents for acute ischaemic stroke.
Objectives
We wished to test the following hypotheses.
Fibrinogen depleting agents reduce the long term risk of death and disability, without an increased risk of early death.
Fibrinogen depleting agents reduce the early recurrence of ischaemic stroke.
The risk of haemorrhage does not outweigh the benefits.
Early treatment is more beneficial than treatment started later (less than six hours only versus the rest, less than three hours only versus the rest).
Methods
Criteria for considering studies for this review
Types of studies
We only included unconfounded truly randomised controlled trials comparing fibrinogen depleting agents with placebo or open control in patients with acute ischaemic stroke.
Types of participants
Trials which included patients of any age or sex within 14 days of onset of a presumed ischaemic stroke were eligible. Ischaemic stroke was defined as either definite (i.e. haemorrhage had been excluded by computed tomography (CT) or magnetic resonance (MR) scanning) or possible (i.e. CT/MR scanning had not been performed).
Types of interventions
We included all types of fibrinogen depleting agents, such as ancrod (extract fromAgkistrodon rhodostoma venom), defibrase (extract from Ahylysantinfarctase or BaiMei Pallas Pit Viper), batroxobin (extract fromBothrops moojeni venom) and extracts from other types of snake venom (Agkistrodon Acutus andAgkistrodon halys venom). We excluded confounded trials in which the treatment or control group received another active therapy (e.g. fibrinogen depleting agent plus other agent versus control or fibrinogen depleting agents versus another agent).
Types of outcome measures
Primary outcomes
Death or dependency at the end of the scheduled follow‐up period. We classified patients as being disabled if they were dependent on others for activities of daily living.
Secondary outcomes
Death from any cause during the scheduled treatment period and the scheduled follow‐up period.
Symptomatic intracranial (intracerebral, subdural, subarachnoid, extradural) haemorrhage i.e. the haemorrhage was detected by a CT scan or MR scan after clinical deterioration, or at autopsy.
Any intracranial haemorrhage (symptomatic or asymptomatic) during the scheduled treatment period (i.e. intracranial haemorrhage was sought systematically by CT/MR scan in all patients who survived to the end of the scheduled treatment period and at autopsy in those who died).
Recurrent stroke due to confirmed ischaemia (i.e. haemorrhage excluded by CT/MR scan or autopsy).
Recurrent stroke of unknown type (i.e. no CT/MR scan or autopsy). For intracranial haemorrhage or recurrent stroke, we attempted to classify each as fatal, major non‐fatal (i.e. alive but disabled/dependent at the end of scheduled follow‐up period), and minor non‐fatal (i.e. alive and independent at the end of scheduled follow‐up period).
Major extracranial haemorrhage (i.e. fatal or requiring surgery or requiring transfusion).
Deep venous thrombosis (DVT) during the scheduled treatment period if this was systematically sought (i.e. if DVT was looked for in all survivors using an imaging technique).
Pulmonary embolism during the scheduled treatment period.
Fatal or non‐fatal myocardial infarction.
Search methods for identification of studies
See the 'Specialized register' section in the Cochrane Stroke Group module.
We searched the Cochrane Stroke Group Trials Register, which was last searched by the Managing Editor in July 2011. In addition, in collaboration with the Cochrane Stroke Group Trials Search Co‐ordinator, we searched the following bibliographic databases:
Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 7) (Appendix 1);
MEDLINE (1950 to July 2011) (Appendix 1);
EMBASE (1980 to July 2011) (Appendix 2);
Web of Science Conference Proceedings (1990 to July 2011) using the terms "ancrod" or "batroxobin" or "defibrase".
In an effort to identify further published, unpublished and ongoing trials:
we searched the following Chinese databases using the terms ("defibrase" or "snake venom " or "batroxobin") and ("stroke" or "cerebrovascular disease"):
The Chinese Stroke Trials Register (September 2011);
China Biological Medicine Databases (CBM‐disc) (1981 to July 2011);
China National Knowledge Infrastructure (CNKI) (1979 to July 2011);
Chinese MD and DD Dissertations in CNKI (1979 to July 2011);
Chinese Academic Conference Papers Database (CACP) (1985 to July 2011);
Wanfang Data (http://www.wanfangdata.com/) (1983 to July 2011);
Chinese scientific periodical database of VIP INFORMATION (VIP) (1989 to July 2011);
we searched the following ongoing trials registers using the terms "ancrod" or "batroxobin" or "defibrase":
ClinicalTrials.gov (http://www.clinicaltrials.gov/) (July 2011);
Current Controlled Trials (www.controlled‐trials.com) (July 2011);
National Center for Complementary and Alternative Medicine (http://www.nccam.nih.gov/clinicaltrials/) (July 2011);
Stroke Trials Directory (www.strokecenter.org/trials/) (July 2011);
we searched reference lists of all relevant papers;
for previous versions of this review we searched the proceedings of the 4th Chinese Stroke Conference (1995), contacted colleagues in Japan and China and contacted representatives of TOBISHI (manufacturer of batroxobin) and Knoll Pharmaceuticals (ancrod). We also handsearched the following journals:
Chinese Journal of Neurology and Psychiatry (renamedChinese Journal of Neurology, 1965 to 1996);
Chinese Journal of Nervous and Mental Diseases (1980 to 1996);
Chinese Journal of Neurosurgery (1985 to 1995);
Chinese Journal of Internal Medicine (1989 to 1995);
Chinese Medical Journal (Beijing) (1987 to 1995);
Journal of Stroke and Neurological Diseases (1984 to 1996);
Journal of Clinical Neurology (1992 to 1996);
Journal of Brain and Neurological Diseases (1995 to 1996).
We did not update these searches for this version of the review.
We searched for trials in all languages and arranged translation of relevant reports published in languages other than English and Chinese.
Data collection and analysis
Pairs of review authors (ML and CC, ML and JW, ML and ZH) independently selected the trials to be included in the review. We resolved disagreements by discussion. At least two review authors assessed the methodological quality of each trial by recording details of the randomisation method, blinding, whether an intention‐to‐treat (ITT) analysis was possible from the published data and the number of patients who were lost to follow‐up. They independently extracted the data which were then cross checked. We tried to extract the data on the number of patients with each outcome event, by allocated treatment group, irrespective of compliance, and whether or not the patient was subsequently deemed ineligible or otherwise excluded from treatment or follow‐up, in order to allow an ITT analysis. Some of the above data (particularly on outcomes) were not available in the publications, and so we requested further information from Knoll Pharmaceuticals and from the principal trialists of the trials (Hossmann 1983;AISS 1994). If data were missing, we performed an available case analysis. The proportion of participants in each group who did not provide data was shown.
We calculated risk ratio (RR) and risk differences (RD) using the Cochrane Review Manager software, RevMan 5.1 (RevMan 2011). We examined heterogeneity between trial results using the I2 statistic test.
The main analyses were based on all trials. However, we also planned priori sensitivity analyses based on:
trials with well concealed treatment allocation (i.e. allocation was given by telephoning a central office, by first entering the data into a computer, by the pharmacy, by using identical numbered containers, or by sequentially numbered, sealed, opaque envelopes) versus less well concealed allocation;
trials with blinded outcome assessment versus unblinded assessment;
trials where all patients had intracranial haemorrhage excluded by CT scan before randomisation versus those without initial CT scanning.
