Evidence review for decompressive hemicraniectomy

National Guideline Centre (UK)

Evidence review for decompressive hemicraniectomy

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

Evidence review H

NICE Guideline, No. 128

Authors

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2019 May.

ISBN-13: 978-1-4731-3386-0

1. Decompressive hemicraniectomy

1.1. Review question: Which patients should be referred for decompressive hemicraniectomy?

1.2. Introduction

In 2-8% of patients with anterior circulation ischaemic stroke (due to occlusion of the internal carotid, middle cerebral artery, anterior cerebral artery, or a combination of these) large-volume brain infarction causes space-occupying brain swelling (“malignant middle cerebral artery syndrome”) which, untreated, has a mortality of about 80%. Hemicraniectomy (neurosurgical removal of part of the skull to reduce intracerebral pressure) is life-saving. The previous NICE guideline CG68 (2008) recommends referring patients under the age of 60 with a severe stroke syndrome, reduced level of consciousness and a CT-defined infarct of at least 50% of the middle cerebral artery territory, for consideration of hemicraniectomy.

There remains uncertainty about the net clinical benefit of hemicraniectomy, especially in people with stroke over the age of 60, because it might increase the number of stroke survivors with serious disability to a greater extent than in younger people. Since the last guideline was published, the DESTINY-II randomised trial has reported the effect of hemicraniectomy in patients over the age of 60 years. This review therefore aimed to establish which patients should be referred for decompressive hemicraniectomy, with a focus on patient age.

1.3. PICO table

For full details see the review protocol in appendix A.

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.⁷ 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.

1.5. Clinical evidence

1.5.1. Included studies

Eight studies were included in the review;⁶^, ¹²^, ¹⁷^, ²¹^, ²²^, ⁴⁰^, ⁴⁶^, ⁵¹ these are summarised in Table 2 and Table 3) below. Evidence from these studies is summarised in the clinical evidence summary below (Table 4).

All the studies are open labelled randomised controlled trials (RCTs), with some having a blinded outcome evaluation (HAMLET¹⁷, HeADDFIRST¹², Zhao⁵¹). It is noted that although open labelled RCTs are the highest quality of study design suitable for these trials, outcomes have been downgraded due to no blinding of patient or care giver and the outcome assessor not being blinded to interventions or the key confounders.

The studies were stratified according to mean or median age, with three being included in the strata for aged over 60 years. The trial by Slezins⁴⁰ was downgraded for indirectness due to the age range being 49 to 81 years and not having subgroup analysis of those aged over 60. This review extracted just the subgroup analysis results of those aged over 60 from the trial by Zhao⁵¹, as the median overall age for the population was over 60.

A Cochrane review⁸ was identified and all the relevant references have been checked and included where appropriate.

See also the study selection flow chart in appendix C, study evidence tables in appendix D, forest plots in appendix E and GRADE tables in appendix H.

1.5.2. Excluded studies

See the excluded studies list in appendix H.

1.5.3. Summary of clinical studies included in the evidence review

Table 2

Summary of studies included in the evidence review for those aged under 60 years.

Table 3

Summary of studies included in the evidence review for those aged over 60 years.

See appendix D for full evidence tables.

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

Table 4

Clinical evidence summary: Decompressive hemicraniectomy compared to medical treatment for those aged under 60 years.

Table 5

Clinical evidence summary: Decompressive hemicraniectomy compared to medical treatment for those over 60 years.

See appendix F for full GRADE tables.

1.6. Economic evidence

1.6.1. Included studies

One health economic study was identified with the relevant comparison and has been included in this review.¹⁸ This is summarised in the health economic evidence profile below (Table 6) and the health economic evidence table in appendix I.

1.6.2. Excluded studies

No health economic studies that were relevant to this question were excluded due to assessment of limited applicability or methodological limitations.

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 6

Health economic evidence profile: surgical decompression versus best medical treatment.

1.6.4. Unit costs

Table 7

UK costs of non-elective long stay decompressive hemicraniectomy.

1.7. Resource costs

The committee has made a recommendation based on this review (see section Error! R eference source not found.) that decompressive hemicraniectomy should be ‘considered’. The recommendation is not expected to have a substantial impact on resources to the NHS in England.

The committee noted that where this recommendation is implemented there would be additional costs relating to the increase in the population eligible for decompressive hemicraniectomy compared to current practice. However, the committee agreed that this would not necessarily lead to significantly more people undergoing surgery compared with current practice; not all people eligible for decompressive hemicraneictomy ultimately go on to have surgery following discussions between carers and physicians. The committee noted that more informed discussion of the outcomes following surgery might reduce the uptake of surgery. In addition, the recommendation on endovascular therapy made elsewhere as part of this guideline update (see evidence review D) will increase the population eligible for and provision of endovascular therapy. This is likely to decrease the population referred for decompressive hemicraniectomy.

1.8. Evidence statements

1.8.1. Clinical evidence statements

1.8.1.1. Aged under 60 years

There was a clinically important benefit of surgery compared to standard care for reduced mortality at 30 days (1 study; n=32; Moderate quality), 6 months (3 studies; n=86; Moderate quality) and 1 year (3 studies; n=134; High quality) and for achieving mRS 0-3 at 6 months (4 studies; n=118; Very Low quality) and 1 year (3 studies; n=134; Low quality).
There was no clinically important difference for the SF-36 mental summary score or VAS but a clinically important harm of surgery for the SF-36 physical summary scale (1 study; n=35; Very Low and Low quality).

1.8.1.2. Aged over 60 years

There was a clinically important benefit of surgery compared to standard care for reduced mortality at 6 months (1 study; n=29; Moderate quality) and 1 year (3 studies; n=162; Moderate quality) and for achieving mRS 0-3 at 1 year (3 studies; n=165; Very Low quality) but the benefit did not reach clinical significance at 6 months (2 studies; n=141; Very Low quality).
Evidence from 1 study in 100 people showed a clinically important benefit of surgery for quality of life at 1 year as measured by the EQ-5D index scale and VAS score (Low quality).

1.8.2. Health economic evidence statements

One cost-utility analysis found that decompressive surgery was not cost effective compared with best medical treatment (ICER: £49,224 per QALY gained). This analysis was assessed as partially applicable with potentially serious 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. Both outcomes were considered to be crucial in decision making. Important outcomes included health and social related quality of life (EQ-5D).

Note that for this review a good functional outcome was defined as a score of 0, 1, 2 or 3 on the mRS because in this population of very severe stroke cases achieving an mRS 3 was agreed to be likely to represent a ‘good’ outcome compared to the expected clinical outcome without surgery.

1.9.1.2. The quality of the evidence

Eight RCTs were included in this review, five being categorised into the under 60 years and three in the over 60 years age category. Trials were categorised according to the age range used for their inclusion criteria, where possible, or using the median age and IQR to determine whether the majority of participants were over or under 60 years of age. Some outcomes were only reported by one trial with few participants for each age category, resulting in imprecise effect estimates. Therefore, the committee were not confident that the outcome reflected the true effect. The trials were all open labelled, which meant patients, care givers and outcome assessors were not blinded to the intervention. Three studies however, had a blinded outcome evaluation. As a result, subjective outcomes (mRS and quality of life) were downgraded for risk of bias. Some results for these outcomes were downgraded further if they showed imprecision through estimates of effect having wide confidence intervals. Additionally one study in the over 60 category was further downgraded for an indirect population.

Evidence ranged from very low to high quality, with the majority of evidence rated as low and moderate quality. The mortality evidence was of high and moderate quality, while the functional outcome data were low and very low quality.

A published cost utility analysis with a Dutch societal perspective was included in the health economic review and was assessed as partially applicable with potentially serious limitations.

