Cover of Evidence review for thrombectomy

Evidence review for thrombectomy

Stroke and transient ischaemic attack in over 16s: diagnosis and initial management

Evidence review D

NICE Guideline, No. 128

Authors

.

London: National Institute for Health and Care Excellence (NICE); .
ISBN-13: 978-1-4731-3386-0
Copyright © NICE 2019.

1. Endovascular therapy

1.1. Review question: What is the clinical and cost effectiveness of endovascular therapy (EVT) with or without intravenous thrombolysis versus intravenous thrombolysis to improve outcomes?

1.2. Introduction

Ischaemic stroke secondary to occlusion of a proximal intracerebral artery is a major and rising source of morbidity and mortality in the UK. Intravenous thrombolytic therapy has formed the mainstay of acute treatment over the last twenty years but increasingly there has been interest in alternative means of vessel recanalisation using neurointerventional endovascular techniques in order to achieve more effective brain reperfusion in an attempt to minimise the damage caused by an occluded artery. Initial evidence provided by randomised trials published in 2013 suggested that endovascular therapy offered no conclusive benefit to patients over standard medical therapy but these trials were criticised for speed of recruitment, use of out-dated technology and mode of patient selection. Since 2015 there have been numerous publications describing a large number of multi-centre randomised controlled trials that have investigated the use of more contemporary neurointerventional techniques. We aim to assess this evidence for the use of endovascular thrombectomy in acute stroke patients suffering a proximal intracerebral arterial occlusion.

1.3. PICO table

For full details see the review protocol in appendix A.

Table 1. PICO characteristics of review question.

Table 1

PICO characteristics of review question.

1.4. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual.23 Methods specific to this review question are described in the review protocol in appendix A.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy upto March 2018, and NICE’s 2018 conflicts of interest policy from April 2018.

1.5. Clinical evidence

1.5.1. Included studies

Ten studies detailed in 15 papers were included in the review;6, 7, 15, 17, 21, 28, 30, 37, 42, 51, 66, 71, 76, 90, 91 these are summarised in Table 2 below and compare endovascular therapy (thrombectomy) with or without thrombolysis (alteplase) versus usual care (with or without thrombolysis). All of the RCT evidence found was based on anterior circulation stroke. Evidence from these studies is summarised in the clinical evidence summary below (Table 2). See also the study selection flow chart in appendix C, forest plots in appendix E, study evidence tables in appendix D, GRADE tables in appendix F and excluded studies list in appendix H.

As no RCT study data was found for posterior circulatory stroke, an additional observational study search was carried out for this stratum. No studies met the inclusion criteria.

1.5.1.1. Anterior circulation stroke

All the studies followed the PROBE design (prospective, randomized, open-label, controlled trial with blinded outcome evaluation). It is noted that although this is the highest quality of study design suitable for these trials, subjective outcomes (EQ-5D and mRS) have been downgraded due to lack of blinding of the interventions for the patient or care giver. All the trials were in people aged 18 and over, but this was considered similar enough to our protocol of 16 years and over not to warrant a downgrade in evidence quality. The majority of studies were funded by industry.

Following the results of MR CLEAN15 which showed efficacy of thrombectomy, the majority of other trials stopped recruitment. Some conducted planned interim analysis; others state that they are underpowered.

A pre-planned subgroup analysis based on time to thrombectomy was performed due to heterogeneity. This resolved the inconsistency and so the results are reported according to the pre-specified subgroups based on time to thrombectomy. The DAWN76 trial investigated thrombectomy performed 6 - 24 hours after a stroke and the DEFUSE 3 trial had time to treatment of 6 - 16 hours after symptom onset and has also been included in the 6 - 24 hour subgroup. The REVASCAT51 and ESCAPE42 trials have been reported individually as thrombectomy was performed within 8 and 12 hours respectively. The remaining studies all performed thrombectomy within 6 hours and have been meta-analysed.

1.5.2. Posterior circulation stroke

No RCT or observational data were found for this stratum that met the protocol criteria. It is noted that the BEST60 trial, a multicentre randomised outcome blinded trial on acute ischaemic stroke due to basilar artery occlusion, has a published protocol. The trial was due to have finished in March 2018 but no results have yet been published and therefore this trial is not included in the review. The trial authors were contacted for further information but no response was received.

1.5.3. Excluded studies

1.5.3.1. Anterior circulation stroke

EASI,53 and IMS III1 were excluded as imaging was not conducted as standard prior to inclusion in study (therefore they do not meet the protocol criterion of having a proven large vessel occlusion on non-invasive angiography).