We planned a priori subgroup analyses based on:
the different types of defibrinogenating agents;
the different times of starting treatment (less than six hours only versus the rest, less than three hours only versus the rest);
individual patient data for patients who entered the trial within three hours, six hours, 12 hours, 24 hours or more than 24 hours after stroke onset;
individual patient data for those patients in which the fibrinogen level was lowered to less than 130 mg/dL by treatment versus those where it remained more than 130 mg/dL.
We carried out subgroup analyses (1) and (2) above; we did not perform the other analyses due to the lack of relevant data.
Results
Description of studies
Results of the search
After reading titles and abstracts, we retained 49 studies for further assessment. Eight trials including a total of 5701 patients were included in this review (seeCharacteristics of included studies): we identified three new trials for inclusion in this update (RDTCI‐2 2005;ESTAT 2006;ASP 2009). Of note, one trial (ASP 2009) was stopped early for futility reasons.ASP 2009 started as two parallel randomised, double‐blind trials, each aiming to recruit 650 participants. The data from the interim analysis (500 participants from two planned trials) were used for the basis of this review.
We excluded 41 studies (seeCharacteristics of excluded studies). Two studies await classification because we need more details to evaluate them (Li 1999;Li 2010).
Included studies
Characteristics of participants in included studies
One trial has only been reported in summary (Olinger 1988) and so few details on patient characteristics were available for this trial. Most patients were relatively young (the mean age ranged from 62 years to 73 years) and there were similar numbers of men and women in the included trials. All patients had a CT scan before treatment to exclude intracranial haemorrhage (Sherman 1996 ‐ personal communication forSTAT 2000). Patients at risk of bleeding (e.g. those with hepatic or renal failure and those on anticoagulant or antiplatelet therapy) were excluded from each trial. Seven trials also excluded patients with severe hypertension, comatose patients, renal or hepatic failure (Hossmann 1983;Olinger 1988;RDTCI 2000;STAT 2000;RDTCI‐2 2005;ESTAT 2006;ASP 2009), whilst two trials also excluded atrial fibrillation (RDTCI 2000;RDTCI‐2 2005), two trials excluded recent stroke (STAT 2000;ESTAT 2006) and two trials excluded patients with recent ischaemic heart disease (Hossmann 1983;AISS 1994). The time from stroke onset to treatment varied from three hours (STAT 2000) to 48 hours (Hossmann 1983).
Interventions in included studies
Six trials used ancrod, five of which administered it intravenously (Olinger 1988;AISS 1994;STAT 2000;ESTAT 2006;ASP 2009) and one subcutaneously (Hossmann 1983). Two trials used defibrase (RDTCI 2000;RDTCI‐2 2005). Five trials testing ancrod used an initial bolus of between 0.5 to 1.0 unit per kg which was designed to produce a rapid reduction in plasma fibrinogen, followed by variable dosage regimens in order to maintain a plasma fibrinogen concentration of between 70 to 130 mg/dL or 1.18 to 2.03 micromol/l. One recent study (ASP 2009) used a brief dosing regimen (participants were infused with ancrod 0.167 IU/kg per hour over two or three hours). In one trial the desired fibrinogen level was achieved in only half of the patients within six hours (AISS 1994), and in another trial the fibrinogen level was achieved in more than 90% of patients within six hours (ASP 2009). One trial used defibrase 10 IU intravenously on day one, and 5 IU on day three and day five (RDTCI 2000). Another trial conducted in China used defibrase 15 IU intravenously on the first day, subsequently 5 IU were infused on the third, fifth, seventh and ninth days respectively (RDTCI‐2 2005). Treatment was given for five days in three trials (RDTCI 2000;STAT 2000;ESTAT 2006), seven days in two trials (Olinger 1988;AISS 1994), nine days in one trial (RDTCI‐2 2005) and 14 days in one (Hossmann 1983).
Outcome measures of included studies
Two of the trials concentrated on biochemical and haematological outcomes and few clinical outcomes were reported (Hossmann 1983;Olinger 1988). Six trials reported activities of daily living in survivors: a good outcome was defined as a Barthel Index score greater than or equal to 90 (out of a maximum of 95 not 100) or the same as the prestroke score in five trials (AISS 1994;RDTCI 2000;STAT 2000;RDTCI‐2 2005;ESTAT 2006) and responders combining modified Rankin Scale (mRS) with pretreatment National Institute of Health Stroke Scale (NIHSS) was used in a recent study (ASP 2009). Responders were defined as follows: (1) participants with a prestroke mRS of 0 to 1 and pretreatment NIHSS score of 5 to 15 who achieved a 90‐day mRS of 0 to 1; (2) participants with a prestroke mRS of 0 to 1 and pretreatment NIHSS scores of 16 who achieved a 90‐day mRS of 0 to 2; and (3) participants with a prestroke mRS score of 2 or more and any pretreatment NIHSS score which, at 90 days, returned to their prestroke mRS or better.The duration of follow‐up was generally adequate: three months in four trials (Olinger 1988;STAT 2000;ESTAT 2006;ASP 2009) and one year in the other four trials.
Excluded studies
We excluded 41 trials because of non‐random allocation (CRG 1982;Zhang 1996); confounding with low molecular weight dextran (Hao 1984;Chen 1996;Yang 2000), with a Chinese medicine (Qiang 1995;Wang 1999;Zhang 2002), with batroxobin (Huang 1996), with ahylsantinfarctase (Wang 1999a), with Ozagrel (Wang 2003) or with xanthinol nicotinate (Zhang 2001) or conventional treatment (Kuang 1996), or comparison of intravenous administration of batroxobin with intra‐carotid artery injection (Zhang 1998); or the outcomes measures were only impairment scales without any of our prespecified outcome measures (Gao 1996;Wu 1997;He 1998;Lian 1998;Zhao 1999;Cai 2000;Chen 2000;Huang 2000;Yu 2000;Fan 2001;Du 2003;Gusev 2006); or outcomes measures were laboratory data (Xu 2000;Guo 2008) or single‐centre results from the larger overall trials included in this review (Cui 2000;Fan 2000;Li 2000;Mei 2000;Sun 2000;Yan 2001;Sun 2002;Lu 2003;Xie 2003;Yu 2003;Wang 2004;Wei 2004;Yang 2004). SeeCharacteristics of excluded studies.
Risk of bias in included studies
Allocation
Seven trials adequately concealed the randomisation sequence from the doctors entering the patients by using sealed, opaque and sequentially numbered envelopes (Hossmann 1983, personal communication) or sequentially numbered identical containers (AISS 1994 personal communication;RDTCI 2000;STAT 2000;RDTCI‐2 2005;ESTAT 2006;ASP 2009).The concealment of one trial (Olinger 1988) was unclear.
Blinding
Seven trials were double‐blind, placebo‐controlled trials (Olinger 1988;AISS 1994;RDTCI 2000,STAT 2000;RDTCI‐2 2005;ESTAT 2006;ASP 2009), but the success of blinding was not recorded. The eighth trial did not use a placebo but the outcome assessor was blind to treatment allocation (Hossmann 1983).