1.9.1.3. Benefits and harms

The evidence showed a clear mortality benefit in the short and longer term in those aged both over and under 60 years when decompressive hemicraniectomy is performed compared to medical treatment alone.

Also, there was a clinically important benefit of surgery for functional outcome (defined as mRS score 0-3) at 6 months and 1 year in those aged under 60 years. However, the committee noted that the benefit was questionable because overall functional outcome was poor. When surgery is performed it results in more patients surviving, but many have poor functional outcomes. To some extent, there is a trade off between reduced mortality but at the expense of overall poor functional outcome. This may be acceptable to a significant proportion of patients. In those aged over 60 years this benefit in the number achieving a ‘good’ functional outcome of 0-3 on the mRS scale was not seen at 6 months follow-up, although a modest clinical benefit was reported at 1 year.

Quality of life (EQ-5D and SF-36) data were not widely reported and ranged from showing a clinically important benefit of surgery in 1 study of the over 60s, to a clinically important harm of surgery for the physical component score but no clinical difference for the mental summary score or the overall visual analogue score in 1 study in the under 60s. Hemicraniectomy inevitably leads to more people surviving with disability, whereby survivors may have a low quality of life. The committee noted that judging quality of life is variable, subjective and emotionally charged, and perspectives might differ greatly between patients and carers.

Overall there is good clinical evidence for the benefit of surgery in regards to mortality, with some supporting evidence of improved functional outcomes and variability in the reported impact on quality of life, which was low in both the treated and untreated groups.

The committee noted that although some of the trials in those aged under 60 years included people who had surgery as long as 96 hours after symptom onset, the benefits in terms of reduced mortality and improved functional outcome appeared to be largely driven by studies which only allowed surgery up to a maximum of 48 hours after onset. Therefore, it was agreed that the reference to surgery being performed within 48 hours of onset should be retained from the original recommendations.

The committee also reviewed the criteria used to determine eligibility for hemicraniectomy from CG68. It was agreed that these were still appropriate and reflect the populations included in the studies used to inform the new recommendations.

The decision to have surgery is very individual and some patients may choose not to have surgery if there is a risk of severe disability, whereas others may wish to go ahead based on mortality benefit alone. For this reason the committee chose to leave the recommendation as a ‘consider’ so that it remained an option for management following discussion with suitable patients and their carers. They also recommended discussion about the risks and benefits of surgery. The committee noted that patients would not be able to be involved at the time because of the severity of the stroke, so the family members or carers would be responsible for making the decision. In deciding whether to opt for surgery considerations should include individual wishes and preferences and the pre-stroke functional status, as surgery would not be appropriate for people with severe disability before stroke. The high likelihood of residual moderate or severe disability after surgery should be made clear.

1.9.2. Cost effectiveness and resource use

The results of a published cost utility analysis with a Dutch societal perspective found that decompressive surgery is not cost effective compared with best medical treatment in adults aged 60 or younger with space-occupying hemispheric infarction.¹⁸ The study estimated the lifetime incremental cost effectiveness ratio to be £49,224 per quality adjusted life year gained. At three years, decompressive surgery had a 2% likelihood of being cost effective at an £66,961 (€80,000) per QALY gained willingness to pay threshold. Although this economic evidence did not support decompressive hemicraniectomy the committee was not confident that it was sufficiently robust to make a strong recommendation not to offer decompressive hemicraniectomy, due to its partial applicability and potentially serious limitations.

To aid the committee’s discussion of the economic evidence, the most appropriate UK NHS reference costs corresponding to the unit costs used in the study were combined with the resource usage over three years reported for the within-trial phase of the study. This allowed calculation of a three-year incremental cost for surgical decompression over best medical treatment of £90,886. The study reported an incremental QALY difference of 1.0 QALYs over the three year within-trial period. Using the estimate of UK incremental costs, the three year ICER generated is £90,886 per QALY gained. The lifetime incremental QALY difference reported in the study was 4.2 QALYs. At a £20,000 per QALY gained willingness to pay threshold, the lifetime incremental cost of surgical decompression would need to be <£84,000 to be considered cost effective. As this value is less than the three year incremental cost, this scenario is highly unlikely as there are additional continuing incremental costs after three years. However,the committee expressed concerns about some of the resource usage reported in the study. Zero days in the nursing home were reported in the ‘best medical treatment’ arm, which the committee considered highly unlikely to be representative of this population and therefore of very limited applicability to the UK setting. Higher nursing home resource usage in the ‘best medical treatment’ arm would increase the total cost of ‘best medical treatment’ and reduce the incremental cost difference between ‘best medical treatment’ and ‘decompressive hemicraniectomy’. This would result in a lower incremental cost effectiveness ratio. Although there still remains uncertainty regarding the cost effectiveness of decompressive hemicraniectomy, undertaking a de novo analysis from a UK perspective was not considered likely to reduce this uncertainty, as the resource use reported in the identified study still remains the only published resource use data, therefore a new model would be based on tenuous assumptions.

In addition, the committee noted that in the under 60 population, the only quality of life data available were from the HAMLET trial, on which the Dutch societal cost utility analysis was based. For the outcome ‘functional outcome score 0-3 mRS at 1 year’, the HAMLET trial has a much smaller effect size than in the DESTINY and DECIMAL trials, which show a trend towards benefit of decompressive hemicraniectomy. Quality of life reported by the HAMLET trial might therefore be expected to be lower than in the other trials. If quality of life data were available from all the trials, the ICER might be improved. Overall, the clinical evidence identified a modest improvement in functional outcome which the committee deemed was clinically important. Despite this slight improvement, functional outcome is poor in this population. Regardless of the limited applicability of the one identified economic study, decompressive hemicraniectomy significantly reduces mortality, while most of the survivors have significant neurological impairment and disability which limits their functional ability. Many people will need ongoing and costly long term nursing care. The committee agreed that considerations other than cost effectiveness were relevant to this issue. The clear mortality benefit of decompressive hemicraniectomy was expected to be important to many people with stroke, their families, and carers, irrespective of the poor functional outcomes of surgery. The committee discussed that the decision to undergo surgery warrants careful discussion between stroke physicians, surgeons, people with stroke and their families and carers. These shared decisions should be made on a case by case basis.

No health economic evidence was identified that considered the cost effectiveness of decompressive hemicraniectomy in people aged over 60. In the over 60 population, quality of life measured on the EQ-5D index and visual analogue scales was reported at 1 year by the DESTINY II trial. Both measures showed an improved quality of life for people undergoing decompressive hemicraniectomy compared with best medical treatment, though baseline quality of life was low. The clinical evidence did not show a differential effect between the over 60 and under 60 population and so, for equity reasons, the restriction of the population eligible for decompressive hemicraniectomy to those under 60 years of age is not supported. Due to the poor, though slightly improved functional outcomes after the surgery, the decision regarding whether a person should have a decompressive hemicraniectomy is a shared decision, to be made in conjunction with individuals, families and carers. In current practice, around 5% of people with stroke undergo decompressive hemicraniectomy. The committee acknowledged that extending the population eligible for surgery is a change to current practice, noting that people aged over 60 will generally take longer to recover from surgery and may therefore accrue higher rehabilitation costs. Without an age cut off, other factors will still be taken into consideration when determining whether a person is suitable for surgery. The committee agreed that increasing the population eligible for decompressive hemicraniectomy would not necessarily lead to significantly more people undergoing surgery; not all people eligible for decompressive hemicraneictomy ultimately go on to have surgery following discussions between carers and physicians. The committee noted that more informed discussion of the outcomes following surgery might reduce the uptake of surgery. In addition, the recommendation on endovascular therapy made elsewhere as part of this guideline update (see evidence review D) will increase the population eligible for endovascuar therapy and increase provision of endovascular therapy. This is likely to decrease the population referred for decompressive hemicraniectomy. The committee therefore does not expect this recommendation to have a substantial resource impact on the NHS in England.