1.5.3.2. Posterior circulation stroke

Observational studies were excluded primarily for being non-comparative, having the wrong interventions or having a mixed stroke population with no separate analysis for the posterior circulation.

See the excluded studies list in appendix H.

1.5.4. Summary of clinical studies included in the evidence review

Table 2. Summary of studies included in the evidence review for anterior circulation stroke.

Table 2

Summary of studies included in the evidence review for anterior circulation stroke.

See appendix D for full evidence tables.

1.5.5. Quality assessment of clinical studies included in the evidence review

1.5.5.1. Anterior circulation stroke
Table 3. Clinical evidence summary: thrombectomy within 6 hours with or without alteplase versus alteplase or standard medical care.

Table 3

Clinical evidence summary: thrombectomy within 6 hours with or without alteplase versus alteplase or standard medical care.

Table 4. Clinical evidence summary: thrombectomy within 8 hours with or without alteplase versus alteplase or standard medical care.

Table 4

Clinical evidence summary: thrombectomy within 8 hours with or without alteplase versus alteplase or standard medical care.

Table 5. Clinical evidence summary: thrombectomy within 12 hours with or without alteplase versus alteplase or standard medical care.

Table 5

Clinical evidence summary: thrombectomy within 12 hours with or without alteplase versus alteplase or standard medical care.

Table 6. Clinical evidence summary: thrombectomy between 6 - 24 hours onset of symptoms versus standard medical care.

Table 6

Clinical evidence summary: thrombectomy between 6 - 24 hours onset of symptoms versus standard medical care.

See appendix F for full GRADE tables.

1.5.5.2. Posterior circulation stroke

No studies were identified.

1.6. Economic evidence

1.6.1. Included studies

Two published health economic studies with the relevant comparison in the population of people presenting within 0-6 hours of onset of ischaemic stroke were included in this review.3861 One of the published economic studies was adapted by the authors for the population of people presenting within 6-24 hours of onset of ischaemic stroke and this health economic study was also included in this review.84 These studies are summarised in the health economic evidence profile below (Table 7) and the health economic evidence table in appendix I.

1.6.2. Excluded studies

Twelve economic studies relating to this review question were identified but were selectively excluded due to the availability of more applicable evidence of a greater methodological quality.2, 10, 16, 29, 46, 50, 104, 113 107 22 88 11 These are listed in appendix H, with reasons for exclusion given.

See also the health economic study selection flow chart in appendix G.

1.6.3. Summary of studies included in the economic evidence review

Table 7. Health economic evidence profile: intravenous tissue-type plasminogen activator and endovascular therapy versus intravenous tissue-type plasminogen activator alone.

Table 7

Health economic evidence profile: intravenous tissue-type plasminogen activator and endovascular therapy versus intravenous tissue-type plasminogen activator alone.

1.6.4. Unit costs

Table 8. UK costs of endovascular therapy, perfusion imaging and intravenous tissue-type plasminogen activator and endovascular therapy.

Table 8

UK costs of endovascular therapy, perfusion imaging and intravenous tissue-type plasminogen activator and endovascular therapy.

Table 9. UK costs of intravenous tissue-type plasminogen activator.

Table 9

UK costs of intravenous tissue-type plasminogen activator.

1.7. Resource costs

The recommendations made in this review that thrombectomy is offered are likely to have a substantial impact on resources for the NHS in England.

Additional costs are likely to be incurred for the following reasons: the population eligible for thrombectomy will be increased; more people with stroke will need to be transferred to centres offering thrombectomy, and additional training will be required. Further work is being carried out to quantify the potential resource impact in this area.

The committee also made a recommendation based on this review (see section Error! R eference source not found.: Error! Reference source not found.) that thrombectomy should be ‘considered’ for people with acute ischaemic stroke last known to be well up to 24 hours previously (including wake up strokes) with confirmed occlusion of the proximal posterior circulation and with potentially salvageable brain tissue. Unlike for stronger recommendations stating that interventions should be adopted, it is not possible to make a judgement about the potential resource impact to the NHS of recommendations regarding interventions that could be used, as uptake is too difficult to predict. However, the committee noted that this is already current best practice.