Incomplete outcome data
Five trials performed an ITT analysis (Hossmann 1983;AISS 1994;STAT 2000;Sherman 1996 (personal communication);ESTAT 2006;ASP 2009). The other three trials did not specifically state that an ITT analysis had been performed. One hundred and forty‐seven and 172 exclusions after randomisation occurred inRDTCI 2000 andRDTCI‐2 2005, respectively. No exclusions after randomisation or losses to follow‐up were reported in two trials (Hossmann 1983;Olinger 1988) for the overall outcome. In one trial, losses to follow‐up were 88 (7.7%) in the treatment group and 58 (5.3%) in the placebo group at three months, 207 (18%) in the treatment group and 179 (16%) in the placebo group at one year (RDTCI 2000). In another trial, losses to follow‐up were 81 (15%) in the treatment group and 53 (10%) in the placebo group at three months, and 158 ( 30%) in the treatment group and 129 ( 25%) in the placebo group at one year (RDTCI‐2 2005).
One trial was ended early for futility reasons (ASP 2009).
No serious imbalances in baseline prognostic factors were reported, although in one trial (AISS 1994), there were more lacunar strokes in the ancrod group (22% versus 13%) and in another trial (STAT 2000) there was slightly more milder strokes (Scandanavian Stroke Scale scores 30 to 39) in the control group (39% versus 34%).
Effects of interventions
1 Fibrinogen depleting agents versus control
1.1 Death or dependency at the end of follow‐up
Six trials (AISS 1994;RDTCI 2000;STAT 2000;RDTCI‐2 2005;ESTAT 2006;ASP 2009) with a total of 5354 patients recorded death and disability in survivors but this was recorded at three months rather than at the end of follow‐up, which lasted one year in four trials (AISS 1994;RDTCI 2000;RDTCI‐2 2005;ESTAT 2006). There was a marginally significant trend for fewer patients being dead or dependent in the fibrinogen depleting agents group (1451/2662, 54.5%) than in the control group (1553/2692, 57.7%) (RR 0.95, 95% CI 0.90 to 0.99).There was no significant heterogeneity (I2 = 16%) (Analysis 1.1).
1.1. Analysis.
Comparison 1 Fibrinogen depleting agents versus control, Outcome 1 Death or dependency at the end of follow‐up.
Two trials conducted in China using defibrase did not perform an ITT analysis. There were incomplete outcome data for 7% of patients (146/2244) inRDTCI 2000 and 13% (134/1053) inRDTCI‐2 2005 at three months. We, therefore, performed an ITT analysis using imputation (we used best‐case and worst‐case scenarios for imputation). The best‐case scenario is that all participants with missing outcomes in the treatment group had good outcomes, and all those with missing outcomes in the control intervention group had poor outcomes (RR 0.86, 95% CI 0.76 to 0.97; I2 = 84% ); the worst‐case scenario is the converse (RR 1.01, 95% CI 0.93 to 1.10; I2 = 65%). There was significant heterogeneity in both analyses. We performed a sensitivity analysis excluding these two studies, which resulted in no significant heterogeneity but also no significant efficacy (RR 0.96, 95% CI 0.90 to 1.02; I2 = 19%). These results are not shown in the forest plots.
1.2 Death from all causes at end of treatment period
Five trials provided data on early deaths (Hossmann 1983;Olinger 1988;AISS 1994;STAT 2000;RDTCI‐2 2005). One trial provided data on the number of early deaths at one month rather than at the end of the treatment period but these data were included in the analysis (AISS 1994). During the scheduled treatment period, there was no difference in the proportion dead in the treatment group (55/774, 7%) compared with the control group (57/810, 7%) (RR 1.00, 95% CI 0.70 to 1.43). However, there was substantial heterogeneity (I2 = 61%) (Analysis 1.2).
1.2. Analysis.
Comparison 1 Fibrinogen depleting agents versus control, Outcome 2 Death from all causes at end of treatment period.
1.3 Death from all causes at end of follow‐up
All eight trials provided data on death at the end of follow‐up. The risk of death from all causes was higher in the treatment group (369/2502, 15%) than in the control group (349/2526, 14%), but the difference was not significant (RR 1.07, 95% CI 0.94 to 1.22). There was no significant heterogeneity (I2 = 0%) (Analysis 1.3).
1.3. Analysis.
Comparison 1 Fibrinogen depleting agents versus control, Outcome 3 Death from all causes at end of follow‐up.
1.4 Any symptomatic intracranial haemorrhage at end of treatment period
Symptomatic intracranial haemorrhages before the end of the treatment period were recorded in eight trials (Hossmann 1983;Olinger 1988;AISS 1994;STAT 2000;ESTAT 2006;ASP 2009; personal communication forRDTCI 2000 andRDTCI‐2 2005), but the events occurred in only five trials (RDTCI 2000;STAT 2000;RDTCI‐2 2005;ESTAT 2006;ASP 2009) and were more common in the treatment group (86/2689, 3%) than in the control group (36/2715, 1%), a significant difference (RR 2.42, 95% CI 1.65 to 3.56) (Analysis 1.4). The absolute difference was 2% suggesting that there might be an extra 20 symptomatic intracranial haemorrhages for every 1000 patients treated.There was significant heterogeneity (I2 = 61%), which appeared to be largely due to a greater risk of intracranial haemorrhage in the ancrod studies (67/1196 (6%) in the active arm, RR 3.30) than in the defibrase studies (19/1493 in the active arm (1%), RR 1.14). We performed a sensitivity analysis excluding these two defibrase studies: symptomatic intracranial haemorrhages were also more common in the treatment group (67/1196, 6%) than in the control group (19/1208, 2%), a significant difference with no significant heterogeneity (RR 3.56, 95% CI 2.15 to 5.87, I2 = 21%).
1.4. Analysis.
Comparison 1 Fibrinogen depleting agents versus control, Outcome 4 Any symptomatic intracranial haemorrhage at end of treatment period.
1.5 Any symptomatic intracranial haemorrhage at end of follow‐up
One trial reported two symptomatic subdural haemorrhages during the follow‐up period, both of which occurred in the placebo group (AISS 1994) (Analysis 1.5).
1.5. Analysis.
Comparison 1 Fibrinogen depleting agents versus control, Outcome 5 Any symptomatic intracranial haemorrhage at end of follow‐up.
1.6 Any intracranial haemorrhage detected on systematic repeat CT during treatment period
Symptomatic intracranial haemorrhage is obviously the most clinically relevant measure of intracranial haemorrhage. However, it may also be susceptible to bias. For example, in trials where the doctor monitoring the patient was aware of the treatment allocation (either because the trial was open or because the treatment was associated with side effects which unblinded the doctor), the threshold for scanning a patient to look for an intracranial haemorrhage may be lower for those on fibrinogen depleting agents than for those in the control group. Haemorrhage detected by systematic neuroimaging (CT or MR) in all survivors at some point in the treatment period or by autopsy in those who died will be less susceptible to this sort of investigation bias. However, it may detect asymptomatic haemorrhages which have little impact on the long‐term outcome and therefore be less clinically meaningful.