In conclusion, the committee thought that the cost effectiveness of decompressive hemicraniectomy remains uncertain. The committee recommended that decompressive hemicraniectomy be considered for some patients, following shared decision making between physicians, surgeons, families and carers. This recommendation was made based on consideration of the clear mortality benefit of decompressive hemicraniectomy, which the committee thought would be important to a significant proportion of the population, irrespective of the overall limited improvement in functional outcome following surgery.

1.9.3. Other factors the committee took into account

The evidence did not support the use of an age cut-off for surgery and therefore the age cut-off had been removed from the recommendation. The committee considered that the patients’ pre-morbid state was much more relevant than age as a marker of potential outcome with and without surgery that would help decision making.

The committee discussed that, aside from removing the age cut-off, the weight of evidence was not strong enough either way to change the recommendation from consider.

It was noted that deciding to have surgery is a very difficult decision and patients should be provided with data of functional outcomes to guide their decision. The committee decided that patients or their carers should be given specific information on the risks and benefits in terms of their functional outcomes and risk of mortality. The decision should be made between the patient, their carers and medical or surgical team.

The committee took into account that the definition of a ‘good’ functional outcome will vary on an individual patient basis, as while one person might prefer to be alive with a functional score of 5, another might think this is an unacceptable state, potentially worse than death.

The committee were also aware of some limited evidence that decompressive hemicraniectomy may be performed beyond 48 hours.

References

1.: Alexander P, Heels-Ansdell D, Siemieniuk R, Bhatnagar N, Chang Y, Fei Y et al. Hemicraniectomy versus medical treatment with large MCA infarct: a review and meta-analysis. BMJ Open. 2016; 6(11):e014390 [PMC free article: PMC5168488] [PubMed: 27884858]

2.: Ayling OGS, Alotaibi NM, Wang JZ, Fatehi M, Ibrahim GM, Benavente O et al. Suboccipital decompressive craniectomy for cerebellar infarction: A systematic review and meta-analysis. World Neurosurgery. 2018; 110:450–459.e5 [PubMed: 29104155]

3.: Back L, Nagaraja V, Kapur A, Eslick GD. Role of decompressive hemicraniectomy in extensive middle cerebral artery strokes: a meta-analysis of randomised trials. Internal Medicine Journal. 2015; 45(7):711–7 [PubMed: 25684396]

4.: Buskens E, Nederkoorn PJ, Buijs-Van Der Woude T, Mali WP, Kappelle LJ, Eikelboom BC et al. Imaging of carotid arteries in symptomatic patients: cost-effectiveness of diagnostic strategies. Radiology. 2004; 233(1):101–12 [PubMed: 15333770]

5.: Cho DY, Chen TC, Lee HC. Ultra-early decompressive craniectomy for malignant middle cerebral artery infarction. Surgical Neurology. 2003; 60(3):227–32; discussion 232-3 [PubMed: 12922040]

6.: Chua AE, Jamora RD. Hemicraniectomy for Malignant Middle Cerebral Artery Infarction (HeMMI): A randomized controlled clinical trial of decompressive hemicraniectomy with standardized medical care versus standardized medical care alone. Acta Medica Philippina. 2015; 49(1):28–33

7.: Chung H, Refoios Camejo R, Barnett D. Alteplase for the treatment of acute ischaemic stroke: NICE technology appraisal guidance. Heart. 2007; 93(12):1616–7 [PMC free article: PMC2095758] [PubMed: 18003692]

8.: Cruz-Flores S, Berge E, Whittle IR. Surgical decompression for cerebral oedema in acute ischaemic stroke. Cochrane Database of Systematic Reviews 2012, Issue 1. Art. No.: CD003435. DOI: 10.1002/14651858.CD003435.pub2. [PubMed: 22258954] [CrossRef]

9.: Delgado-López P, Mateo-Sierra O, García-Leal R, Agustín-Gutiérrez F, Fernández-Carballal C, Carrillo-Yagüe R. Decompressive craniectomy in malignant infarction of the middle cerebral artery. Neurocirugia. 2004; 15(1):43–55 [PubMed: 15039849]

10.: Dhand A, Landau WM, Kelly AG, Holloway RG, Jaeschke R, Juettler E. Hemicraniectomy for middle-cerebral-artery stroke. New England Journal of Medicine. 2014; 370(24):2346–8 [PubMed: 24918381]

11.: Elsawaf A, Galhom A. Decompressive craniotomy for malignant middle cerebral artery infarction: Optimal timing and literature review. World Neurosurgery. 2018; 116:e71–e78 [PubMed: 29653270]

12.: Frank JI, Schumm LP, Wroblewski K, Chyatte D, Rosengart AJ, Kordeck C et al. Hemicraniectomy and durotomy upon deterioration from infarction-related swelling trial: randomized pilot clinical trial. Stroke. 2014; 45(3):781–7 [PMC free article: PMC4033520] [PubMed: 24425122]

13.: Georgiadis D, Schwarz S, Aschoff A, Schwab S. Hemicraniectomy and moderate hypothermia in patients with severe ischemic stroke. Stroke. 2002; 33:1584–8 [PubMed: 12052995]

14.: Geurts M, van der Worp HB, Kappelle LJ, Amelink GJ, Algra A, Hofmeijer J et al. Surgical decompression for space-occupying cerebral infarction: outcomes at 3 years in the randomized HAMLET trial. Stroke. 2013; 44(9):2506–8 [PubMed: 23868265]

15.: Gupta R, Connolly ES, Mayer S, Elkind MS. Hemicraniectomy for massive middle cerebral artery territory infarction: a systematic review. Stroke. 2004; 35(2):539–43 [PubMed: 14707232]

16.: Hofmeijer J, Algra A, Gijn J, Amelink GJ, Kappelle LJ, Worp HB. HAMLET: hemicraniectomy after middle cerebral artery infarction with life-threatening oedema trial. International Journal of Stroke. 2008; 3:(Suppl 1):81

17.: Hofmeijer J, Kappelle LJ, Algra A, Amelink GJ, van Gijn J, van der Worp HB et al. Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): a multicentre, open, randomised trial. Lancet Neurology. 2009; 8(4):326–33 [PubMed: 19269254]

18.: Hofmeijer J, van der Worp HB, Kappelle LJ, Eshuis S, Algra A, Greving JP et al. Cost-effectiveness of surgical decompression for space-occupying hemispheric infarction. Stroke. 2013; 44(10):2923–5 [PubMed: 23943217]

19.: Inamasu J, Kaito T, Watabe T, Ganaha T, Yamada Y, Tanaka T et al. Decompressive hemicraniectomy for malignant hemispheric stroke in the elderly: comparison of outcomes between individuals 61-70 and >70 years of age. Journal of Stroke and Cerebrovascular Diseases. 2013; 22(8):1350–4 [PubMed: 23489954]

20.: Juttler E, Bosel J, Amiri H, Schiller P, Limprecht R, Hacke W et al. DESTINY II: Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery II. International Journal of Stroke. 2011; 6(1):79–86 [PubMed: 21205246]

21.: Juttler E, Schwab S, Schmiedek P, Unterberg A, Hennerici M, Woitzik J et al. Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY): a randomized, controlled trial. Stroke. 2007; 38(9):2518–25 [PubMed: 17690310]

22.: Juttler E, Unterberg A, Woitzik J, Bosel J, Amiri H, Sakowitz OW et al. Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke. New England Journal of Medicine. 2014; 370(12):1091–100 [PubMed: 24645942]

23.: Kamran S, Akhtar N, Salam A, Alboudi A, Rashid H, Kamran K et al. Decompressive hemicraniectomy for malignant middle cerebral artery stroke: South Asian experience. Journal of Stroke and Cerebrovascular Diseases. 2017; 26(10):2306–12 [PubMed: 28579508]

24.: Khoozestan A. Comparison of hemicraniectomy and conservative management on short term prognosis of patients with stem of middle cerebral artery infarction, admitted in ahvaz golestan hospital [IRCT201112018272N1]. 2012. Available from: http://en.irct.ir/trial/8695 Last accessed: 14/08/2018.