1.8. Evidence statements

1.8.1. Clinical evidence statements

1.8.1.1. Anterior circulation stroke
  • Six trials in 1334 people were included investigating the use of mechanical thrombectomy with or without thrombolysis, within 6 hours after the onset of symptoms of acute ischaemic stroke, compared to thrombolysis or usual care with follow up at 90 days. Thrombectomy showed a clinical benefit compared to control for functional independence, measured by mRS (increase in those with a score of 0–2; Moderate quality). No clinical difference in mortality, serious adverse events or quality of life was reported (Moderate quality). It is uncertain if there are any differences in symptomatic and non-symptomatic intracerebral haemorrhage outcomes due to low event rates (Low quality).
  • One trial in 206 people receiving thrombectomy within 8 hours, with or without thrombolysis, compared to usual care showed a benefit of thrombectomy for functional independence (Low quality) and for quality of life measured by EQ-5D (Moderate quality). This trial also reported an uncertain impact on mortality rates, symptomatic intra-cranial haemorrhage and recurrent stroke (Low quality).
  • One trial in 316 people receiving thrombectomy, with or without thrombolysis, within 12 hours compared to control, again showed a clinical benefit of thrombectomy for functional independence and mortality (Moderate quality). The study also reported a clinical benefit of thrombectomy for reduced incidence of malignant middle cerebral syndrome compared to control (High quality) and for improved quality of life (EQ-5D visual analogue scale) at 90 days (Moderate quality) and an uncertain impact on symptomatic intracerebral haemorrhage (Low quality).
  • Two studies in 388 people investigated thrombectomy, with or without thrombolysis, after 6 hours, but within 24 hours of symptom onset in acute ischaemic stroke. These studies showed a clinical benefit of thrombectomy for functional outcome and mortality at 90 days follow up (Very Low to Moderate quality) and no clinical difference in symptomatic intracerebral haemorrhage (Low quality). Procedural complications were reported as a harm of thrombectomy (High quality).
1.8.1.2. Posterior circulation stroke

No studies were identified for this stratum.

1.8.2. Health economic evidence statements

  • One cost-utility analysis found that IV t-PA and mechanical thrombectomy was cost effective compared with IV t-PA alone for treating acute ischaemic stroke, within 0-6 hours of stroke onset. (ICER: £7,648 per QALY gained). This analysis was assessed as directly applicable with minor limitations.
  • One cost-utility analysis found that IV t-PA and mechanical thrombectomy was dominant over IV t-PA alone for treating acute ischaemic stroke, within 0-6 hours of stroke onset. This analysis was assessed as directly applicable with minor limitations.
  • One cost-utility analysis found that mechanical thrombectomy following best medical therapy was cost effective compared with medical therapy alone for treating acute ischaemic stroke, 6-24 hours after stroke onset. This analysis was assessed as directly applicable with minor limitations.

1.9. The committee’s discussion of the evidence

1.9.1. Interpreting the evidence

1.9.1.1. The outcomes that matter most

The critical outcomes identified for this review were functional outcome (modified Rankin Scale) and mortality at 90 days and 1 year. The committee considered both outcomes to be vital in decision making. Important outcomes included intracerebral haemorrhage, procedural complications and quality of life (EQ-5D). Patient reported outcome measures were also considered, but no evidence was identified.

1.9.1.2. The quality of the evidence

Ten RCTs detailed in 15 papers were included in the review. The studies included people with large vessel occlusion demonstrated by CT or MRI. All were in the anterior circulation population. No randomised trials were found for the posterior circulation stroke population so observational studies were sought, but none that met the inclusion criteria were identified. The trials were all prospective randomised open blinded end-point (PROBE) trials. This meant that patients and care givers were not blinded to the intervention, but the outcome assessors were. Subjective outcomes (mRS and quality of life) were therefore downgraded for risk of bias. Some outcomes, including symptomatic intracerebral haemorrhage and recurrent stroke, had very few events and therefore had estimates of effect with wide confidence intervals and were downgraded for imprecision.

A subgroup analysis of timing of thrombectomy was performed for all outcomes. The studies were grouped into those performing thrombectomy within 6 hours, up to 8 hours, up to 12 hours and those conducted at any time more than 6 hours and up to 24 hours after the onset of stroke.

The majority of studies were funded by industry, but the committee considered that the evidence should not be downgraded for publication bias and that the study design ensured robustness of evidence. It was noted that following the results of MR CLEAN,15 which showed efficacy of thrombectomy, the majority of other trials stopped recruitment early due to superior efficacy of thrombectomy. Some conducted planned interim analysis; others state that they are underpowered. Although the committee recognised the potential for an overestimation of treatment effect in the trials that were stopped early, evidence was not downgraded because of this.

Evidence ranged from very low to high quality, with the majority of the evidence rated as moderate quality.

Three cost utility analyses from the UK NHS perspective were included in the health economic review and were assessed as directly applicable with minor limitations.