Five trials reported intracranial haemorrhage detected by repeat CT during the treatment period (within the first 72 hours after beginning the infusion inASP 2009, on day 15 in theHossmann 1983 trial, on day 10 in theAISS 1994 trial, and on day seven to 10 in theSTAT 2000 andESTAT 2006 trials). In theAISS 1994 trial, some survivors in one centre did not have a repeat CT scan and so, to prevent possible bias, all patients from this centre were omitted from this analysis in the trial report. Unfortunately, it did not report how many patients were excluded. For the purposes of our analysis, we have therefore assumed that patients from this centre did not have intracranial haemorrhage. This should not bias the risk ratio, provided the distribution of intracranial haemorrhages between treatment and control in this centre was the same as in other centres, but it does mean that the absolute risk of any intracranial haemorrhage is underestimated. Overall, 157/1186 (13%) of patients in the treatment group had a haemorrhage on repeat CT scanning compared with 80/1198 (7%) in control group (RR 1.98, 95% CI 1.54 to 2.56) (Analysis 1.6). If the point estimate is correct, it implies that fibrinogen depleting agents therapy might cause an extra 60 intracranial haemorrhages detected by repeat CT (including asymptomatic patients) for every 1000 patients treated.
1.6. Analysis.
Comparison 1 Fibrinogen depleting agents versus control, Outcome 6 Any intracranial haemorrhage detected on systematic repeat CT during treatment period.
1.7 Recurrent stroke (ischaemic/unknown type) at end of treatment period
Only one trial recorded the number of recurrent ischaemic strokes or recurrent strokes of unknown pathology (i.e. where no CT/MR scan was performed) during the treatment period, but no recurrence occurred (Hossmann 1983) (Analysis 1.7).
1.7. Analysis.
Comparison 1 Fibrinogen depleting agents versus control, Outcome 7 Recurrent stroke (ischaemic/unknown type) at end of treatment period.
1.8 Recurrent stroke (ischaemic/unknown type) at end of follow‐up
Four trials (Hossmann 1983;Olinger 1988;RDTCI 2000;RDTCI‐2 2005) reported this outcome during the follow‐up period. There were fewer recurrences in the treatment group (62/1331, 5%) than in the control group (94/1343, 7%), the difference was significant (RR 0.67, 95% CI 0.49 to 0.92, 2P = 0.01).There was no significant heterogeneity (I2 = 0%) (Analysis 1.8). Data on the severity of recurrent strokes or intracranial haemorrhages at the end of follow‐up were not available.
1.8. Analysis.
Comparison 1 Fibrinogen depleting agents versus control, Outcome 8 Recurrent stroke (ischaemic/unknown type) at end of follow‐up.
1.9 Venous thrombotic events
One trial (STAT 2000) collected data on thrombophlebitis, but we were not sure if DVT was looked for systematically in all survivors. It showed 10 events occurred in the ancrod group (10/248, 4%) and 17 in control patients (17/252, 6.7%), a non‐significant difference. Two trials recorded pulmonary embolism (Hossmann 1983;STAT 2000). Three events occurred in the ancrod group (3/503) and 12 in control patients (12/497), a significant result (RR 0.25, 95% CI 0.07 to 0.88, 2P = 0.03) (Analysis 1.9). Myocardial infarction was recorded in only one trial (Hossmann 1983) but no events occurred.
1.9. Analysis.
Comparison 1 Fibrinogen depleting agents versus control, Outcome 9 Venous thrombotic events.
1.10 Any stroke or symptomatic intracranial haemorrhage
The overall effect of fibrinogen depleting agents on new intracranial events is best assessed by this composite outcome i.e. summing the outcomes from section (2) and (4). It is possible that these agents may reduce the risk of early or late recurrent ischaemic stroke but that this benefit is outweighed by an increase in intracranial haemorrhage. Data on this outcome at the end of the scheduled treatment period were only available from one trial (Hossmann 1983) but no events occurred.
1.11 Major extracranial haemorrhage
Three trials (Hossmann 1983;Olinger 1988;AISS 1994) reported this outcome but no major extracranial haemorrhages occurred either during the treatment period or during follow‐up. The overall risk was therefore less than 1%. Two retroperitoneal haemorrhages occurred in the placebo group (STAT 2000).
2 Different agents
The subgroup analyses of different agents showed no difference between defibrase and ancrod in their effects on death/dependency (Analysis 2.1), death from all causes (Analysis 2.2) and recurrent stroke (Analysis 2.4) at the end of follow‐up. However, defibrase appeared to be associated with a lower risk of symptomatic intracranial haemorrhage (RR 1.15 95% CI 0.60 to 2.20) than ancrod (RR 3.56, 95% CI 2.15 to 5.87) (Analysis 2.3).
2.1. Analysis.
Comparison 2 Different agents, Outcome 1 Death or dependency at the end of follow‐up.
2.2. Analysis.
Comparison 2 Different agents, Outcome 2 Death from all causes at the end of follow‐up.
2.4. Analysis.
Comparison 2 Different agents, Outcome 4 Recurrent stroke (ischaemic/unknown type) at the end of follow‐up.
2.3. Analysis.
Comparison 2 Different agents, Outcome 3 Any symptomatic intracranial haemorrhage at the end of treatment period.
3 Different treatment time from onset
The subgroup analyses by time to treatment showed no difference in treatment effects on death/dependency (Analysis 3.1) or death from all causes (Analysis 3.2) or intracranial haemorrhage (Analysis 3.3) between trials recruiting within three hours of stroke onset and those recruiting within six hours. However, there were limited data and different trials contributed to different time windows and, therefore, these results may not be reliable.
3.1. Analysis.
Comparison 3 Different treatment time from onset, Outcome 1 Death or dependency at the end of follow‐up.
3.2. Analysis.
Comparison 3 Different treatment time from onset, Outcome 2 Death from all causes at end of follow‐up.
3.3. Analysis.
Comparison 3 Different treatment time from onset, Outcome 3 Any intracranial haemorrhage detected on systematic repeat CT during treatment period.
Discussion
Summary of main results
We have included eight trials involving 5701 patients in this review so far. The results show only a moderately significant difference for fewer dead or dependent patients (5% relative risk reduction) at the end of follow‐up in the treatment group but this result was not robust in a worst‐case sensitivity analysis. There were also fewer stroke recurrences in the treatment group (62/1331, 5%) than in the control group (94/1343, 7%) (RR 0.67, 95% CI 0.49 to 0.92). However, this should be interpreted cautiously as data were only available for about 50% of all patients randomised. Symptomatic intracranial haemorrhage in the treatment group was about double that in the control group (RR 2.42, 95% CI 1.65 to 3.56) and any intracranial haemorrhage detected by repeated CT scan (including asymptomatic intracranial haemorrhages) was higher in treatment group (RR 1.98, 95% CI 1.54 to 2.56). In absolute terms, for every 1000 patients treated in the acute phase, death or dependency would be avoided in about 30 people after three months and 20 symptomatic intracranial haemorrhages would be caused.
Overall completeness and applicability of evidence
In short, treatment with these agents may reduce the risk of death or dependency or recurrence at the end of follow‐up. This promising result needs to be confirmed in more studies. The results of the review are limited by the following factors.
