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The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2010 Feb 17;2010(2):CD005953. doi: 10.1002/14651858.CD005953.pub2

Extracranial‐intracranial arterial bypass surgery for occlusive carotid artery disease

Felix Fluri 1, Stefan Engelter 1, Philippe Lyrer 1,
Editor: Cochrane Stroke Group
PMCID: PMC6544774  PMID: 20166076

Abstract

Background

The EC/IC Bypass Study Group found no benefit of extracranial to intracranial (EC/IC) bypass surgery over medical therapy in patients with symptomatic carotid artery occlusion (sCAO). However, the study was criticised for many reasons and the real effect of this treatment is still not known conclusively.

Objectives

To determine whether bypass surgery plus medical care is superior to medical care alone in patients with sCAO.

Search methods

We searched the Cochrane Stroke Group Trials Register (last searched June 2009). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966 to June 2009) and EMBASE (1980 to June 2009). We also searched ongoing trials and research registers, checked reference lists of relevant articles, and contacted colleagues, trial authors and researchers.

Selection criteria

Randomised controlled trials (RCT) and non‐random studies of EC/IC bypass surgery plus best medical treatment compared with best medical treatment alone to prevent subsequent stroke, improve cerebral haemodynamics and reduce dependency after stroke.

Data collection and analysis

Two review authors independently selected studies for inclusion, and extracted data items on the number of outcome events onto a data extraction form. We only analysed secondary outcomes if the study provided information on at least one primary outcome. We also used intention‐to‐treat analysis where possible.

Main results

We included 21 trials, including two RCTs, involving 2591 patients. For all endpoints, no benefit of EC/IC bypass surgery was shown either in the RCTs (any death: odds ratio (OR) 0.81, 95% confidence interval (CI) 0.62 to 1.05, P = 0.11; stroke: OR 0.99, 95% CI 0.79 to 1.23, P = 0.91; death and dependency: OR 0.94, 95% CI 0.74 to 1.21, P = 0.64), or in the non‐RCTs (any death: OR 1.00, 95% CI 0.62 to 1.62, P = 0.99; stroke: OR 0.80, 95% CI 0.54 to 1.18, P = 0.25; death and dependency: OR 0.80, 95% CI 0.50 to 1.29, P = 0.37).

Authors' conclusions

EC/IC bypass surgery in patients with sCAO disease was neither superior nor inferior to medical care alone. However, most studies included patients irrespective of their cerebral haemodynamics. Participation in an ongoing RCT, which is restricted to patients with impaired haemodynamics, is recommended as these patients might benefit from bypass surgery.

Plain language summary

Extracranial‐intracranial arterial bypass surgery for occlusive carotid artery disease

Patients with symptomatic occlusion (obstruction) of the carotid artery have a high risk of subsequent stroke. Anticoagulant treatment and antiplatelet agents are not very effective in these patients and a surgical procedure known as extracranial‐intracranial (EC/IC) arterial bypass surgery has been a treatment option. In this review, we included 21 trials (two randomised controlled trials and 19 non‐random studies, with a total of 2591 patients). We found that EC/IC bypass surgery in patients with symptomatic carotid artery occlusive disease was no better or worse than medical care alone. A multi‐centre trial comparing EC/IC bypass surgery with best medical treatment in patients with both a high risk of stroke and haemodynamic compromise (impaired blood flow) is underway, and aims to discover whether EC/IC bypass surgery is beneficial in this specific group of patients.

Background

Up to 15% of patients presenting with anterior circulation ischaemia have complete occlusion of the ipsilateral carotid artery (Bozzao 1989; Pessin 1977; Thiele 1980). Their annual risk for subsequent stroke is 5% to 7% (Grubb 1986; Klijn 1997), and the risk of stroke ipsilateral to the occluded carotid artery is 2% to 6% per year (Hankey 1991; Klijn 1997). The efficacy of anticoagulant treatment or antiplatelet agents in patients with symptomatic occlusion of the carotid artery is small (Klijn 1997). Cerebral revascularisation of the anterior or posterior circulation by extracranial to intracranial (EC/IC) anastomosis is thought to be a therapeutic option for preventing subsequent transient ischaemic attack or stroke in patients with occlusive carotid disease.

EC/IC bypass surgery is an operative procedure which most commonly involves the anastomosis of the superficial temporal artery to the middle cerebral artery. Results of the first EC/IC bypass were published in 1967 (Donaghy 1967; Yasargil 1969) and it became a widespread method in the next decade. In 1985, the EC/IC Bypass Study Group showed no benefit of EC/IC bypass surgery over medical therapy in patients with symptomatic carotid occlusion (EC/IC Bypass Study 1985). However, the study was criticised for including all patients with occlusion of the carotid artery irrespective of their cerebral haemodynamics. No stratification was done to separate patients with embolic stroke but sufficient intracranial haemodynamics from those with ongoing haemodynamic compromise. Thus, the negative result of the EC/IC bypass study does not necessarily mean that EC/IC bypass is not beneficial for some patients with substantial haemodynamic compromise due to occlusion of the carotid artery (Ausman 1986; Day 1986; Sundt 1987; Vorstrup 1992).