1.9.1.3. Benefits and harms Anterior circulation stroke

The evidence showed a clear clinical benefit for functional outcome (higher functional independence; mRS score of 0–2 and by ordinal shift analysis) compared to usual care, which was IV thrombolysis in the majority of studies, when thrombectomy was performed within 6, 8, or 12 hours. IV thrombolysis was administered in both the thrombectomy and usual care groups in the majority of patients. This benefit was even seen in studies recruiting between 6 and 24 hours of stroke onset, when few patients in either the thrombectomy or usual care group received thrombolyisis as this is outside the licenced time window, with either no clinical difference or a clinical benefit of thrombectomy for mortality. The committee discussed the evidence from the study of thrombectomy within 8 hours, which had a direction of effect suggesting a possible harm of thrombectomy from increased mortality. This was not consistent with the other trials or the mortality outcome at 12 months from the same trial, where the direction of effect favoured thrombectomy. The committee agreed that this small absolute difference from a single trial with imprecision around the estimate was not convincing enough to indicate a true clinical harm of thrombectomy, but may reflect a small increase in intracerebral haemorrhages seen in this trial among those receiving thrombectomy.

The majority of people also received IV alteplase across both arms of the studies, as part of best medical practice. The committee noted that people receiving thrombectomy between 6 and 24 hours after stroke onset were outside of usual eligibility criteria and treatment with alteplase is less likely in this group as it is indicated for use within 4.5 hours of symptom onset. The committee discussed the studies that included people up to 8 and 12 hours after onset, noting that the majority of participants recived IV alteplase, which was likely to reflect the proportion who were included within the licenced time window for IV thrombolysis. As a minority of patients in the studies including those who had thrombectomy 6-24 hours after stroke onset received IV thrombolysis and a benefit of thrombectomy alone was still seen, the committee agreed that, in line with the licencing criteria, those presenting during this later time window should not routinely be offered IV thrombolysis.

There was also specific evidence from a trial that included people with the procedure performed up to 12 hours after stroke onset, that thrombectomy was associated with fewer cases of malignant middle cerebral artery syndrome at 90 days. No evidence was identified for this outcome for thrombectomy performed within other time frames.

The committee discussed the findings for the adverse event symptomatic intracerebral haemorrhage. For thrombectomy plus thrombolysis within 6 hours there was no clinical difference for this outcome. For the later time points there were fewer cases of symptomatic intracerebral haemorrhage in the standard care group; however, the number of events was small and the effect estimates were imprecise. Since this potential harm was not reflected in the primary outcome measures and there was uncertainty in the true effect, the committee did not believe this to be a clinically important difference.

Quality of life (EQ-5D) was reported across several studies and showed either no difference or a benefit of thrombectomy with or without thrombolysis within 6, 8 and 12 hours, compared to control at 90 days. No data were available for this outcome from the 2 studies reporting on thrombectomy performed between 6 and 24 hours after stroke onset.

Some procedural complications associated with thrombectomy were noted, but were considered to be outweighed by the benefits of functional outcome improvement. Other studies reported on serious adverse events and recurrent stroke at 90 days and showed no clear clinical difference between treatment arms.

Overall there is strong evidence for a clinical benefit of thrombectomy, together with intravenous thrombolyisis if within the licenced time window, for improving functional outcome when performed in people last known to be well up to 24 hours previously, with no clinical difference in mortality rates. Therefore, the committee made strong recommendations for thrombectomy up to 24 hours after stroke onset (that is, from when a person was last known to be well) in people with appropriate clinical and radiological characteristics. The committee agreed that it was important to specify that this should be done in people who present with an acute ischaemic stroke syndrome as it is possible to have an occlusion without stroke symptoms and intervention should not currently be attempted in these people. It is also important that the occlusion is confirmed by CTA or MRA if performed within 6 hours and CT perfusion or MRI DWI sequences if performed beyond 6 hours in order to identify a target for reperfusion with thrombectomy.