Loss to follow‐up or exclusions after randomisation meant that the result for the primary outcome was not robust in sensitivity analyses.
Some outcomes had limited data when compared with the total number of patients included in the trials, which may raise the issue of reporting bias.
The confidence intervals for death were wide and so it is not possible to exclude a significant excess in mortality with treatment.
It seemed that defibrase caused less intracranial haemorrhage than ancrod but this must be interpreted with caution because different types of patients were recruited into each group. For example, the defibrase trials excluded patients with atrial fibrillation whereas, the ancrod trials did not. Whether defibrase is really safer than ancrod would require direct randomised comparisons.
The lack of individual patient data and the limited number of trials meant that it was not possible to assess whether there were significant differences in treatment effect in important subgroups such as patients treated within three hours compared with those treated later (as is the case with thrombolysis), those with elevated baseline fibrinogen levels or who had the largest drop in fibrinogen with treatment who might benefit more, or between different agents.
The variation in the definition of dependency (different scores and different cut‐offs) and the timing of its assessment in different trials which might affect its interpretation. Although the I2 statistic for death or dependency was low, suggesting no major heterogeneity between trials, we believe this variation means the result should be interpreted cautiously.
For these reasons, the results of this review need to be interpreted cautiously although we believe that these agents are worthy of further study. The benefits of defibrinogenating agents appear to be smaller than the benefits of thrombolysis (Wardlaw 2009) and are based on much fewer data. However, we are not aware of any randomised trials that directly compare thrombolysis with defibrinogenating agents.
Quality of the evidence
The quality of reporting in general was good. Seven trials adequately concealed the randomisation sequence and blinded outcome assessment. Five trials performed an ITT analysis while two trials using defibrase did not.
Authors' conclusions
Implications for practice.
The data from the trials included in this review indicate that, compared with control, fibrinogen depleting agents tested in patients with acute ischaemic stroke have a marginal effect in terms of death or dependency after follow‐up of at least three months, and may reduce the risk of recurrent ischaemic stroke during the follow‐up period. However, there was evidence of a significant increase of intracranial haemorrhage. In addition, these results are not statistically robust and so the evidence was still not strong enough to recommend routine use of fibrinogen depleting agents for the treatment of acute ischaemic stroke.
Implications for research.
Further trials are needed to determine reliably whether there is worthwhile benefit, and if so, which categories of patients (within three hours of onset, hyperfibrinogenemia, different stroke subtypes according to the TOAST classification (Adams 1993), are a few examples) are most likely to benefit. In addition, at a methodological level, it is dangerous that researchers who take part in collaborative multicentre trials report their individual single‐centre results separately.
What's new
| Date | Event | Description |
|---|---|---|
| 31 October 2013 | Amended | Missing headings added to forest plots. |
History
Protocol first published: Issue 1, 1997 Review first published: Issue 1, 1997
| Date | Event | Description |
|---|---|---|
| 5 December 2011 | New citation required but conclusions have not changed | New first author |
| 5 December 2011 | New search has been performed | Three trials (2775 patients) have been added to this review. However, the conclusions have not changed. The evidence is still not strong enough to recommend the routine use of fibrinogen depleting agents for the treatment of acute ischaemic stroke |
| 19 August 2008 | Amended | Converted to new review format |
| 6 April 2003 | New search has been performed | Changes from previous version of this review are as follows: data from two big trials (2744 extra patients) have been added |
Acknowledgements
We would like to thank Hazel Fraser for providing us with references to the relevant trials from the Cochrane Stroke Group Trials Register, Brenda Thomas for help to develop trial searching strategies and Professor Hideki Origasa for searching the Japanese literature, Dr Li He, Dr Le Zhang, Dr Zhao Han and other volunteers for searching Chinese journals, Professor Volker Hossmann, Dr David Levy and Dr David G Sherman for providing us with additional data of their trials.
If anyone knows of trials that we have omitted we would be grateful if they could contact Dr Ming Liu.
Appendices
Appendix 1. MEDLINE search strategy
We used the following search strategy for MEDLINE (Ovid) and adapted it for CENTRAL.
1. exp snakes/ or exp snake venoms/ or venoms/ 2. ancrod/ or batroxobin/ or venombin a/ 3. Fibrinogen/de, ai [Drug Effects, Antagonists & Inhibitors] 4. (batroxobin or defibrase or defibrol or hemocoagulase or reptilase or ancrod or agkistrodon or arvin or arwin or venacil or viprinex or venom$ or defibrinogen$ or fibrinogen deplet$ or acutase or acutobin).tw. 5. 1 or 2 or 3 or 4 6. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or exp brain ischemia/ or carotid artery diseases/ or carotid artery thrombosis/ or intracranial arterial diseases/ or cerebral arterial diseases/ or exp "intracranial embolism and thrombosis"/ or exp stroke/ 7. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw. 8. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw. 9. 6 or 7 or 8 10. 9 and 5 11. limit 10 to humans
Appendix 2. EMBASE search strategy
We used the following search strategy for EMBASE (Ovid).