Haemodynamic compromise of ipsilateral artery occlusion is divided into three stages (Derdeyn 2002; Powers 1987; Powers 1991):

  • Stage 0: normal cerebral haemodynamics;

  • Stage 1: autoregulatory vasodilation;

  • Stage 2: autoregulatory failure (increased oxygen extraction fraction (OEF)), also termed 'misery perfusion' (Baron 1981).

Several studies have been carried out to evaluate whether the subgroup of patients with haemodynamic compromise due to occlusion of the carotid artery might benefit from bypass surgery. In addition, more recently there have been two other randomised controlled trials (RCTs) of EC/IC bypass (COSS; JET 2006). With these considerations in mind, we tried to evaluate whether EC/IC bypass surgery plus best medical treatment compared with best medical treatment alone prevents subsequent stroke, improves cerebral haemodynamics and reduces dependency after stroke in all eligible patients for EC/IC bypass or only in patients with impaired haemodynamics.

Objectives

The objective was to determine whether bypass surgery and medical care in patients with a symptomatic carotid artery occlusion was superior to medical care alone, both in all patients and in the subgroup of patients with haemodynamic compromise.

A further purpose of this review was to determine to what degree the intervention resulted in the correction of haemodynamic compromise in the affected hemisphere.

Finally we aimed to assess safety: death (all causes, vascular, non‐vascular) and stroke (all); intracranial haemorrhage; major extracranial haemorrhage; myocardial infarction; non‐vascular complication of surgery; and infection.

Methods

Criteria for considering studies for this review

Types of studies

The review has two parts, Part 1 and Part 2, each with two divisions, labelled (a) and (b). Division (a) included all patients undergoing EC/IC bypass surgery without measurement of cerebral haemodynamics, while division (b) assessed only those patients with impaired haemodynamics measured by positron emission tomography (PET), single photon emission computed tomography (SPECT), perfusion magnetic resonance (PMR) imaging, and ultrasound.

Part 1

Only randomised controlled trials (RCTs) of EC/IC bypass surgery plus best medical treatment compared with best medical treatment alone to prevent subsequent stroke, improve cerebral haemodynamics and reduce dependency after stroke, including:

  • (a) all patients without measurement of haemodynamic status before the intervention;

  • (b) only patients with impaired haemodynamics before the intervention measured using a method mentioned above.

Part 2

All studies (except RCTs) of EC/IC bypass surgery plus best medical treatment compared with best medical treatment alone to prevent subsequent stroke, improve cerebral haemodynamics and reduce dependency after stroke, including:

  • (a) all patients without measurement of haemodynamic status before the intervention;

  • (b) only patients with impaired haemodynamics before the intervention measured using a method mentioned above.

Types of participants

Patients with symptomatic (transient ischaemic attack or stroke) occlusion of internal carotid arteries demonstrated by angiography and less than 50% stenosis of the contralateral internal carotid artery and, where available, measured haemodynamic compromise identified by PET, SPECT, PMR imaging and ultrasound. Patients with transient ischaemic monocular blindness were not eligible unless hemispheric symptoms also were present. Patients with asymptomatic occlusion of the internal carotid artery were not eligible because of the low risk of subsequent ischaemic stroke (Powers 2000).

Patients who had undergone thrombendarterectomy of the contralateral internal carotid artery prior to EC/IC bypass were eligible. We excluded all studies including patients with non‐atherosclerotic conditions causing or likely to cause cerebral ischaemia (including carotid dissection, fibromuscular dysplasia, Moyamoya disease, arteritis and other vasculopathy likely to cause cerebral events) from the analysis. If this information was not available, we only used the published data.

Types of interventions

We included any surgical bypass procedure for the treatment of patients with radiologically demonstrated unilateral occluded internal carotid artery, irrespective of the approach and type of graft employed. The bypass patients as well as the control patients should have received best medical treatment for preventing stroke.

Types of outcome measures

Primary outcomes
  1. Death from all causes.

  2. Any stroke during the follow‐up period. This combined outcome included ischaemic strokes, intracranial haemorrhage, or stroke of unknown aetiology.

  3. Death or dependency at the end of follow up. This composite outcome included all patients who qualified either for death or dependency (handicap) which was defined according to the modified Rankin Scale (mRS): independency (mRS 0 to 2) was distinguished from dependency (3 to 5). If the Glasgow Outcome Scale (GOS) was used, we considered good recovery and moderate disability as surrogates for independence, and considered severe disability and persistent vegetative state as dependence. When mRS values were not available, we defined independence as recovery (that is, patients are able to look after their own affairs without assistance) or return to work. In cases of 'deterioration', 'worsened', 'fair' or 'poor' outcome, we assumed dependency as 'partial improvement', 'no improvement', 'no recovery', 'inability to walk without assistance', or 'requiring some help for bodily activities of daily living'. This algorithm was also used for the Cochrane Review of carotid artery dissection (Lyrer 2003).

Secondary outcomes
  1. Vascular death, which we defined as death caused by:

    • stroke or a complication of stroke (e.g. brain herniation, status epilepticus);

    • coronary artery disease or a complication of it (e.g. myocardial infarction, congestive heart failure, arrhythmia);

    • sudden death;

    • pulmonary embolism;

    • peripheral vascular disease;

    • haemorrhage (intracranial or extracranial); or

    • other vascular causes (for example, rupture of aneurysm, dissection) including 'vascular death' mentioned without specification in the publications.