The committee discussed their experience that the plain CT scan may be assessed using the Alberta Stroke Program Early CT Score (ASPECTS), with a score of more than 6 indicating a good volume of salvageable brain tissue. They noted that in the presence of a low ASPECTS score, imaging with CT perfusion or MRI could be considered within an earlier timeframe. Even within 6 hours of stroke onset it is possible for there to be a malignant core of severe, established ischaemic change that cannot be salvaged as collaterals have already failed; in such cases there is no potential for benefit of intervention and the procedure could cause harm and so would not be indicated. When thrombectomy is undertaken between 6 and 24 hours after stroke onset, potential benefit must be demonstrated by further appropriate imaging with CT or MRI because the evidence of effectiveness from the trials was based on more highly selected populations using CT perfusion and MRI diffusion and perfusion scans and effectiveness in a broader population is likely to be lower. In terms of clinical characteristics, it is important to consider the NIHSS score and overall functional capacity prior to the stroke to determine suitability for this intervention. Most studies used an entry criteria of a pre morbid Rankin (mRS) <2 for thrombectomy. There was a range of NIHSS severity scores across the trials ranging from no NIHSS thresholds to an NIHSS score of 10 or more pre-thrombectomy. Some utilised an ASPECTs score of >6 as an entry criterion. It was the view of the committee that evidence on these clinical parameters will become clearer as experience with thrombectomy increases. The committee agreed that providing additional criteria to take into account when considering thrombectomy would be helpful for those setting up a new service and also a helpful guide for referring centres. Based on the evidence reviewed it was not possible to specify strict threshold criteria for eligibility based on pre-stroke functional status, clinical severity of stroke or the extent of established infarction on initial brain imaging. This is because there was variation in the trial entry criteria used in the studies and the committee agreed that these factors should be considered as part of the clinical judgment on an individual basis. However, it was important to make a recommendation that can be implemented in practice. Therefore, mRS and NIHSS eligibility thresholds have been included consistent with the NHS England Clinical Commissioing Policy: Mechanical thrombectomy for acute ischaemic stroke. No criteria have been set for the extent of established infarction because the ASPECTS score was not included in the commissioning document, nor was it used as an entry criteria in most of the clinical trials.

The committee noted that although the benefit in mRS appeared to increase at later thrombectomy time thresholds, this does not mean that it is better to wait and perform thrombectomy later after stroke onset. This effect could be a consequence of the stricter patient selection criteria used, because the trials including thrombectomy performed later after stroke onset used more advanced imaging. This increased selectivity would have resulted in a population with a greater chance of benefit from the intervention by identifying and including only those with a favourable collateral flow. The larger effect size in the later time thresholds might also be explained by the difference between the people in the control groups. People in the control arm presenting within 4.5 hours of stroke onset are eligible for thrombolysis, whereas beyond this time threshold and up until 24 hours of stroke onset, this treatment option is no longer available to the people in the control group, for whom aspirin may be the only option. The difference in mRS score between the thrombectomy and control Stroke and transient ischaemic attack in over 16s: evidence review D FINAL (May 2019) Endovascular therapy arms for those presenting within 6-24 hours of stroke onset may therefore be greater than the difference for those presenting 0-6 hours of stroke onset. The committee highlighted the need for rapid treatment for all patients with ischaemic stroke and that, when indicated, thrombectomy should be performed as soon as possible after presentation.

Posterior circulation stroke

In the absence of evidence on the effectiveness and safety of thrombectomy compared to thrombolysis or standard care in the posterior circulation stroke population the committee agreed to make a consensus recommendation. They agreed that the prognosis is usually very poor in those with basilar artery occlusion, which accounts for approximately 95% of interventions for proximal posterior artery occlusions, with around an 80% mortality and as few as 2-5% making a full neurological recovery in the absence of recanalisation or reperfusion interventions. The committee agreed that in their experience the prevalent current practice is to consider intravenous thrombolysis and/or mechanical thrombectomy in these people and that good outcomes can be achieved. Diagnosis may be delayed because posterior circulation strokes can present non-focally and/or with a reduced conscious level, and so thrombectomy is often performed later than 6 hours after onset and good outcomes can still be achieved at this time. Stroke onset in this group should therefore be defined as sudden onset of focal neurological symptoms clinically localised to the PCA circulation or a sudden deterioration from initial minor symptoms.

The main potential risk of thrombectomy and thrombolysis in this population relates to outcomes of intervening when there is already established disabling ischaemic brain injury. For example, in basilar artery occlusions if there is irreversible bilateral damage to the pons, even if the basilar artery is opened the person may be left with “locked-in-syndrome” with complete face and body paralysis but clear consciousness. The committee agreed that it is standard practice to perform brain imaging and look for established tissue damage in the brain regions affected by the arterial occlusion, particularly in areas of the brain stem before intervening to avoid increasing the number of patients surviving with severe neurological disability. Imaging with CT perfusion or MR DWI techniques should be performed regardless of how soon after onset a person presents with posterior circulation stroke to demonstrate that there is salvageable brain tissue. Furthermore, even if there may be some salvageable brain tissue it is important to identify whether small but functionally critical areas of the posterior circulation have been damaged, although the committee acknowledge that this can be difficult to identify. A small infarct in specific areas, for example, in areas of the brain supplied by the basilar artery, can have devastating consequences for functional outcomes. The committee noted that MRI may be superior to CT perfusion for assessing critical areas of the brain stem, and that both modalities will sometimes be needed.