25.: Li YP, Hou MZ, Lu GY, Ciccone N, Wang XD, Dong L et al. Neurologic functional outcomes of decompressive hemicraniectomy versus conventional treatment for malignant middle cerebral artery infarction: A systematic review and meta-analysis. World Neurosurgery. 2017; 99:709–25.e3 [PubMed: 28024976]

26.: Lin TK, Chen SM, Huang YC, Chen PY, Chen MC, Tsai HC et al. The outcome predictors of malignant large infarction and the functional outcome of survivors following decompressive craniectomy. World Neurosurgery. 2016; 93:133–8 [PubMed: 27297245]

27.: Lu X, Huang B, Zheng J, Tao Y, Yu W, Tang L et al. Decompressive craniectomy for the treatment of malignant infarction of the middle cerebral artery. Scientific Reports. 2014; 4:7070 [PMC free article: PMC4233335] [PubMed: 25400113]

28.: Lucas C, Thines L, Dumont F, Leclerc X, Riegel B, Cordonnier C et al. Decompressive surgery for malignant middle cerebral artery infarcts: the results of randomized trials can be reproduced in daily practice. European Neurology. 2012; 68(3):145–9 [PubMed: 22832365]

29.: Macleod M, Hofmeijer J, Gijn J, Worp HB. Hemicraniectomy After Middle cerebral artery infarction with Life-threatening Edema Trial (HAMLET: iSRCTN94237756). UK Stroke Forum Conference 2006. 2006;

30.: McKenna A, Wilson CF, Caldwell SB, Curran D. Functional outcomes of decompressive hemicraniectomy following malignant middle cerebral artery infarctions: a systematic review. British Journal of Neurosurgery. 2012; 26(3):310–5 [PubMed: 22320444]

31.: Mohan Rajwani K, Crocker M, Moynihan B. Decompressive craniectomy for the treatment of malignant middle cerebral artery infarction. British Journal of Neurosurgery. 2017; 31(4):401–9 [PubMed: 28604106]

32.: National Institute for Health and Care Excellence. Developing NICE guidelines: the manual. London. National Institute for Health and Care Excellence, 2014. Available from: http://www.nice.org.uk/article/PMG20/chapter/1%20Introduction%20and%20overview [PubMed: 26677490]

33.: Neugebauer H, Heuschmann PU, Juttler E. Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery - Registry (DESTINY-R): design and protocols. BMC Neurology. 2012; 12:115 [PMC free article: PMC3517444] [PubMed: 23031451]

34.: Omay SB, Carrion-Grant GM, Kuzmik GA, Fu M, Grant R, Schindler JL et al. Decompressive hemicraniectomy for ischemic stroke in the pediatric population. Neurosurgical Review. 2013; 36(1):21–5 [PubMed: 22886322]

35.: Organisation for Economic Co-operation and Development (OECD). Purchasing power parities (PPP). 2017. Available from: http://www.oecd.org/sdd/prices-ppp/ Last accessed: 2/2/2018.

36.: Pledl HW, Hoyer C, Rausch J, Ebert AD, Seiz M, Arp M et al. Decompressive hemicraniectomy in malignant middle cerebral artery infarction: The ‘real world’ beyond studies. European Neurology. 2016; 76(1-2):48–56 [PubMed: 27379413]

37.: Post PN, Stiggelbout AM, Wakker PP. The utility of health states after stroke: a systematic review of the literature. Stroke. 2001; 32(6):1425–9 [PubMed: 11387509]

38.: Schwab S, Rieke K, Krieger D, Hund E, Aschoff A, Kummer R et al. Craniectomy in space-occupying middle cerebral artery infarcts. Der nervenarzt. 1995; 66(6):430–7 [PubMed: 7543659]

39.: Sengeze N, Kutlahan S, Karaslan T. Comparison of the decompressive surgery and medical therapy only results in malignant middle cerebral artery infarction. International Journal of Stroke. 2014; 9:(Suppl 3):96

40.: Slezins J, Keris V, Bricis R, Millers A, Valeinis E, Stukens J et al. Preliminary results of randomized controlled study on decompressive craniectomy in treatment of malignant middle cerebral artery stroke. Medicina. 2012; 48(10):521–4 [PubMed: 23324248]

41.: Streib CD, Hartman LM, Molyneaux BJ. Early decompressive craniectomy for malignant cerebral infarction: Meta-analysis and clinical decision algorithm. Neurology Clinical Practice. 2016; 6(5):433–43 [PMC free article: PMC5100704] [PubMed: 27847685]

42.: Vahedi K. Decompressive hemicraniectomy for malignant hemispheric infarction. Current Treatment Options in Neurology. 2009; 11(2):113–9 [PubMed: 19210913]

43.: Vahedi K, Bousser MG. DECIMAL. Decompressive craniectomy in malignant middle cerebral artery infarcts [NCT00190203]. 2004. Available from: https://clinicaltrials.gov/show/NCT00190203 Last accessed: 14/08/2018. Stroke and transient ischaemic attack in over 16s: evidence review H FINAL (May 2019) Decompressive hemicraniectomy

44.: Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurology. 2007; 6(3):215–22 [PubMed: 17303527]

45.: Vahedi K, Vicaut E, Blanquet A, Payen D, Bousser MG. Decimal trial: decompressive craniectomy in malignant middle cerebral artery infarcts: a sequential design, multicenter, randomized, controlled trial. International Stroke Conference 2005, New Orleans, Louisiana, February 2-4, 2005. 2005;

46.: Vahedi K, Vicaut E, Mateo J, Kurtz A, Orabi M, Guichard JP et al. Sequential-design, multicenter, randomized, controlled trial of early decompressive craniectomy in malignant middle cerebral artery infarction (DECIMAL Trial). Stroke. 2007; 38(9):2506–17 [PubMed: 17690311]

47.: van Middelaar T, Nederkoorn PJ, van der Worp HB, Stam J, Richard E. Quality of life after surgical decompression for space-occupying middle cerebral artery infarction: systematic review. International Journal of Stroke. 2015; 10(2):170–6 [PubMed: 25042345]

48.: Vibbert M, Mayer SA. Early decompressive hemicraniectomy following malignant ischemic stroke: the crucial role of timing. Current Neurology and Neuroscience Reports. 2010; 10(1):1–3 [PubMed: 20425217]

49.: Worp HB. Hemicraniectomy after middle cerebral artery infarction with life-threatening edema trial. Trials. 2006; 7(29) [PMC free article: PMC1570365] [PubMed: 16965617]

50.: Yang MH, Lin HY, Fu J, Roodrajeetsing G, Shi SL, Xiao SW. Decompressive hemicraniectomy in patients with malignant middle cerebral artery infarction: A systematic review and meta-analysis. Surgeon Journal of the Royal Colleges of Surgeons of Edinburgh & Ireland. 2015; 13(4):230–40 [PubMed: 25661677]