  2. Serious vascular events (during follow‐up period) or vascular death. This composite outcome included all patients who qualified for outcome events 1, 3, 4 or 5.

  3. Myocardial infarction. All patients with fatal or non‐fatal myocardial infarction. Patients who died of occlusive coronary artery disease as reported by autopsy, are classified as 'fatal myocardial infarction'.

  4. Ischaemic stroke (during follow‐up period). We defined ischaemic stroke as any neurological deficit due to cerebral ischaemia lasting longer than 24 hours, and showing no evidence of any other underlying pathology (e.g. haemorrhage, tumour).

  5. Intracranial haemorrhage. Intracranial haemorrhage included any subarachnoid haemorrhage, subdural haemorrhage, epidural haematoma, or parenchymatous intracerebral haemorrhage, as confirmed by neuroradiological investigations or by autopsy. We did not consider haemorrhagic transformation of an ischaemic infarction as intracranial haemorrhage.

  6. Major extracranial haemorrhage. We took the definition of a major extracranial haemorrhage from the original publication. If no definition was given, we defined major as a fatal bleeding, or one requiring surgery, transfusion or (prolonged) hospitalisation. If a haemorrhage was declared 'serious' or 'severe' in the publication, we considered it a major haemorrhage for the purpose of this review.

  7. Local haemorrhage requiring surgery. All patients with local haematoma requiring surgical exploration, haematoma evacuation, or the application of a suture, a patch, or a bypass met the criteria for this outcome event.

  8. Transient ischaemic attack or amaurosis fugax.

  9. Normalisation of cerebral haemodynamics, using PET, computerised tomography (CT), SPECT or ultrasound criteria, which we defined as a normalisation of hemispheric oxygen extraction fraction (OEF) ratios or decreased OEF ratio after EC/IC‐bypass surgery.

  10. Non‐vascular complications of surgery (for example, wound infection, limited function of the EC/IC bypass).

For all outcome events, we only included patients once. If one patient experienced more than one non‐fatal event, we only recorded the first one.

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 June 2009. In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966 to June 2009) (Appendix 1) and EMBASE (1980 to June 2009) (Appendix 2). In an effort to identify further published, unpublished and ongoing studies we searched reference lists of relevant papers, contacted colleagues, trial authors and researchers, and searched the following clinical trials and research registers:

Data collection and analysis

Two review authors (FF, SE) independently selected studies for inclusion. The same two review authors independently extracted data items on the number of outcome events onto a data extraction form. In cases of disagreement, the review authors reached consensus by discussion.

The data that we analysed are listed in the 'Types of outcome measures' section. We only analysed secondary outcomes if the study provided information on at least one primary outcome. We used intention‐to‐treat analysis. For the EC/IC bypass study, we also included the 118 patients who did not meet the inclusion criteria and, thus, were excluded from the analysis published in 1985 (EC/IC Bypass Study 1985).

Statistical methods

We calculated a weighted estimate of the odds for each outcome event across studies using the Peto odds ratio (OR) method.

Results

Description of studies

See the 'Characteristics of included studies' and the' Characteristics of excluded studies' sections.

We have identified a total of two randomised controlled trials (RCTs) comparing EC/IC bypass and best medical treatment with medical care alone and fulfilling the inclusion criteria (EC/IC Bypass Study 1985; JET 2006). One RCT is still in progress (COSS). For Part 1a, we found a total of 1691 patients, whereas for Part 1b we only included data for 195 patients from the JET study (JET 2006). Length of follow up in the EC/IC bypass study was 55.8 months, and in the JET study was 25 months. We identified 118 drop‐outs in the EC/IC bypass study, whereas in the JET study 10 patients dropped out. Furthermore, detailed patient data were only given as percentages in the EC/IC bypass study, thus we had to translate these percentages into patient numbers, a procedure which is only approximate (our efforts to get absolute numbers for all necessary outcome variables by contacting the investigators were unsuccessful). In the EC/IC bypass study, only 78% of all randomised patients had a brain CT. In Part 1b, haemodynamic compromise was determined by measuring quantitatively cerebral blood flow using PET, SPECT and the Xenon inhalation method in the JET study.

For Part 2a, we identified 19 non‐randomised trials (900 patients), which reported at least one primary outcome variable. Part 2b included three studies, involving 65 patients. The methods of measuring haemodynamic compromise as a selection criteria for EC/IC bypass varied widely: PET study (Ishikawa 1992), acetazolamide test (Karnik 1992) and Xenon/CT cerebral blood flow measurements (Yonas 1996).

Risk of bias in included studies

See 'Characteristics of included studies' section.

Quality assessment of trials

We obtained details regarding blinding, randomisation (generation and concealment of randomisation sequence) and number of randomised patients, as well as the number of drop‐outs, withdrawals, cross‐over treatments and those lost to follow up. If information was missing, we tried to contact the corresponding authors. All three review authors independently performed quality assessment and, if there was disagreement, reached consensus by discussion.