The committee also agreed that, as the technique is similar, it would be reasonable to extrapolate the lack of clinically significant harm for mortality and intracerebral haemorrhage seen in anterior circulation stroke evidence. Alongside the potential for benefit in a severely ill population this supports the use of thrombectomy and thrombolysis as soon as possible after presentation when appropriate.

In conclusion, given the poor outlook without intervention, clinical experience of good outcomes being achieved with intervention and supportive evidence from the anterior stroke population, the committee agreed that thrombectomy and thrombolysis should be considered. The population included in the recommendation is people last known well up to 24 hours previously with acute ischaemic stroke and confirmed occlusions of the proximal posterior circulation where potentially salvageable brain tissue has been demonstrated by imaging with MRI or CT techniques. It is also important to consider the initial NIHSS score and overall functional capacity prior to the stroke to determine suitability for this intervention. The committee did not make a research recommendation as they are aware of ongoing research in this area including the BEST trial and the BASICS (Basilar Artery International Cooperation Study) trial. BASICS is currently recruiting participants in Europe. The population is those with CTA or MRA confirmed basilar occlusion and people will be randomised between standard care with additional intra-arterial therapy within 6 hours of onset versus standard care alone.

1.9.2. Cost effectiveness and resource use

The results of a published cost–utility analysis with a UK NHS perspective estimated that thrombectomy alongside intravenous thrombolysis (where appropriate) is cost effective compared with intravenous thrombolysis alone, when performed within six hours of stroke onset. The study estimated the incremental cost effectiveness ratio to be £7,648 per QALY gained with a 100% likelihood of being cost effective at both a £20,000 and £30,000 threshold. A second cost utility analysis with a UK NHS perspective estimated that thrombectomy and intravenous thrombolysis was dominant (more effective and less costly) compared with intravenous thrombolysis alone.

The economic studies considered the cost effectiveness of thrombectomy alongside intravenous thrombolysis (compared with intravenous thrombolysis alone) in a refined population of people presenting within 6 hours of stroke onset, who had already undergone CT angiography or MR angiography (to determine whether they might benefit from thrombectomy) prior to randomisation. While CT/MR angiography is necessary to perform thrombectomy, intravenous thrombolysis can be administered following a CT head with no contrast. The committee noted that the economic analyses did not include the costs of CT/MR angiography, as all people in the trials received imaging. The committee therefore considered the current NHS reference cost of £121 for CT angiography and £202 for MR angiography.

To consider how including the costs of CT/MR angiography might affect the cost effectiveness of mechanical thrombectomy within 0-6 hours of ischaemic stroke onset, the committee noted the results of a threshold analysis which showed that the cost of mechanical thrombectomy would need to increase by 139% to render it borderline cost effective at a cost effectiveness threshold of £20,000 per QALY. The committee was informed by a published modelling study which used data from the Sentinel Stroke National Audit Programmea. The modelling study indicates that 40% of people with CT-confirmed ischaemic stroke (presenting within 12 hours) are found to have an occlusion of a large artery on CT Angiography, and so are potentially eligible for thrombectomy. Therefore, to find one person potentially eligible for thrombectomy, 2.5 CT angiography scans would be required. The committee judged that including the costs of the 2.5 scans needed to find one person potentially eligible for thrombectomy in the intervention arm would be unlikely to change the results of the cost–utility analyses.

The committee was confident that the economic evidence accurately demonstrates that offering thrombectomy alongside intravenous thrombolysis (where not contraindicated) to people with confirmed occlusion of the proximal anterior circulation determined by CT/MR angiography is cost-effective compared with current practice (intravenous thrombolysis alone following a CT head with no contrast) and would therefore be a good use of NHS resources.

The results of a cost utility analysis with a UK NHS perspective demonstrated the cost effectiveness of thrombectomy and best medical therapy compared with best medical therapy alone, when performed between 6-24 hours after stroke onset. The study estimated the incremental cost effectiveness ratio to be £1,227 per QALY gained when thrombectomy was performed between 6-12 hours of stroke onset, £4,103 per QALY gained when performed within 6-16 hours of stroke onset and £2,984 per QALY gained when performed within 6-24 hours of stroke onset.