1. exp snake venom/ or exp snake/ or venom/ 2. ancrod/ or batroxobin/ or venombin a/ 3. fibrinogen/pd 4. (batroxobin or defibrase or defibrol or hemocoagulase or reptilase or ancrod or agkistrodon or arvin or arwin or venacil or viprinex or venom$ or defibrinogen$ or fibrinogen deplet$ or acutase or acutobin).tw. 5. 1 or 2 or 3 or 4 6. cerebrovascular disease/ or cerebral artery disease/ or cerebrovascular accident/ or stroke/ or vertebrobasilar insufficiency/ or carotid artery disease/ or exp carotid artery obstruction/ or exp brain infarction/ or exp brain ischemia/ or exp occlusive cerebrovascular disease/ 7. stroke patient/ or stroke unit/ 8. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw. 9. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw. 10. 6 or 7 or 8 or 9 11. 10 and 5 12. limit 11 to human
Data and analyses
Comparison 1. Fibrinogen depleting agents versus control.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death or dependency at the end of follow‐up | 6 | 5354 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.90, 0.99] |
| 2 Death from all causes at end of treatment period | 5 | 1584 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.70, 1.43] |
| 3 Death from all causes at end of follow‐up | 8 | 5028 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.94, 1.22] |
| 4 Any symptomatic intracranial haemorrhage at end of treatment period | 8 | 5404 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.42 [1.65, 3.56] |
| 5 Any symptomatic intracranial haemorrhage at end of follow‐up | 3 | 182 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.21 [0.01, 4.34] |
| 6 Any intracranial haemorrhage detected on systematic repeat CT during treatment period | 5 | 2384 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.98 [1.54, 2.56] |
| 7 Recurrent stroke (ischaemic/unknown type) at end of treatment period | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 8 Recurrent stroke (ischaemic/unknown type) at end of follow‐up | 4 | 2674 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.49, 0.92] |
| 9 Venous thrombotic events | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 9.1 Thrombophlebitis | 1 | 500 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.28, 1.28] |
| 9.2 Pulmonary embolism/infarction | 2 | 1000 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.25 [0.07, 0.88] |
Comparison 2. Different agents.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death or dependency at the end of follow‐up | 6 | 5354 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.90, 0.99] |
| 1.1 Ancrod versus control | 4 | 2354 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.90, 1.02] |
| 1.2 defibrase versus control | 2 | 3000 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.87, 1.00] |
| 2 Death from all causes at the end of follow‐up | 8 | 5028 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.94, 1.22] |
| 2.1 Ancrod versus control | 6 | 2404 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.95, 1.29] |
| 2.2 Defibrase versus control | 2 | 2624 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.76, 1.29] |
| 3 Any symptomatic intracranial haemorrhage at the end of treatment period | 8 | 5404 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.42 [1.65, 3.56] |
| 3.1 Ancrod versus control | 6 | 2404 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.56 [2.15, 5.87] |
| 3.2 Defibrase versus control | 2 | 3000 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.60, 2.20] |
| 4 Recurrent stroke (ischaemic/unknown type) at the end of follow‐up | 4 | 2674 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.49, 0.92] |
| 4.1 Ancrod versus control | 2 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.02, 7.32] |
| 4.2 Defibrase versus control | 2 | 2624 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.50, 0.93] |
Comparison 3. Different treatment time from onset.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death or dependency at the end of follow‐up | 6 | 10708 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.91, 0.98] |
| 1.1 Treatment started < 6 hours | 4 | 2354 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.89, 1.04] |
| 1.2 Treatment started > 6 hours | 2 | 3000 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.87, 1.00] |
| 1.3 Treatment started < 3 hours | 1 | 500 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.79, 1.05] |
| 1.4 Treatment started > 3 hours | 5 | 4854 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.90, 1.00] |
| 2 Death from all causes at end of follow‐up | 7 | 10016 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.98, 1.18] |
| 2.1 Treatment started < 6 hours | 4 | 2354 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.96, 1.30] |
| 2.2 Treatment started > 6 hours | 3 | 2654 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.76, 1.25] |
| 2.3 Treatment started < 3 hours | 1 | 500 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.81, 1.51] |
| 2.4 Treatment started > 3 hours | 6 | 4508 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.92, 1.23] |
| 3 Any intracranial haemorrhage detected on systematic repeat CT during treatment period | 5 | 4768 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.98 [1.66, 2.37] |
| 3.1 Treatment started < 6 hours | 4 | 2354 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.01 [1.56, 2.60] |
| 3.2 Treatment started > 6 hours | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.58] |
| 3.3 Treatment started < 3 hours | 1 | 500 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.91 [1.29, 2.82] |
| 3.4 Treatment started > 3 hours | 4 | 1884 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.03 [1.46, 2.83] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
AISS 1994.
| Methods | C: sequentially numbered identical containers Doctor, patients, and assessor blinded (1 unblinded dosing supervisor was not involved in treatment or assessment) Ex during trial: none Losses to FU: 2 in Rx and 1 in control for Barthel Index | |
| Participants | Country: USA 132 patients Age: mean 67 years (range 44 to 75 years) Sex: 65% male Moderate (SSS < 40) ischaemic stroke 100% CT before entry < 6 hours from stroke onset Comparability: slightly more lacunar stroke in Rx group (22% versus 13%) | |
| Interventions | Rx: ancrod 0.5 u/kg iv over 6 hours on day 1, followed by 0.15 to 0.24 u/kg depending on plasma fibrinogen level (target 70 to 100 mg/dL) Control: placebo 250 mL saline iv Duration: 7 days Only 15/64 (23%) achieved the target fibrinogen level of < 100 mg/dL within 6 hours of treatment | |
| Outcomes | Death at 1 month, 1 year Disability at 3 months (Barthel index ≤ 90 or worse than pretreatment score) Symptomatic intracranial haemorrhage Intracranial haemorrhage in routine repeat CT (CT at 2 to 10 days) Major extracranial haemorrhage | |
| Notes | FU: 12 months for death; 3 months for Barthel Index Ex: coma, postoperative stroke, heart disease, renal or hepatic failure, bleeding tendency | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Did not report |
| Allocation concealment (selection bias) | Low risk | Sequentially numbered identical containers |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Doctor, patients, and assessor blinded |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | No exclusions after randomisation or losses to follow‐up were reported |
| Selective reporting (reporting bias) | Unclear risk | The study protocol was not available |
| Other bias | Unclear risk | None known |
ASP 2009.
| Methods | C: identical‐appearing vials were assigned by using an interactive voice response system Patients and assessors blinded Ex during trial: none Losses to FU: 0 in Rx, 3 in control at 90 days | |
| Participants | 500 patients Age: mean 70.2 years in Rx group, mean 69.6 years in placebo group Sex: 49.2% male Ischaemic stroke with pretreatment NIHSS ≧ 5 (pretreatment NIHSS 1a > 2 were excluded) 100% CT or MRI before entry < 6 hours from stroke onset Comparability: similar | |
| Interventions | Rx: 0.5 IU/kg ancrod for 3 hours in patients with pretreatment fibrinogen levels ≧ 200 mg/dL or 0.33 IU/kg ancrod for 2 hours in patients with pretreatment fibrinogen levels 100 to 199 mg/dL Control: placebo Duration: 2 or 3 hours | |
| Outcomes | Death at 90 days Disability at 90 days (mRS ) Symptomatic intracerebral haemorrhage Asymptomatic intracerebral haemorrhage | |
| Notes | FU: 90 days for death and disability Ex: neuroimaging evidence of haemorrhage; coma; NIHSS < 5; use or intended use of thrombolytic agent; previous stroke; blood pressure > 185/105 mmHg; fibrinogen < 100 mg/dL; intrinsic or extrinsic coagulation disorders; patients with medical condition not likely to survival through 90 days; previous exposure to ancrod or snake bites | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated codes |
| Allocation concealment (selection bias) | Low risk | Identical‐appearing vials |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Patients and assessors blinded |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | ITT analysis |
| Selective reporting (reporting bias) | Low risk | No obvious selective reporting was found |
| Other bias | High risk | Ended early for futility reasons |
ESTAT 2006.
| Methods | C: sequentially numbered prepacks Doctor, patients, and assessor blinded (1 unblinded dosing supervisor was not involved in treatment or assessment) Ex during trial: none Losses to FU: 4 in Rx group, 5 in control group at 3 months; 16 in Rx group, 13 in control group at 1 year | |
| Participants | Countries: European countries, Australia and Israel 1222 patients Age: 68.5 years (range 20 to 95 years) Sex: 60% male Moderate (SSS < 40) ischaemic stroke 100% CT before entry < 6 hours from stroke onset Comparability: similar | |
| Interventions | Rx: ancrod continuous 72‐hour intravenous infusion, followed by daily single infusions lasting about 1 hour for 2 days, to reach and maintain a target fibrinogen concentration (1.2 to 2.1 μmol/L) Control: placebo Duration: 5 days | |
| Outcomes | Death at 3 months, 12 months Disability at 3 months (Barth Index < 95 or worse than pretreatment score) Symptomatic intracerebral haemorrhage Asymptomatic intracerebral haemorrhage | |
| Notes | FU: 12 months for death; 3 months for disability Ex: comatose, recent stroke, neurological deficit interfering with evaluation, recent surgery, recent thrombolytic therapy, severe high or low blood pressure, bleeding tendency, prior treatment with ancrod, very mild stroke (SSS ≥ 40 at baseline) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated codes |
| Allocation concealment (selection bias) | Low risk | Sequentially numbered prepacks |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Doctor, patients, and assessor blinded |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | ITT analysis |
| Selective reporting (reporting bias) | Low risk | No obvious selective reporting was found |
| Other bias | Unclear risk | None known |
Hossmann 1983.