Effects of interventions

Part 1a

Primary outcomes
Death from all causes

We obtained data from two included trials for 1691 participants. The EC/IC bypass study had a trend towards fewer fatal outcome events in the group who had EC/IC bypass surgery than in the control group (EC/IC Bypass Study 1985). In the JET study, death from all causes as an outcome event was uncommon and similar in the EC/IC bypass group (two events) to the group with best medical treatment only (one event) (JET 2006). Across both studies we observed no significant difference between treatment and control groups regarding death from all causes (OR 0.81, 95% CI 0.62 to 1.05, P = 0.11) (Analysis 1.1). 

1.1. Analysis.

1.1

Comparison 1 EC/IC bypass versus best medical treatment: RCTs only, Outcome 1 Death from all causes.

Any stroke during follow up

Analysis of 'any stroke during follow up' was based on two trials of 1691 participants. The OR of 0.99 (95% CI 0.79 to 1.23, P = 0.91) indicated neither harm nor benefit of EC/IC bypass for any stroke during follow up (Analysis 1.2). 

1.2. Analysis.

1.2

Comparison 1 EC/IC bypass versus best medical treatment: RCTs only, Outcome 2 Any stroke during follow up.

Death or dependency

Only the EC/IC bypass study reported on death or dependency (1377 participants). We observed no significant difference between treatment and control groups for 'death or dependency' (OR 0.94, 95% CI 0.74 to 1.21) (Analysis 1.3).

1.3. Analysis.

1.3

Comparison 1 EC/IC bypass versus best medical treatment: RCTs only, Outcome 3 Death or dependency.

Secondary outcomes
Vascular death

One trial (EC/IC Bypass Study 1985) reported data enabling us to analyse vascular death at the end of the follow‐up period (1377 participants). Data analysis revealed no significant difference between patients who underwent EC/IC bypass surgery and the control group regarding vascular death (OR 0.96, 95% CI 0.71 to 1.29, P = 0.77) (Analysis 1.4). 

1.4. Analysis.

1.4

Comparison 1 EC/IC bypass versus best medical treatment: RCTs only, Outcome 4 Vascular death.

Stroke, serious vascular events or vascular death

Both RCTs provided data enabling the analysis of this composite endpoint at the end of the follow‐up period (1573 participants). Across both studies, the OR of 0.68 (95% CI 0.51 to 0.91) indicated a statistically significant beneficial effect in favour of surgery in reducing events at the end of the follow‐up period (P = 0.009) (Analysis 1.5).

1.5. Analysis.

1.5

Comparison 1 EC/IC bypass versus best medical treatment: RCTs only, Outcome 5 Stroke, serious vascular events or vascular death.

Myocardial infarction

Both RCTs reported myocardial infarction (1522 patients). No significant difference between the treatment groups was shown (OR 0.78, 95% CI 0.46 to 1.32, P = 0.35) (Analysis 1.6).

1.6. Analysis.

1.6

Comparison 1 EC/IC bypass versus best medical treatment: RCTs only, Outcome 6 Myocardial infarction.

Ischaemic stroke

Both RCTs reported ischaemic stroke at the end of the follow‐up period (1573 participants). No statistically significant difference between the surgical group and the group with best medical treatment was shown (OR 0.69, 95% CI 0.44 to 1.08) (Analysis 1.7).

1.7. Analysis.

1.7

Comparison 1 EC/IC bypass versus best medical treatment: RCTs only, Outcome 7 Ischaemic stroke.

Intracranial haemorrhage

Neither RCT reported on the occurrence of intracranial haemorrhage after EC/IC bypass surgery.

Major extracranial haemorrhage

Neither RCT collected data about major extracranial haemorrhage.

Local haemorrhage requiring surgery

Neither trial reported any data for this outcome event.

Transient ischaemic attack or amaurosis fugax

Neither trial reported on the occurrence of transient ischaemic attack or amaurosis fugax after EC/IC bypass surgery or best medical treatment alone.

Normalisation of cerebral haemodynamics

Normalisation of cerebral haemodynamics was not measured in either trial.

Non‐stroke complication of surgery

No data about non‐stroke complication of surgery are available.

Part 1b

Only the JET study randomised patients exclusively with haemodynamic compromise for EC/IC bypass surgery (JET 2006), thus it was not possible for us to conduct a meaningful meta‐analysis.

Part 2a

Primary outcomes
Death from all causes

We obtained data from 19 trials (900 participants). Only 11 studies reported on such events. Data analysis indicated neither benefit nor harm of EC/IC bypass surgery (OR 1.00, 95% CI 0.62 to 1.62) (Analysis 2.1).

2.1. Analysis.

2.1

Comparison 2 EC/IC bypass versus best medical treatment: all studies, Outcome 1 Death from all causes.

Any stroke during follow up

Analysis of 'any stroke during follow up' was based on 18 trials (881 participants). We did not observe any significant difference between the treatment and control groups regarding stroke (OR 0.80, 95% CI 0.54 to 1.18) (Analysis 2.2).

2.2. Analysis.

2.2

Comparison 2 EC/IC bypass versus best medical treatment: all studies, Outcome 2 Any stroke during follow up.

Death or dependency

Eight trials reported on death or dependency (346 participants). We did not observe any significant difference between the treatment and control groups regarding death or dependency (OR 0.80, 95% CI 0.50 to 1.29) (Analysis 2.3).