51.: Zhao J, Su YY, Zhang Y, Zhang YZ, Zhao R, Wang L et al. Decompressive hemicraniectomy in malignant middle cerebral artery infarct: a randomized controlled trial enrolling patients up to 80 years old. Neurocritical Care. 2012; 17(2):161–71 [PubMed: 22528280]

Appendices

Appendix A. Review protocols

Table 7. Review protocol: Decompressive hemicraniectomy

Table 8. Health economic review protocol

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 9. 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 10. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

NHS EED and HTA (CRD) search terms

Appendix C. Clinical evidence selection

Figure 1. Flow chart of clinical study selection for the review of decompressive hemicraniectomy

Appendix D. Clinical evidence tables

Download PDF (338K)

Appendix E. Forest plots and ordinal shift graphs

E.1. Decompressive hemicraniectomy vs medical treatment in those under 60 years

Figure 1. Mortality at 30 days

Figure 2. Mortality at 6 months

Figure 3. Mortality at 1 year

Figure 4. Functional outcomes, score of 0-3 on mRS scale at 6 months

Figure 5. Functional outcomes, score of 0-3 on mRS scale at 1 year

Figure 6. Quality of life, SF-36 at 1 year (range: 0-100, high is good outcome)

E.2. Decompressive hemicraniectomy vs medical treatment in those over 60 years

Figure 7. Mortality, 6 months

Figure 8. Mortality, 1 year

Figure 9. Functional outcomes, mRS 0-3 at 6 months

Figure 10. Functional outcomes, mRS 0-3, 1 year

Figure 11. Quality of life, EQ-5D, index scale (range: −0.205 “dead” to 1.0 “perfect health”), 1 year

Figure 12. Quality of Life, EQ-5D, visual analogue scale (range: 0-100, high is good outcome), 1 year

E.3. Ordinal shift analysis for decompressive hemicraniectomy vs medical treatment

Figure 13. mRS distribution at 6 months

Figure 14. mRS distribution at 1 year

Appendix F. GRADE tables

Table 11. Clinical evidence profile: Decompressive hemicraniectomy vs medical treatment for those under 60yrs

Table 12. Clinical evidence profile: Decompressive hemicraniectomy vs medical treatment for those over 60yrs

Appendix G. Health economic evidence selection

Figure 15. Flow chart of health economic study selection for the guideline

Appendix H. Excluded studies

H.1. Excluded clinical studies

Table 13. Studies excluded from the clinical review

Appendix I. Health economic evidence tables

Download PDF (185K)

FINAL

Intervention evidence review

This evidence review was developed by the National Guideline Centre

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK577869PMID: 35167208

Table 1PICO characteristics of review question

Population	People with large volume acute anterior circulation ischaemic stroke with complicating space-occupying brain oedema (sometimes described as malignant middle cerebral artery infarction), evident on cerebral computed tomography or magnetic resonance imaging.
Intervention	Decompressive surgery plus best medical treatment (ICP monitoring, ventilation, mannitol, other diuretics, corticosteroids, hyperventilation, barbiturates, etc.)
Comparison	Best medical therapy (ICP monitoring, ventilation, mannitol, other diuretics, corticosteroids, hyperventilation, barbiturates, etc.)
Outcomes	Critical Mortality 6 months Mortality 1 year Functional outcome (degree of disability or dependence in daily activities) at 6 months and 1 year: Modified Rankin scale (mRS) score of 0-3 or ordinal shift analysis Important Quality of life (both health- and social-related)
Study design	Randomised controlled trials Systematic reviews and meta-analyses of the above

Table 2Summary of studies included in the evidence review for those aged under 60 years

Study

Intervention and comparison

Population

Outcomes

Chua, 2015⁶

HeMMi Trial

Decompressive surgery plus medical therapy (n=16)

Medical therapy (n=13)

Adults aged 18 to 65 years (mean=50.2 yrs, SD=8.3yrs)

Philippines

Mortality at 6 months
mRS at 6 months

Frank, 2014¹²

HeADDFIRST trial

Decompressive surgery plus medical treatment (n=15)

Medical treatment (n=10)

Adults aged 18 to 75 years (median=55.1 yrs, IQR=45.45 to 62.4yrs)

United Kingdom

Mortality at 6 months
mRS at 6 months

Hofmeijer, 2009¹⁷

HAMLET trial

Decompressive surgery (n=32)

Medical treatment (n=32)

Adults aged 18 to 60 years (mean=48.7 yrs, SD=9.05yrs)

Netherlands

Mortality at 1 year
mRS at 1 year
Quality of life at 1 year

Juttler, 2007²¹

DESTINY trial

Decompressive surgery plus conservative treatment (n=17)

Conservative treatment (n=15)

Adults aged 18 to 60 years (mean=44.6 yrs, SD=9.1yrs)

Germany

Mortality at 30 days and 1 year
mRS at 6 months and 1 year

Vahedi, 2007⁴⁶

DECIMAL trial

Decompressive surgery plus standard medical therapy (n=20)

Standard medical therapy (n=18)

Adults aged 18 to 55 years (mean=43.4 yrs, SD=8.4yrs)

France

Mortality at 6 months and 1 year
mRS at 6 months and 1 year

Table 3Summary of studies included in the evidence review for those aged over 60 years

Study

Intervention and comparison

Population

Outcomes

Juttler, 2014²²

DESTINY II trial

Decompressive surgery (n=49)

Conservative treatment (n=63)

Adults aged 61 and above (median=70, range=61 to 82yrs)

Germany

Mortality at 1 year
mRS at 6 months and 1 year
Quality of life at 1 year

Slezins, 2012⁴⁰

Decompressive surgery plus medical management (n=11)

Medical management (n=13)

Adults aged 49 to 81 years (mean=61.5 yrs, range=49 to 81yrs)

Latvia

Mortality at 1 year
mRS at 6 months and 1 year

Zhao, 2012⁵¹

Decompressive surgery plus standard medical treatment (n=16)

Standard medical treatment (n=13)

Adults aged 61 to 80 years (median=69.25 yrs)

China

Mortality at 6 months and 1 year
mRS at 6 months and 1 year

Table 4Clinical evidence summary: Decompressive hemicraniectomy compared to medical treatment for those aged under 60 years

Outcomes

No of Participants (studies) Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with Medical Treatment

Risk difference with DHC (95% CI)

Mortality at 30 days

(1 study)

30 days

⊕⊕⊕⊝

MODERATE¹

due to imprecision

RR 0.22

(0.06 to 0.88)

533 per 1000

416 fewer per 1000

(from 64 fewer to 501 fewer)

Mortality at 6 months

(3 studies)

6 months

⊕⊕⊕⊝

MODERATE¹

due to imprecision

RR 0.52

(0.32 to 0.86)

545 per 1000

262 fewer per 1000

(from 76 fewer to 371 fewer)

Mortality at 1 year

134

(3 studies)

1 year

⊕⊕⊕⊕

HIGH

RR 0.34

(0.21 to 0.56)

594 per 1000

392 fewer per 1000

(from 261 fewer to 469 fewer)

Functional outcomes at 6 months

Score of 0-3 on mRS scale (range: 0-6, high is poor outcome)

118

(4 studies)

6 months

⊕⊝⊝⊝

VERY LOW¹^,²

due to risk of bias, imprecision

RR 1.39

(0.76 to 2.56)

283 per 1000

110 more per 1000

(from 68 fewer to 441 more)

Functional outcomes at 1 year

Score of 0-3 on mRS scale (range: 0-6, high is poor outcome)

134

(3 studies)

1 year

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

RR 1.52

0.90 to 2.57

250 per 1000

130 more per 1000

(from 25 fewer to 392 more)

Quality of life, 1 year, SF-36 mental summary (range: 0-100, high is good outcome)

(1 study)

1 year

⊕⊝⊝⊝

VERY LOW¹^,²

due to risk of bias, imprecision

The mean SF-36 mental summary in the control groups was

The mean SF-36 mental summary in the intervention groups was

2 higher

(5.92 lower to 9.92 higher)

Quality of life, 1 year, SF-36 physical summary (range: 0-100, high is good outcome)

(1 study)

1 year

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

The mean SF-36 physical summary in the control groups was

The mean SF-36 physical summary in the intervention groups was

7 lower

(13.85 to 0.15 lower)

Quality of life, 1 year, VAS (range: 0-100, high is good outcome)

(1 study)

1 year

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

The mean VAS in the control groups was

The mean VAS in the intervention groups was

7 lower

(27.49 lower to 13.49 higher)

1: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs.