The population of the trials investigating thrombectomy in people presenting between 6 and 24 hours after stroke onset is refined to those that would benefit from thrombectomy compared with the entire population of people presenting in this later timeframe, as the inclusion criteria of the clinical trials specified that perfusion imaging was performed. The economic study therefore considered the cost effectiveness of thrombectomy, delivered in the later timeframe, in a population of people who had already undergone perfusion imaging.

The committee agreed that it was not current practice to offer perfusion imaging to all those presenting within 6-24 hours of onset of ischaemic stroke and so considered the costs of perfusion imaging in the context of the results of the cost utility analysis. Threshold analyses found that the cost of thrombectomy would need to exceed £35,517 using the efficacy data at 12 hours, £33,185 at 16 hours and £43,140 at 24 hours to be borderline cost effective at a cost effectiveness threshold of £20,000 per QALY gained. The committee estimated that 2-4 perfusion scans would need to be carried out to yield one person eligible for thrombectomyb. Using the results of the threshold analyses and the current unit costs of CT angiography and perfusion, the committee judged that including the costs of four additional scans in the thrombectomy arm would be unlikely to change the results of the cost–utility analysis.

The economic and clinical evidence informed the committee’s decision to make a strong recommendation to offer thrombectomy for people presenting between 6-24 hours of stroke onset, where occlusion of the proximal anterior circulation is confirmed and where potential benefit has been determined by further appropriate imaging with CT or MRI and appropriate clinical radiological mismatch.

No economic or clinical evidence was identified for the use of thrombectomy for posterior circulation stroke. The committee noted that around 5-10% of all strokes are in the posterior circulation. Prognosis is poor in basilar artery occlusion in the absence of reperfusion. The committee chose to make a consensus recommendation that thrombectomy alongside intravenous thrombolysis (where not contraindicated and within the licensed time window) is considered for those last known to be well up to 24 hours previously (including wake up strokes), aligning with current practice. thrombectomy should be considered only for those with salvageable brain tissue demonstrated with MRI or CT techniques. The committee stressed the need to demonstrate salvageable brain tissue in all people presenting up to 24 hours of stroke onset, as damage to functionally important areas of the brain could have a significant impact on functional outcomes. The committee thought that this would mitigate the risk of locked-in syndrome or other poor outcomes in this population.

The committee was aware of the significant change to current practice and the substantial resource impact which will arise from these recommendations. In current practice, around 10% of people presenting with stroke in the UK are eligible for thrombectomy. This population will likely increase as a result of these recommendations. The prevalence of thrombectomy is increasing; it is currently performed in most of the neuroscience centres in England. In addition, most neurointervention centres currently operate on a 9:00-17:00 basis. To implement these recommendations, radiographers and staff at neurointervention centres will be required 24 hours per day. The committee also discussed the possibility that the new recommendations could result in a large increase in referrals to centres which deliver thrombectomy services. The committee noted that there are likely to be additional costs incurred in transferring people to centres where thrombectomy is available. The new recommendations are therefore expected to result in a significant change from current practice, which is likely to have a substantial resource impact on the NHS. However, the committee were highly confident that increasing the provision of thrombectomy will be a cost effective use resources, due to the downstream cost savings it will produce such as decreased demand for rehabilitation, long term care and decompressive hemicraniectomies.

In conclusion, the committee agreed the cost effectiveness evidence accurately demonstrates that offering thrombectomy with best medical therapy beyond six hours of stroke and up to 24 hours after stroke onset as well as thrombectomy with intravenous thrombolysis within six hours of stroke onset would be an efficient use of NHS resources. No health economic evidence was identified for the cost effectiveness of thrombectomy for posterior circulation ischaemic stroke and a consensus recommendation to consider thrombectomy was made. The committee was aware of the significant up-front investment that will be required for the implementation of these recommendations.

1.9.3. Other factors the committee took into account

The committee discussed age as an equality consideration and noted that three studies had inclusion criteria of up to 80 years of age, one at up to 85 and one of up to 90 years, the remaining studies included all those aged over 18 years old. The group considered that the evidence was applicable to the population of those aged 16 years and over with no separate recommendations for any age group and no upper age limit. It was also noted that the included studies allowed clinical judgement about the use of general anaesthetic when performing thrombectomy.