2.3. Analysis.

2.3

Comparison 2 EC/IC bypass versus best medical treatment: all studies, Outcome 3 Death or dependency.

Secondary outcomes
Vascular death

Analysis of 'vascular death' was based on 19 trials (900 participants) and indicated no significant benefit of EC/IC bypass surgery compared with the group undergoing best medical treatment only (OR 0.95, 95% CI 0.56 to 1.63) (Analysis 2.4).

2.4. Analysis.

2.4

Comparison 2 EC/IC bypass versus best medical treatment: all studies, Outcome 4 Vascular death.

Stroke, serious vascular events or vascular death

Thirteen trials provided data enabling the analysis of this composite endpoint at the end of the follow‐up period (673 participants). Across all studies a trend was indicated in favour of EC/IC bypass surgery (OR 0.69, 95% CI 0.45 to 1.04) (Analysis 2.5).

2.5. Analysis.

2.5

Comparison 2 EC/IC bypass versus best medical treatment: all studies, Outcome 5 Stroke, serious vascular events or vascular death.

Myocardial infarction

Two studies reported on myocardial infarction (79 participants). No statistically significant difference between both treatment groups was shown (OR 2.67, 95% CI 0.41 to 17.60). Furthermore, due to the small number of events (N = 3), meaningful interpretation was not possible (Analysis 2.6).

2.6. Analysis.

2.6

Comparison 2 EC/IC bypass versus best medical treatment: all studies, Outcome 6 Myocardial infarction.

Ischaemic stroke

Thirteen trials reported ischaemic stroke at the end of the follow‐up period (640 participants). The OR was 0.72 in favour of EC/IC bypass surgery, but the 95% CI of 0.44 to 1.18 indicated no statistical significance (Analysis 2.7).

2.7. Analysis.

2.7

Comparison 2 EC/IC bypass versus best medical treatment: all studies, Outcome 7 Ischaemic stroke.

Intracranial haemorrhage

Data on this outcome event were sparse; only four trials provided data (361 participants). There was no statistically significant difference between the treated and the control group (OR 1.14, 95% CI 0.44 to 2.93) (Analysis 2.8).

2.8. Analysis.

2.8

Comparison 2 EC/IC bypass versus best medical treatment: all studies, Outcome 8 Intracranial haemorrhage.

Major extracranial haemorrhage

No trials reported data for this outcome.

Local haemorrhage requiring surgery

No trials contained data for this outcome event.

Transient ischaemic attack or amaurosis fugax

For the outcome 'transient ischaemic attack or amaurosis fugax' at the end of the follow‐up period, we obtained data from 11 trials (524 participants). Across trials a statistically significant beneficial effect in favour of EC/IC bypass surgery in reducing transient ischaemic attack or amaurosis fugax was indicated (OR 0.34, 95% CI 0.16 to 0.69, P = 0.003) (Analysis 2.9).

2.9. Analysis.

2.9

Comparison 2 EC/IC bypass versus best medical treatment: all studies, Outcome 9 Transient ischaemic attack or amaurosis fugax.

Normalisation of cerebral haemodynamics

Analysis was based on three trials (56 participants) showing a lack of normalisation of cerebral haemodynamics after EC/IC bypass surgery (OR 6.63, 95% CI 1.85 to 23.78) (Analysis 2.10).

2.10. Analysis.

2.10

Comparison 2 EC/IC bypass versus best medical treatment: all studies, Outcome 10 Normalisation of cerebral haemodynamics.

Non‐stroke complication of surgery

No data were available for this outcome.

Part 2b

Three studies formed a subgroup of patients with haemodynamic compromise as a selection criterion for EC/IC bypass surgery. We only found data for the endpoints 'death from all causes' and 'any stroke during follow up' (Analysis 3.1; Analysis 3.2). No statistically significant difference between treatment groups was shown for these endpoints.

3.1. Analysis.

3.1

Comparison 3 Haemodynamic compromise as selection criterion for EC/IC bypass, Outcome 1 Any stroke during follow up.

3.2. Analysis.

3.2

Comparison 3 Haemodynamic compromise as selection criterion for EC/IC bypass, Outcome 2 Death from all causes.

Discussion

We identified 21 trials (including two RCTs) involving 2591 patients. For all primary endpoints, neither benefit nor harm from EC/IC bypass surgery could be shown either in the RCTs ('any death': OR 0.81, 95% CI 0.62 to 1.05, P = 0.11; 'stroke': OR 0.99, 95% CI 0.79 to 1.23, P = 0.91; 'death and dependency': OR 0.94, 95% CI 0.74 to 1.21, P = 0.64), or in the non‐RCTs ('any death': OR 1.00, 95% CI 0.62 to 1.62, P = 0.99; 'stroke': OR 0.80, 95% CI 0.54 to 1.18, P = 0.25; 'death and dependency': OR 0.80, 95% CI 0.50 to 1.29, P = 0.37). One possible explanation for these neutral results was the inclusion in most studies of patients with occlusion of the carotid artery irrespective of their cerebral haemodynamics. No stratification was done to separate patients with embolic stroke but sufficient intracranial haemodynamics from those with ongoing haemodynamic compromise. After the data analysis of studies selecting patients for EC/IC bypass without measurement of haemodynamic compromise, it still remained unclear whether EC/IC bypass was beneficial or not for some patients with substantial haemodynamic compromise due to occlusion of the carotid artery (Ausman 1986; Day 1986; Sundt 1987; Vorstrup 1992). In order to address this question, we carried out a sub‐analysis of the randomised controlled trials (RCTs) (Part 1b) and of the non‐RCTs (Part 2b). For the RCTs, only the JET study had randomised patients with haemodynamic compromise for EC/IC bypass surgery (JET 2006). However, this study did not compare surgically treated patients showing haemodynamic compromise with those with normal or almost normal haemodynamics. Of the non‐RCTs, only three studies qualified for Part 2b. However, there were very few endpoints, preventing meaningful analysis. In summary, neither the RCTs nor the non‐RCTs showed a benefit of EC/IC bypass, probably because haemodynamic compromise was not taken into account in most cases.