2: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.

Table 5Clinical evidence summary: Decompressive hemicraniectomy compared to medical treatment for those over 60 years

Outcomes

No of Participants (studies) Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with Medical Treatment

Risk difference with Decompressive Hemicraniectomy (95% CI)

Mortality, 6 months

(1 study)

6 months

⊕⊕⊕⊝

MODERATE¹

due to imprecision

RR 0.20

(0.05 to 0.8)

609 per 1000

487 fewer per 1000

(from 122 fewer to 579 fewer)

Mortality, 1 year

162

(3 studies)

1 years

⊕⊕⊕⊝

MODERATE²

due to indirectness

RR 0.52

(0.39 to 0.7)

758 per 1000

364 fewer per 1000

(from 227 fewer to 462 fewer)

Functional outcomes, 6 months

Score of 0-3 on mRS scale (range: 0-6, high is poor outcome)

141

(2 studies)

6 months

⊕⊝⊝⊝

VERY LOW¹^,³

due to risk of bias, imprecision

RR 2.45

(0.55 to 10.91)

16 per 1000

23 more per 1000

(from 7 fewer to 159 more)

Functional outcomes, 1 year

Score of 0-3 on mRS scale (range: 0-6, high is poor outcome)

165

(3 studies)

1 year

⊕⊝⊝⊝

VERY LOW¹^,³

due to risk of bias, imprecision

RR 3.18

(1.03 to 9.83)

34 per 1000

100 more per 1000

(from 10 more to 180 more)⁴

Quality of life, 1 year

EQ-5D scale (range: −0.205 “dead” to 1.0 “perfect health”)

100

(1 study)

1 years

⊕⊕⊝⊝

LOW¹^,³

due to risk of bias, imprecision

The mean quality of life, EQ-5D in the control groups was

−0.1

The EQ-5D in the intervention groups was

0.10 higher

(0 to 0.2 higher)

Quality of life, 1 year

EQ-5D, visual analogue scale (range 0-100; high is good outcome)

(1 study)

1 years

⊕⊕⊝⊝

LOW¹^,³

due to risk of bias, imprecision

The mean EQ-5D VAS in the control groups was

7.6

The mean EQ-5D VAS in the intervention groups was

16.40 higher

(6.54 to 26.26 higher)

1: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs.

2: Downgraded by 1 or 2 increments because the majority of the evidence included an indirect or very indirect population respectively.

3: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.

4: Calculated from risk difference.

Table 6Health economic evidence profile: surgical decompression versus best medical treatment

Study

Applicability

Limitations

Other comments

Incremental cost

Incremental effects

Cost effectiveness

Uncertainty

Hofmeijer, 2013¹⁸ (The Netherlands, health system perspective)

Partially applicable^(a)

Potentially serious limitations^(b)

Within-trial analysis (RCT) with Markov model posttrial extrapolation.

HAMLET RCT included in clinical review¹⁴. Markov model simulating a lifetime time horizon.

£206,742^(c)

4.2 QALYs

ICER: £49,224 per QALY gained (da)

: Abbreviations: da: deterministic analysis; ICER: incremental cost-effectiveness ratio; NR: not reported; QALY: quality-adjusted life years; RCT: randomised controlled trial

(a): Within-trial analysis with post-trial extrapolation, from Dutch societal perspective

(b): Treatment effects derived from HAMLET trial only, which reported less favourable outcomes for decompressive surgery compared with other trials. Discounting of costs and outcomes not reported for post-trial Markov model, sensitivity analysis not undertaken for lifetime horizon. Outpatient department and general practitioner resource use obtained retrospectively. Recurrent stroke not modelled. Cycle lengths of Markov model not reported.

(c): Converted using 2009 purchasing power parities³⁵

Table 7UK costs of non-elective long stay decompressive hemicraniectomy

Currency Description	Unit Cost	Average length of stay
AA52D – AA52A Very Major Intracerebral Procedures, 19 years and over, inclusive of excess bed days, with CC Score 0-3 to CC Score 12+; as recorded for Non-Elective Long Stay	£9,174 - £15,386	8.54 – 22.60 days
AA52B Very Major Intracerebral Procedures, 19 years and over, weighted for complications and co-morbidities for HRG codes: AA52A, AA52B, AA52C and AA52D; as recorded for Non-Elective Long Stay	£10,721	12.17 days