| Methods | C: sequentially numbered, sealed, opaque envelopes Patients and assessors blinded Ex during trial: none Losses to FU: none | |
| Participants | Country: Germany 30 patients Age: mean: 65 years (range 44 to 75 years) Sex: 53% male Ischaemic stroke 100% CT before entry < 48 hours from stroke onset Comparability: age, sex and pre‐Rx neurological deficit similar | |
| Interventions | Rx: ancrod 1 u/kg subcutaneous injection/day until fibrinogen level 100 to 130 mg/dL, then variable dose to keep fibrinogen 100 to 130 mg/dL Control: open Duration: 14 days Both groups: 10% LMWD 500 mL/day iv for 10 days and 20% mannitol 250 mL/day iv for 5 days | |
| Outcomes | Death at 2 weeks, 12 months Symptomatic haemorrhage Intracranial haemorrhage on routine repeat CT at 15 days Recurrent ischaemic/unknown stroke Major extracranial haemorrhage Pulmonary embolism MI | |
| Notes | FU: 12 months Ex: recent MI, severe high blood pressure, hepatic or renal insufficiency, bleeding tendency | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Did not report |
| Allocation concealment (selection bias) | Low risk | Sequentially numbered, sealed, opaque envelopes |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Patients and assessors blinded |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | ITT analysis |
| Selective reporting (reporting bias) | Unclear risk | The study protocol was not available. |
| Other bias | Unclear risk | None known |
Olinger 1988.
| Methods | C: unclear, placebo controlled trial Doctor, patients, and assessor blinded Ex during trial: ? none Losses to FU: ? none | |
| Participants | Country: USA 20 patients Age: 30 to 80 years Sex: unknown Ischaemic stroke 100% CT before entry ? time from stroke onset ? comparability of groups | |
| Interventions | Rx: ancrod 0.5 u/kg over 6 hours then iv 12 to 24 hourly infusion according to fibrinogen level (target 100 mg/dL) Control: placebo (saline) Duration: 7 days | |
| Outcomes | Death at 7 days, 3 months Symptomatic intracranial haemorrhage Major extracranial haemorrhage Recurrent ischaemic/unknown stroke | |
| Notes | FU: 90 days Ex: comatose, recent MI, severe high blood pressure, renal or hepatic failure, bleeding tendency. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Did not report |
| Allocation concealment (selection bias) | Unclear risk | Did not report |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Doctor, patients, and assessor blinded |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | No exclusions after randomisation or losses to follow‐up were reported |
| Selective reporting (reporting bias) | Unclear risk | The study protocol was not available |
| Other bias | Unclear risk | None known |
RDTCI 2000.
| Methods | C: sequentially numbered identical containers Doctor, patients, and assessor blinded Ex during trial: ? none Losses to FU: 207 in Rx group and 179 in placebo group at 1 year; 88 in Rx group and 58 in placebo group at 3 months | |
| Participants | Country: China 2244 patients Age: mean 62 years (range 35 to 80 years) Sex: 60% male Moderate cerebral infarction 100% CT before entry < 24 hours from stroke onset Comparability: age, sex similar between groups | |
| Interventions | Rx: defibrase 10 U iv on day 1, 5 U on day 3 and day 5 Control: placebo Duration: 5 days | |
| Outcomes | Death at 3 month, 1 year; ADL at 3 months Neurological deficit scale at 2 weeks Recurrent stroke at 1 year Adverse events | |
| Notes | FU: 12 months for death; 3 months for ADL Ex: bleeding tendency; pregnant; hypersensitivity; used fibrinolytic or defibrase within 1 week; heart, renal or hepatic failure; atrial fibrillation; severe high blood pressure | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated codes |
| Allocation concealment (selection bias) | Low risk | Sequentially numbered identical containers |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Doctor, patients and assessors blinded |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Per‐protocol analysis |
| Selective reporting (reporting bias) | Unclear risk | The study protocol was not available |
| Other bias | Unclear risk | None known |
RDTCI‐2 2005.
| Methods | C: sequentially numbered identical containers Doctor, patients and assessors blinded Ex during trial: ? none Losses to FU: 81 in Rx group and 53 in placebo group at 3 months; 158 in Rx group and 129 in control group at 1 year | |
| Participants | Country: China 1053 patients Age: mean 62 years in Rx group, mean 62 years in placebo group Sex: 63% male Moderate cerebral infarction 100% CT before entry < 12 hours from stroke onset Comparability: age, sex, weight, mean blood pressure | |
| Interventions | Rx: defibrase 15 U iv on day 1, 5 U on day 3, day 5 and day 7 Control: placebo Duration: 9 days | |
| Outcomes | Death at 3 months, 1 year Dependency at 3 months (Barthel Index < 95) Neurological deficit scale at 2 weeks Recurrent stroke at 1 year Adverse events | |
| Notes | FU: 12 months for death; 3 months for ADL Ex: bleeding tendency; pregnant; hypersensitivity; used fibrinolytic or defibrase within one week; heart, renal or hepatic failure; atrial fibrillation; severe high blood pressure | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated codes |
| Allocation concealment (selection bias) | Low risk | Sequentially numbered identical containers |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Doctor, patients and assessors blinded |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Per‐protocol analysis |
| Selective reporting (reporting bias) | Unclear risk | The study protocol was not available |
| Other bias | Unclear risk | None known |
STAT 2000.