The findings about normalisation of impaired haemodynamics across the non‐RCTs confirms that EC/IC bypass is effective in restoring normal haemodynamics (Yonas 1996). However, whether this surrogate marker translates into a clinical benefit is unproven. The fact that the JET trial (JET 2006) failed to show a clinical benefit for the primary outcomes ('death from all causes' or 'any stroke') prompts scepticism as to whether the criteria 'impaired haemodynamics' is clinically important enough to predict a potentially beneficial effect of EC/IC bypass surgery. In addition, the best method of determining the presence or absence of impaired haemodynamics remains to be established and the variability between methods used to determine haemodynamic compromise has yet to be defined. The ongoing COSS trial, which uses a more sophisticated measure of impaired haemodynamics, may give clearer answers (COSS).

As a limitation, only two RCTs (EC/IC Bypass Study 1985; JET 2006) have been identified for this meta‐analysis. Furthermore, the inclusion criteria of both RCTs differ, thus a meta‐analysis across both studies could produce misleading conclusions. Potential benefit or harm cannot be excluded definitively. For the non‐RCTs, the most important limitation is the non‐randomised treatment allocation, which involves a high risk of bias. In addition, the majority of studies available for this meta‐analysis were single group reports of small numbers of participants without sub‐stratification by haemodynamic compromise. In the studies reported, only 255 of 2591 patients (9.8%) had pre‐operative assessments of cerebral haemodynamics, while 2336 of 2591 patients (90.2%) did not. Even fewer data were available comparing pre and post‐operative measurements with clinical outcome parameters. Overall the quality of most studies was poor.

Authors' conclusions

Implications for practice.

EC/IC‐bypass surgery in patients with a symptomatic carotid artery occlusive disease was neither superior nor inferior to medical care alone. Thus, the role of EC/IC bypass surgery in symptomatic carotid disease remains undetermined. However, most studies included patients irrespective of their cerebral haemodynamics. Patients currently being submitted for EC/IC bypass procedures need protocol‐driven assessment delivered by multi‐disciplinary teams. Participation in an ongoing randomised controlled trial (RCT), which is restricted to patients with impaired haemodynamics, is recommended as these patients might benefit from bypass surgery.

Implications for research.

The optimum bypass has yet to be determined and whether a branch of the superficial temporal artery is sufficient in all cases to reverse the degree of measured haemodynamic compromise and provide a measurable clinical benefit is unknown. In addition, establishing a reliable, widely accessible and cost‐effective method of assessing impaired cerebral haemodynamics is of paramount importance.

The data suggest the necessity of a multicentre, prospective RCT comparing EC/IC bypass with the best medical treatment in a selected subgroup of patients at high risk of stroke and with identified haemodynamic compromise. One such study is still ongoing; it remains to be seen whether measuring haemodynamic compromise will help to determine whether patients with symptomatic carotid artery occlusive disease benefit from EC/IC bypass surgery. Establishing the safety, efficacy and benefit of surgical bypass can only be established by the future use of multicentre RCTs.

History

Protocol first published: Issue 2, 2006
 Review first published: Issue 2, 2010

Date Event Description
22 September 2008 Amended Converted to new review format.

Acknowledgements

We wish to thank Hazel Fraser and Brenda Thomas for searching and providing us with lists of the relevant trials from the Cochrane Stroke Group Trials Register. We thank Graeme Hankey, Kameshwar Prasad, Brenda Thomas and David Porter for their helpful comments on an earlier version of this manuscript.

Appendices

Appendix 1. MEDLINE search strategy

The following search strategy was used for MEDLINE (Ovid) and was modified for the other databases.

1. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or exp brain ischemia/ or carotid artery diseases/ or carotid artery thrombosis/ or carotid stenosis/ or cerebrovascular accident/ or exp brain infarction/ or exp hypoxia‐ischemia, brain/ or exp intracranial arterial diseases/ or cerebral arterial diseases/ or exp "intracranial embolism and thrombosis"/ or vasospasm, intracranial/ 
 2. (stroke$ or cva).tw. 
 3. ((cerebr$ or brain$ or carotid or cerebellar or intracranial or vertebrobasilar or MCA) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or occlud$ or arteriosclero$ or stenosis or steno‐occlus$ or obstruct$)).tw. 
 4. transient isch$.tw. 
 5. 1 or 2 or 3 or 4 
 6. cerebral revascularization/ 
 7. exp cerebral arteries/su 
 8. arterial occlusive diseases/su 
 9. *vascular surgical procedures/ 
 10. *anastomosis, surgical/ 
 11. (extra?cranial adj5 intra?cranial).tw. 
 12. ((cerebral or brain or arterial or surgical or microsurgical) adj5 (anastomosis or revascular$ or bypass or graft)).tw. 
 13. (temporal artery adj5 middle cerebral artery).tw. 
 14. ((temporal or occipital) adj5 intracranial).tw. 
 15. (EC‐IC or ECIC or EC#IC or extra‐intracranial or STA‐MCA).tw. 
 16. or/6‐15 
 17. 5 and 16 
 18. limit 17 to human

Appendix 2. EMBASE search strategy

The following search strategy was used for EMBASE (Ovid).