: Source: NHS Reference Costs, 2016-2017

Table 7Review protocol: Decompressive hemicraniectomy

Field	Content
Review question	Which patients should be referred for decompressive hemicraniectomy?
Type of review question	Intervention A review of health economic evidence related to the same review question was conducted in parallel with this review. For details see the health economic review protocol for this NICE guideline.
Objective of the review	To examine the effects of decompressive surgery in people with acute ischaemic stroke with cerebral oedema, and to determine if decompressive surgery is effective in improving survival or reducing the risk of disability.
Eligibility criteria – population / disease / condition / issue / domain	People aged over 16 with large volume acute anterior circulation ischaemic stroke with or without complicating space-occupying brain oedema (sometimes described as malignant middle cerebral artery infarction), evident on cerebral computed tomography or magnetic resonance imaging
Eligibility criteria – intervention(s) / exposure(s) / prognostic factor(s)	Decompressive surgery plus medical treatment (mannitol, other diuretics, corticosteroids, hyperventilation, barbiturates, etc)
Eligibility criteria – comparator(s) / control or reference (gold) standard	Medical treatment alone
Outcomes and prioritisation	Critical Mortality 90 days Mortality 1 year Functional outcome (degree of disability or dependence in daily activities) at 90 days and 1 year: Modified Rankin Score (mRS) of 3 and 4 – 5 Important Quality of life (both health- and social-related)
Eligibility criteria – study design	Randomised controlled intervention trials
Other inclusion exclusion criteria	Inclusion Language: Restrict to English only Setting: Emergency department, High dependency or intensive care units, Hyperacute or acute stroke units, Other hospital settings
Proposed sensitivity / subgroup analysis, or meta-regression	Strata Age older than 60 years Subgroups Surgery within 24h, 48h, 72h of stroke onset Dominant/non-dominant hemisphere
Selection process – duplicate screening / selection / analysis	Studies are sifted by title and abstract. Potentially significant publications obtained in full text are then assessed against the inclusion criteria specified in this protocol.
Data management (software)	EndNote will be used for reference management, sifting, citations and bibliographies. EviBASE will be used for data extraction and quality assessment for clinical studies. Pairwise meta-analyses will be performed using Cochrane Review Manager (RevMan5). GRADEpro will be used to assess the quality of evidence for each outcome.
Information sources – databases and dates	Databases: Medline, Embase, Cochrane Library Language: Restrict to English only Date restriction: 2007 Key papers Gupta R, Connolly ES, Mayer S et al. Hemicraniectomy for massive middle cerebral artery territory infarction: a systematic review. Stroke 2004;35(2):539–543. Vahedi K, Hofmeijer J, Juettler E et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurology 2007;6(3): 215–222. Hofmeijer J, Kappelle LJ, Algra A et al. (2009) Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Lifethreatening Edema Trial [HAMLET]): a multicentre, open, randomised trial. Lancet Neurology 8:326-333. Juttler E, Schwab S, Schmiedek P et al. (2007) Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY): a randomized, controlled trial. Stroke 38:2518-2525. Cruz-Flores S, Berge E, and Whittle IR. (2012) Surgical decompression for cerebral oedema in acute ischaemic stroke. [Review][Update of Cochrane Database Syst Rev. 2002;(3):CD003435; PMID: 12137695]. Cochrane Database of Systematic Reviews 1:CD003435.
Identify if an update	Yes 2 papers included in CG68, date cut off 2007 Question in CG68: Which patients should be referred for decompressive hemicraniectomy? Recommendations from CG68 1.9.2.1 People with middle cerebral artery infarction who meet all of the criteria below should be considered for decompressive hemicraniectomy. They should be referred within 24 hours of onset of symptoms and treated within a maximum of 48 hours. Aged 60 years or under. Clinical deficits suggestive of infarction in the territory of the middle cerebral artery, with a score on the National Institutes of Health Stroke Scale (NIHSS) of above 15. Decrease in the level of consciousness to give a score of 1 or more on item 1a of the NIHSS. Signs on CT of an infarct of at least 50% of the middle cerebral artery territory, with or without additional infarction in the territory of the anterior or posterior cerebral artery on the same side, or infarct volume greater than 145 cm3 as shown on diffusion weighted MRI. 1.9.2.2 People who are referred for decompressive hemicraniectomy should be monitored by appropriately trained professionals skilled in neurological
Author contacts	https://www.nice.org.uk/guidance/indevelopment/gid-ng10071
Highlight if amendment to previous protocol	For details please see section 4.5 of Developing NICE guidelines: the manual.
Search strategy – for one database	For details please see appendix B
Data collection process – forms / duplicate	A standardised evidence table format will be used, and published as appendix D of the evidence report.
Data items – define all variables to be collected	For details please see evidence tables in Appendix D (clinical evidence tables) or H (health economic evidence tables).
Methods for assessing bias at outcome / study level	Standard study checklists were used to critically appraise individual studies. For details please see section 6.2 of Developing NICE guidelines: the manual The risk of bias across all available evidence was evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group http://www.gradeworkinggroup.org/
Criteria for quantitative synthesis	For details please see section 6.4 of Developing NICE guidelines: the manual.
Methods for quantitative analysis – combining studies and exploring (in)consistency	For details please see the separate Methods report for this guideline.
Meta-bias assessment – publication bias, selective reporting bias	For details please see section 6.2 of Developing NICE guidelines: the manual.
Confidence in cumulative evidence	For details please see sections 6.4 and 9.1 of Developing NICE guidelines: the manual.
Rationale / context – what is known	For details please see the introduction to the evidence review.
Describe contributions of authors and guarantor	A multidisciplinary committee developed the evidence review. The committee was convened by the National Guideline Centre (NGC) and chaired by Jason Kendall in line with section 3 of Developing NICE guidelines: the manual. Staff from NGC undertook systematic literature searches, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate, and drafted the evidence review in collaboration with the committee. For details please see Developing NICE guidelines: the manual.
Sources of funding / support	NGC is funded by NICE and hosted by the Royal College of Physicians.
Name of sponsor	NGC is funded by NICE and hosted by the Royal College of Physicians.
Roles of sponsor	NICE funds NGC to develop guidelines for those working in the NHS, public health and social care in England.
PROSPERO registration number	Not registered

Table 8Health economic review protocol

Review question	All questions – health economic evidence
Objectives	To identify health economic studies relevant to any of the review questions.
Search criteria	Populations, interventions and comparators must be as specified in the clinical review protocol above. Studies must be of a relevant health economic study design (cost–utility analysis, cost-effectiveness analysis, cost–benefit analysis, cost–consequences analysis, comparative cost analysis). Studies must not be a letter, editorial or commentary, or a review of health economic evaluations. (Recent reviews will be ordered although not reviewed. The bibliographies will be checked for relevant studies, which will then be ordered.) Unpublished reports will not be considered unless submitted as part of a call for evidence. Studies must be in English.
Search strategy	A health economic study search will be undertaken using population-specific terms and a health economic study filter – see appendix B2 of reviews. For questions being updated, the search will be run from 2007, which was the cut-off date for the searches conducted for NICE guideline CG68. For the new review question on endovascular therapy, the search will be run from 2007 as studies published before 2007 are not likely to be relevant.
Review strategy	Studies not meeting any of the search criteria above will be excluded. Studies published before 2002, abstract-only studies and studies from non-OECD countries or the USA will also be excluded. Studies published after 2002 that were included in the previous guideline will be reassessed for inclusion and may be included or selectively excluded based on their relevance to the questions covered in this update and whether more applicable evidence is also identified. Each remaining study will be assessed for applicability and methodological limitations using the NICE economic evaluation checklist which can be found in appendix H of Developing NICE guidelines: the manual (2014).³² Inclusion and exclusion criteria If a study is rated as both ‘Directly applicable’ and with ‘Minor limitations’ then it will be included in the guideline. A health economic evidence table will be completed and it will be included in the health economic evidence profile. If a study is rated as either ‘Not applicable’ or with ‘Very serious limitations’ then it will usually be excluded from the guideline. If it is excluded then a health economic evidence table will not be completed and it will not be included in the health economic evidence profile. If a study is rated as ‘Partially applicable’, with ‘Potentially serious limitations’ or both then there is discretion over whether it should be included. Where there is discretion The health economist will make a decision based on the relative applicability and quality of the available evidence for that question, in discussion with the guideline committee if required. The ultimate aim is to include health economic studies that are helpful for decision-making in the context of the guideline and the current NHS setting. If several studies are considered of sufficiently high applicability and methodological quality that they could all be included, then the health economist, in discussion with the committee if required, may decide to include only the most applicable studies and to selectively exclude the remaining studies. All studies excluded on the basis of applicability or methodological limitations will be listed with explanation as excluded health economic studies in appendix H. The health economist will be guided by the following hierarchies. Setting: UK NHS (most applicable). OECD countries with predominantly public health insurance systems (for example, France, Germany, Sweden). OECD countries with predominantly private health insurance systems (for example, Switzerland). Studies set in non-OECD countries or in the USA will be excluded before being assessed for applicability and methodological limitations. Health economic study type: Cost–utility analysis (most applicable). Other type of full economic evaluation (cost–benefit analysis, cost-effectiveness analysis, cost–consequences analysis). Comparative cost analysis. Non-comparative cost analyses including cost-of-illness studies will be excluded before being assessed for applicability and methodological limitations. Year of analysis: The more recent the study, the more applicable it will be. Studies published in 2002 or later (including any such studies included in the previous guideline) but that depend on unit costs and resource data entirely or predominantly from before 2002 will be rated as ‘Not applicable’. Studies published before 2002 (including any such studies included in the previous guideline) will be excluded before being assessed for applicability and methodological limitations. Quality and relevance of effectiveness data used in the health economic analysis: The more closely the clinical effectiveness data used in the health economic analysis match with the outcomes of the studies included in the clinical review the more useful the analysis will be for decision-making in the guideline.