| Methods | C: sequentially numbered identical containers Doctor, patients, and assessor blinded (1 unblinded dosing supervisor was not involved in treatment or assessment) Ex during trial: none Losses to FU: 4 in Rx group, 1 in control group | |
| Participants | Countries: USA and Canada 500 patients Age: mean 73 years (range 34 to 98 years) Sex: 51% male Moderate (SSS < 40) ischaemic stroke % CT before entry: unknown < 3 hours from stroke onset Comparability: slightly more milder stroke (SSS scores 30 to 39) in control group (39% versus 34%) | |
| Interventions | Rx: ancrod 0.167 IU/kg iv per hour for over 72 hours, followed by 0.125 and 0.082 IU/kg over 1 hour at 96 and 120 hours depending on plasma fibrinogen level (target 1.18 to 2.03 micromol/L) Control: placebo (identical‐appearing supplies with saline) iv Duration: 5 days | |
| Outcomes | Death at 3 month Disability at 3 months (Barthel index < 95 or worse than pretreatment score) Symptomatic intracranial haemorrhage Asymptomatic Intracranial haemorrhage/extracranial haemorrhage | |
| Notes | FU: 90 days Ex: comatose, recent stroke, neurological deficit interfering with evaluation, recent surgery, recent thrombolytic therapy, severe high or low blood pressure, bleeding tendency, prior treatment with ancrod | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated codes |
| Allocation concealment (selection bias) | Low risk | Sequentially numbered identical containers |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Doctor, patients, and assessor blinded |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | ITT analysis |
| Selective reporting (reporting bias) | Unclear risk | The study protocol was not available |
| Other bias | Unclear risk | None known |
ADL: activities of daily living C: concealment of allocation CT: computerised tomography Ex: exclusion FU: follow‐up ITT: intention‐to‐treat iv: intravenous LMWD: low molecular weight dextran MI: myocardial infarction MRI: magnetic resonance imaging mRS: modified Rankin Scale NIHSS: National Institutes of Health Stroke Scale Rx: treatment SSS: Scandinavian Stroke Scale
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Cai 2000 | No relevant outcome recorded (only impairment measured) |
| Chen 1996 | Confounded (batroxobin versus LMWD) |
| Chen 2000 | No relevant outcome recorded (only impairment measured) |
| CRG 1982 | Non‐random allocation based on patient preference; confounded (defibrase versus at least 3 of the following drugs: vasodilators, antiplatelet agents, dextran, Chinese medicine, acupuncture etc) |
| Cui 2000 | Single‐centre results from a multicentre trial included in this review |
| Du 2003 | No relevant outcome recorded (only impairment measured) |
| Fan 2000 | Single‐centre results from a multicentre trial included in this review |
| Fan 2001 | No relevant outcome recorded (only impairment measured) |
| Gao 1996 | No relevant outcome recorded (only impairment measured) |
| Guo 2008 | No relevant outcome recorded (laboratory data) |
| Gusev 2006 | No relevant outcome recorded (only impairment measured) |
| Hao 1984 | Confounded (antithrombotic enzymes ofAgkistrodon halys venom versus LMWD) |
| He 1998 | No relevant outcome recorded (only impairment measured) |
| Huang 1996 | Confounded (svate versus batroxobin) |
| Huang 2000 | No relevant outcome recorded (only impairment measured) |
| Kuang 1996 | Batroxobin in the treatment of transient ischaemic attacks; confounded (batroxobin versus conventional treatment including dextran, Chinese medicine, antiplatelet agents, calcium antagonists, free radical scavengers etc) |
| Li 2000 | Single‐centre results from a multicentre trial included in this review |
| Lian 1998 | No relevant outcome recorded (only impairment measured) |
| Lu 2003 | Single‐centre results from a multicentre trial included in this review |
| Mei 2000 | Single‐centre results from a multicentre trial included in this review |
| Qiang 1995 | Confounded (batroxobin versus a Chinese medicine) |
| Sun 2000 | Single‐centre results from a multicentre trial included in this review |
| Sun 2002 | Single‐centre results from a multicentre trial included in this review |
| Wang 1999 | Confounded (defibrase versus dextran plus dan shen) |
| Wang 1999a | Confounded (defibrase versus ahylsantinfarctase) |
| Wang 2003 | Confounded (defibrase versus ozagrel) |
| Wang 2004 | Single‐centre results from a multicentre trial included in this review |
| Wei 2004 | Single‐centre results from a multicentre trial included in this review |
| Wu 1997 | No relevant outcome recorded (only impairment measured) |
| Xie 2003 | Single‐centre results from a multicentre trial included in this review |
| Xu 2000 | No relevant outcome recorded (laboratory data) |
| Yan 2001 | Single‐centre results from a multicentre trial included in this review |
| Yang 2000 | Confounded (defibrase versus dextran plus dan shen) |
| Yang 2004 | Single‐centre results from a multicentre trial included in this review |
| Yu 2000 | No relevant outcome recorded (only impairment measured) |
| Yu 2003 | Single‐centre results from a multicentre trial included in this review |
| Zhang 1996 | Non‐randomised |
| Zhang 1998 | Comparison of iv administration of batroxobin with intra‐carotid artery injection |
| Zhang 2001 | Confounded (defibrase versus xanthinol nicotinate ) |
| Zhang 2002 | Confounded (defibrase versus ligustrazine) |
| Zhao 1999 | No relevant outcome recorded (only impairment measured) |
iv: intravenous LMWD: low molecular weight dextran
Characteristics of studies awaiting assessment [ordered by study ID]
Li 1999.
| Methods | |
| Participants | |
| Interventions | |
| Outcomes | |
| Notes | No available information |
Li 2010.
| Methods | C: Envelope Patients, and assessor blinded (one unblinded doctor was not involved in treatment or assessment) Ex during trial: none Losses to FU: none |
| Participants | Countries: China 150 patients Age: unknown Sex: unknown Moderate (mean NIHSS 7) ischaemic stroke % CT before entry: unknown 6 to 24 hours from stroke onset Comparability: similar |
| Interventions | Rx: batroxobin 10 U iv on day 1, 5 U on day 3 and day 5 Control: placebo Duration: 5 days |
| Outcomes | Death at 3, 6 months Disability at 3, 6 months Neurological deficit scale at 2 weeks Adverse events |
| Notes | Ex: haemorrhagic infarction; platelet < 100*109/mm3 or fibrinogen < 1g/L; bleeding tendency; pregnant; recent surgery or trauma; used fibrinolytic or defibrase within 2 weeks; heart, renal or hepatic failure; shock or severe high blood pressure |
C: concealment of allocation CT: computerised tomography Ex: exclusion FU: follow‐up iv: intravenous NIHSS: National Institutes of Health Stroke Scale Rx: treatment
Differences between protocol and review
We only included randomised controlled trials comparing fibrinogen depleting agents with placebo or open control in patients with acute ischaemic stroke in this updated review.
Contributions of authors
Zilong Hao: collected data, undertook searches, appraised the quality of papers; selected trials for inclusion, extracted data from papers. Data management: entered data into RevMan and checked the data and wrote the review.
Ming Liu: designed the review, collected data, developed the search strategy, undertook searches, appraised the quality of papers, selected trials for inclusion, contacted authors for additional data, extracted data from papers. Data management: entered data into RevMan, carried out analysis and interpretation of the data. Wrote the review.
Carl Counsell: designed and conducted the original review and commented on the manuscript of the updated review.,
Joanna Wardlaw: searched for trials, performed previous work that formed the basis of this review, provided general advice on the review and assisted with writing the review, and commented on drafts.
Sen Lin: collected data, undertook searches, appraised the quality of papers; selected trials for inclusion, extracted data from papers.
Xiaoling Zhao: collected data, undertook searches, appraised the quality of papers; selected trials for inclusion, extracted data from papers. Data management: entered data into RevMan and checked the data and commented on drafts for previous version.
Sources of support
Internal sources
West China Hospital, Sichuan University, China.
Chinese Cochrane Centre, Chinese Centre of Evidence‐based Medicine, China.
External sources
Chest, Heart and Stroke Scotland, UK.
World Health Organization, Not specified.
Wellcome Trust, UK.
Medical Research Council, UK.
University of Edinburgh, UK.
China Medical Board of New York (Grant number: 98‐680), USA.
University of Aberdeen, UK.
Employing institution for Dr Counsell
Declarations of interest
None known.
Edited (no change to conclusions)
References
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