1. 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/ 
 2. (stroke$ or cva).tw. 
 3. ((cerebr$ or brain$ or carotid or cerebellar or intracranial or vertebrobasilar or MCA) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or occlud$ or arteriosclero$ or stenosis or steno‐occlus$ or obstruct$)).tw. 
 4. transient isch$.tw. 
 5. brain atherosclerosis/ 
 6. exp carotid artery/ or exp brain artery/ 
 7. artery occlusion/ or exp thromboembolism/ 
 8. 6 and 7 
 9. 1 or 2 or 3 or 4 or 5 or 8 
 10. cerebrovascular surgery/ or brain artery bypass/ or extraintracranial anastomosis/ 
 11. artery anastomosis/ or artery bypass/ 
 12. *bypass surgery/ or *artery graft/ or *revascularization/ 
 13. *superficial temporal artery/ 
 14. (extra?cranial adj5 intra?cranial).tw. 
 15. ((cerebral or brain or arterial or surgical or microsurgical) adj5 (anastomosis or revascular$ or bypass or graft)).tw. 
 16. (temporal artery adj5 middle cerebral artery).tw. 
 17. ((temporal or occipital) adj5 intracranial).tw. 
 18. (EC‐IC or ECIC or EC#IC or extra‐intracranial or STA‐MCA).tw. 
 19. or/10‐18 
 20. 9 and 19 
 21. limit 20 to human

Data and analyses

Comparison 1. EC/IC bypass versus best medical treatment: RCTs only.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Death from all causes 2 1691 Odds Ratio (M‐H, Fixed, 95% CI) 0.81 [0.62, 1.05]
2 Any stroke during follow up 2 1691 Odds Ratio (M‐H, Fixed, 95% CI) 0.99 [0.79, 1.23]
3 Death or dependency 1 1377 Odds Ratio (M‐H, Fixed, 95% CI) 0.94 [0.74, 1.21]
4 Vascular death 1 1377 Odds Ratio (M‐H, Fixed, 95% CI) 0.96 [0.71, 1.29]
5 Stroke, serious vascular events or vascular death 2 1573 Odds Ratio (M‐H, Fixed, 95% CI) 0.68 [0.51, 0.91]
6 Myocardial infarction 2 1522 Odds Ratio (M‐H, Fixed, 95% CI) 0.78 [0.46, 1.32]
7 Ischaemic stroke 2 1573 Odds Ratio (M‐H, Fixed, 95% CI) 0.69 [0.44, 1.08]

Comparison 2. EC/IC bypass versus best medical treatment: all studies.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Death from all causes 19 900 Odds Ratio (M‐H, Fixed, 95% CI) 1.00 [0.62, 1.62]
2 Any stroke during follow up 18 881 Odds Ratio (M‐H, Fixed, 95% CI) 0.80 [0.54, 1.18]
3 Death or dependency 8 346 Odds Ratio (M‐H, Fixed, 95% CI) 0.80 [0.50, 1.29]
4 Vascular death 19 900 Odds Ratio (M‐H, Fixed, 95% CI) 0.95 [0.56, 1.63]
5 Stroke, serious vascular events or vascular death 13 673 Odds Ratio (M‐H, Fixed, 95% CI) 0.69 [0.45, 1.04]
6 Myocardial infarction 2 79 Odds Ratio (M‐H, Fixed, 95% CI) 2.67 [0.41, 17.60]
7 Ischaemic stroke 13 640 Odds Ratio (M‐H, Fixed, 95% CI) 0.72 [0.44, 1.18]
8 Intracranial haemorrhage 4 361 Odds Ratio (M‐H, Fixed, 95% CI) 1.14 [0.44, 2.93]
9 Transient ischaemic attack or amaurosis fugax 11 524 Odds Ratio (M‐H, Fixed, 95% CI) 0.34 [0.16, 0.69]
10 Normalisation of cerebral haemodynamics 3 56 Odds Ratio (M‐H, Fixed, 95% CI) 6.63 [1.85, 23.78]

Comparison 3. Haemodynamic compromise as selection criterion for EC/IC bypass.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Any stroke during follow up 3 65 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.13 [0.01, 2.52]
2 Death from all causes 3 65 Peto Odds Ratio (Peto, Fixed, 95% CI) 9.49 [0.18, 489.97]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Auer 1980.

Methods Non‐random
Participants 38
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up, death or dependency
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Benvenuti 1984.

Methods Non‐random, retrospective
Participants 257
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

de Weerd 1989.