Current practice is for IV thrombolysis administered as soon as ischaemic stroke is diagnosed, if the patient is within 4.5 hours of onset of symptoms and has no contraindications. Thrombectomy should then be undertaken if appropriate, checking as the procedure is about to start whether the thrombolysis has already achieved recovery and the thrombectomy is no longer required. Access to thrombectomy services varies across the country; rapid access remains a logistical challenge with different pathway models under evaluation. The committee discussed that few centres offer a 24-hour service and that most operate within 9 to 5 working hours Monday to Friday. It was also noted that staff at district general hospitals will always contact a stroke or neurointerventional specialist before deciding to transfer the patient for thrombectomy. The receiving centres will decide whether or not there would be a benefit of thrombectomy based on imaging evidence and the clinical scenario. Detailed consideration of detection of salvageable tissue was considered to be beyond the scope of this guideline. The optimal neuroimaging pathways should be determined by individual clinical networks based on local expertise and resources.

The committee discussed implementation of this recommendation and that this would increase the numbers of people undergoing thrombectomy, particularly those with stroke onset more than 6 hours prior to possible intervention. This may require more specialist centres or increased transport to areas where this procedure can be performed, and may present challenges for implementation, including access to imaging (in particular CT angiography) to select those who can benefit from treatment. A practical approach to implementation may be for District General Hospitals to perform further imaging and for reporting to be done by the specialist centre. Also, the CTA should be performed immediately after the plain CT once haemorrhage is excluded to avoid a second visit to the CT scanner. Regarding CT perfusion, the committee discussed that this is not currently performed in all areas but that most CT scanners can accommodate this technique with an appropriate software package. The only additional requirement would be a second injection after the CTA.

The committee noted the risk that if further imaging with CT or MRI is not available, people who would be eligible may not receive thrombectomy. They also noted that with CT perfusion, blood volume maps may be useful to predict infarction and in DWI MRI, lesions with low apparent diffusion coefficient (ADC) values predict early infarction.

The current model is to access local stroke centre for diagnosis and intravenous thrombolysis and transfer to a specialist thrombectomy centre. Service models include ‘mother ship’ model where all cases are triaged to a very large stroke centre with centralisation, which may be better for urban areas; and the ‘drip and ship’ models where the IV thrombolysis is started in the spoke hospital pending transfer to the larger centre (hub). Optimal networked arrangements will depend on the geography of region.

NICE have published other guidance which is relevant to this review:

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Appendices

Appendix B. Literature search strategies

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual 2014, updated 2017 https://www.nice.org.uk/guidance/pmg20/resources/developing-nice-guidelines-the-manual-pdf-72286708700869

For more detailed information, please see the Methodology Review.

B.1. Clinical search literature search strategy

Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies for interventions as these concepts may not be well described in title, abstract or indexes and therefore difficult to retrieve. Search filters were applied to the search where appropriate.

Table 12. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

Cochrane Library (Wiley) search terms

B.2. Health Economics literature search strategy

Health economic evidence was identified by conducting a broad search relating to the stroke population in NHS Economic Evaluation Database (NHS EED – this ceased to be updated after March 2015) and the Health Technology Assessment database (HTA) with no date restrictions. NHS EED and HTA databases are hosted by the Centre for Research and Dissemination (CRD). Additional searches were run on Medline and Embase for health economics.

Table 13. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

NHS EED and HTA (CRD) search terms

Appendix D. Clinical evidence tables

D.1. Anterior circulation stroke (randomised studies)

Download PDF (444K)

D2. Posterior circulation stroke (observational studies)

No studies were identified

Appendix F. GRADE tables

F.1. Thrombectomy within 6 hours with or without alteplase versus alteplase or standard medical care

Image

Table

93/650 (14.3%)

F.2. Thrombectomy within 8 hours with or without alteplase versus alteplase or standard medical care

Image

Table

19/103 (18.4%)

F.3. Thrombectomy within 12 hours with or without alteplase versus alteplase or standard medical care

Image

Table

17/164 (10.4%)

F.4. Thrombectomy between 6 - 24 hours onset of symptoms versus standard medical care

Image

Table

33/199 (16.6%)

Appendix H. Excluded studies

H.2. Excluded health economic studies

Published health economic studies that met the inclusion criteria (relevant population, comparators, economic study design, published 2002 or later and not from non-OECD country or USA) but that were excluded following appraisal of applicability and methodological quality are listed below. See the health economic protocol for more details.

Table 15. Studies excluded from the health economic review

Appendix I. Health economic evidence tables

Download PDF (242K)

Footnotes

a

McMeekin P, White P, James MA, Price CI, Flynn D, Ford GA. Estimating the number of UK stroke patients eligible for endovascular thrombectomy. 2017; 2(4): 319-326

b

Jadhav AP, Desai, SM, Kenmuir CL, Rocha M, Starr MT, et al. Eligibiilty for endovascular trial enrolment in the 6- to 24-hour time window: analysis of a single comprehensive stroke center. 2018; 49(4): 1015-1017