Methods Non‐random
Participants 34
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

EC/IC Bypass Study 1985.

Methods RCT
Participants 1377
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up, death or dependency
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Hartmann 1987.

Methods Non‐random, retrospective
Participants 41
Interventions EC/IC bypass
Outcomes Increased mean rCBF after EC/IC bypass
Notes Main focus: CBF measurement
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Heilbrun 1982.

Methods Non‐random
Participants 49
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Ishikawa 1992.

Methods Non‐random
Participants 63
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Jeffree 2009.

Methods Non‐random
Participants 23
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up, death or dependency
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

JET 2006.

Methods RCT
Participants 206, report on 196, 1 excluded due to protocol violation
Interventions EC/IC bypass
Outcomes Death from all causes, re‐stroke with disability
Notes Randomisation procedure not described in detail
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Jordan 1984.

Methods Non‐random
Participants 34
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Karnik 1992.

Methods Non‐random
Participants 104: 14 underwent EC/IC bypass, 14 received best medical treatment 
 Blood flow velocity measurement was assessed in 6 patients with EC/IC bypass surgery and in 4 controls
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up, improvement of vasomotor reactivity in patients with EC/IC bypass after acetazolamide application
Notes Randomisation procedure not described in detail
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Kobayashi 1991.

Methods Non‐random
Participants 11
Interventions EC/IC bypass
Outcomes Any stroke during follow up, death or dependency
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Ma 2007.

Methods Non‐random
Participants 11
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up, death or dependency
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Powers 1989.

Methods Non‐random
Participants 52
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Satiani 1985.

Methods Non‐random
Participants 42
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Tanahashi 1985.

Methods Non‐random
Participants 60
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up, death or dependency
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Thomas 1984.

Methods Non‐random
Participants 11
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up, improvement of CBF after EC/IC bypass
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Unclear risk D ‐ Not used

Yasui 1991.

Methods Non‐random, retrospective
Participants 55
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up, death or dependency
Notes Only patients with viable brain tissue
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Unclear risk D ‐ Not used

Yonas 1996.

Methods Non‐random, retrospective
Participants 46
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Unclear risk D ‐ Not used

Yoshimoto 1995.

Methods Non‐random, retrospective
Participants 70
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up, death or dependency
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

Yoshinaga 1996.

Methods Non‐random
Participants 19
Interventions EC/IC bypass
Outcomes Death from all causes, any stroke during follow up
Notes
Risk of bias
Bias Authors' judgement Support for judgement
Allocation concealment? Low risk A ‐ Adequate

CBF: cerebral blood flow 
 EC/IC bypass: extracranial to intracranial bypass 
 rCBF: regional cerebral blood flow 
 RCT: randomised controlled trial

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Binder 1982 The study compared neuropsychological function between patients with EC/IC bypass and patients with aspirin and dipyridamole treatment, while data about primary and secondary outcome events defined for this review were not given
Danaila 1984 In this study, the authors present a mixture of Moyamoya disease, fibromuscular and atherosclerotic steno‐occlusive ICA and MCA disease
Fields 1976 The surgical group had only thrombendarterectomy of occluded carotid artery rather than EC/IC bypass, and were compared with patients receiving only best medical treatment
Lenzi 1988 Patients who underwent EC/IC bypass procedure were not compared with a control group receiving best medical treatment
McCormick 1991 No comparison of surgically‐treated patients with a medically‐treated group
Meyer 1982 Patients with Moyamoya disease are mixed with atherosclerotic ICA occlusion
Sunada 1989 EC/IC bypass patients were compared with normal volunteers
Wu 1986 Patients with Moyamoya disease are mixed with atherosclerotic ICA occlusion

EC/IC bypass: extracranial to intracranial bypass 
 ICA: internal carotid artery 
 MCA: middle cerebral artery

Characteristics of ongoing studies [ordered by study ID]

COSS.

Trial name or title Carotid Occlusion Surgery Study
Methods
Participants Patients with atherosclerotic occlusion of one or both carotid arteries, with hemispheric TIA or mild‐to‐moderate stroke (Barthel Index > 60) in the territory of an occluded carotid artery within 120 days and with increased OEF measured by PET ipsilateral to the symptomatic carotid artery occlusion
Interventions EC/IC bypass
Outcomes All strokes in patients with symptomatic carotid occlusion and high OEF
Starting date February 2000
Contact information http://www.cosstrial.org/coss/contact.asp
Notes

EC/IC bypass: extracranial to intracranial bypass 
 OEF: oxygen extraction fraction 
 PET: positron emission tomography 
 TIA: transient ischaemic attack

Differences between protocol and review

None.

Contributions of authors

Felix Fluri: developing the protocol, writing the protocol, extracting data, drafting the review. 
 Stefan Engelter: developing the protocol, extracting data, revising the review draft. 
 Philippe Lyrer: developing the protocol, writing the protocol, fundraising, revising the review draft.

Sources of support

Internal sources

  • Scientific Fund of the Stroke Programme, Neurology Department, University Hospital, Basel, Switzerland.

External sources

  • No sources of support supplied

Declarations of interest

The authors received an in‐house grant from the Department of Neurology, University Hospital Basel, to perform the review.

New

References

References to studies included in this review

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