Table 9Database date parameters and filters used

Database

Dates searched

Search filter used

Medline (OVID)

01 January 2018 – 22 June 2018

Exclusions

Randomised controlled trials

Systematic review studies

Embase (OVID)

01 January 2018 – 22 June 2018

Exclusions

Randomised controlled trials

Systematic review studies

The Cochrane Library (Wiley)

Cochrane Reviews to 2018 Issue 6 of 12

CENTRAL to 2018 Issue 5 of 12

DARE, and NHSEED to 2015 Issue 2 of 4

HTA to 2016 Issue 4 of 4

None

Medline (Ovid) search terms

1.	exp Stroke/
2.	(stroke or strokes).ti,ab.
3.	((cerebro* or cerebral) adj2 (accident or apoplexy)).ti,ab.
4.	(CVA or poststoke*1).ti,ab.
5.	exp Intracranial Hemorrhages/
6.	(brain adj2 (attack1 or hemorrhag or haemorrhag* or bleed* or infarct*)).ti,ab.
7.	((intracerebral or intracranial or cerebral* or cerebro* or cerebrum or cerebellum or subarachnoid* or choroidal or basal ganglia or subdural) adj3 (hemorrhag* or haemorrhag* or bleed*)).ti,ab.
8.	exp Brain infarction/
9.	exp Carotid Artery Thrombosis/
10.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or crescendo or transient or lacunar) adj3 (infarct or thrombo* or emboli* or occlus* or hypoxi*)).ti,ab.
11.	exp Brain Ischemia/
12.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or crescendo or transient or lacunar) adj3 isch?emi).ti,ab.
13.	Ischemic Attack, Transient/
14.	(isch?emi* adj2 attack*).ti,ab.
15.	TIA.ti,ab.
16.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or crescendo or transient or lacunar) adj3 (oedema or edema* or swell* or swollen or enlarg*)).ti,ab.
17.	or/1-16
18.	letter/
19.	editorial/
20.	news/
21.	exp historical article/
22.	Anecdotes as Topic/
23.	comment/
24.	case report/
25.	(letter or comment*).ti.
26.	or/18-25
27.	randomized controlled trial/ or random*.ti,ab.
28.	26 not 27
29.	animals/ not humans/
30.	exp Animals, Laboratory/
31.	exp Animal Experimentation/
32.	exp Models, Animal/
33.	exp Rodentia/
34.	(rat or rats or mouse or mice).ti.
35.	or/28-34
36.	17 not 35
37.	decompression, surgical/ or neurosurgical procedures/ or craniotomy/ or trephining/
38.	(decompress* or craniectom* or craniotom* or hemi-craniect* or hemicraniect* or trepa* or treph*).ti,ab.
39.	(hippocampectom* or lobectom* or strokectom*).ti,ab.
40.	37 or 38 or 39
41.	36 and 40
42.	randomized controlled trial.pt.
43.	controlled clinical trial.pt.
44.	randomi#ed.ti,ab.
45.	placebo.ab.
46.	randomly.ti,ab.
47.	Clinical Trials as topic.sh.
48.	trial.ti.
49.	or/42-48
50.	Meta-Analysis/
51.	exp Meta-Analysis as Topic/
52.	(meta analy* or metanaly* or metaanaly* or meta regression).ti,ab.
53.	((systematic* or evidence) adj3 (review or overview*)).ti,ab.
54.	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
55.	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
56.	(search* adj4 literature).ab.
57.	(medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab.
58.	cochrane.jw.
59.	((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab.
60.	or/50-59
61.	49 or 60
62.	41 and 61
63.	limit 62 to English language

Embase (Ovid) search terms

1.	*cerebrovascular accident/ or cardioembolic stroke/ or exp experimental stroke/ or lacunar stroke/
2.	(stroke or strokes).ti,ab.
3.	((cerebro* or cerebral) adj2 (accident or apoplexy)).ti,ab.
4.	(CVA or poststroke or poststrokes).ti,ab.
5.	brain hemorrhage/ or brain ventricle hemorrhage/ or cerebellum hemorrhage/ or subarachnoid hemorrhage/
6.	(brain adj2 (attack1 or hemorrhag or haemorrhag* or bleed* or infarct*)).ti,ab.
7.	((intracerebral or intracranial or cerebral* or cerebro* or cerebrum or cerebellum or subarachnoid* or choroidal or basal ganglia or subdural) adj3 (hemorrhag* or haemorrhag* or bleed*)).ti,ab.
8.	brain infarction/ or brain infarction size/ or brain stem infarction/ or cerebellum infarction/
9.	*Carotid Artery Thrombosis/
10.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or transient or lacunar) adj3 (infarct or thrombo* or emboli* or occlus* or hypoxi*)).ti,ab.
11.	brain ischemia/ or hypoxic ischemic encephalopathy/
12.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or crescendo or transient or lacunar) adj3 isch?emi).ti,ab.
13.	*Transient ischemic attack/
14.	(isch?emi* adj2 attack*).ti,ab.
15.	TIA.ti,ab.
16.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or crescendo or transient or lacunar) adj3 (oedema or edema* or swell* or swollen or enlarg*)).ti,ab.
17.	or/1-16
18.	letter.pt. or letter/
19.	note.pt.
20.	editorial.pt.
21.	case report/ or case study/
22.	(letter or comment*).ti.
23.	or/18-22
24.	randomized controlled trial/ or random*.ti,ab.
25.	23 not 24
26.	animal/ not human/
27.	nonhuman/
28.	exp Animal Experiment/
29.	exp Experimental Animal/
30.	animal model/
31.	exp Rodent/
32.	(rat or rats or mouse or mice).ti.
33.	or/25-32
34.	17 not 33
35.	limit 34 to English language
36.	braint decompression/ or decompression surgery/ or decompression/
37.	skull surgery/ or craniectomy/ or cranioplasty/ or craniotomy/ or neurosurgery/
38.	(decompress* or craniectom* or craniotom* or hemi-craniect* or hemicraniect* or trepa* or treph*).ti,ab.
39.	(hippocampectom* or lobectom* or strokectom*).ti,ab.
40.	or/36-39
41.	35 and 40
42.	random*.ti,ab.
43.	factorial*.ti,ab.
44.	(crossover* or cross over*).ti,ab.
45.	((doubl* or singl) adj blind).ti,ab.
46.	(assign* or allocat* or volunteer* or placebo*).ti,ab.
47.	crossover procedure/
48.	single blind procedure/
49.	randomized controlled trial/
50.	double blind procedure/
51.	or/42-50
52.	systematic review/
53.	meta-analysis/
54.	(meta analy* or metanaly* or metaanaly* or meta regression).ti,ab.
55.	((systematic* or evidence) adj3 (review or overview*)).ti,ab.
56.	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
57.	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
58.	(search* adj4 literature).ab.
59.	(medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab.
60.	cochrane.jw.
61.	((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab.
62.	or/52-61
63.	51 or 62

Cochrane Library (Wiley) search terms

#1.	MeSH descriptor: [Stroke] explode all trees
#2.	(stroke or strokes):ti,ab
#3.	((cerebro* or cerebral) near/2 (accident or apoplexy)):ti,ab
#4.	(CVA or poststroke or poststrokes):ti,ab
#5.	MeSH descriptor: [Intracranial Hemorrhages] explode all trees
#6.	(brain near/2 (attack1 or hemorrhag or haemorrhag* or bleed* or infarct*)):ti,ab
#7.	((intracerebral or intracranial or cerebral* or cerebro* or cerebrum or cerebellum or subarachnoid* or choroidal or basal ganglia or subdural) near/3 (hemorrhag* or haemorrhag* or bleed*)):ti,ab
#8.	MeSH descriptor: [Brain Infarction] explode all trees
#9.	MeSH descriptor: [Carotid Artery Thrombosis] explode all trees
#10.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or transient or lacunar) near/3 (infarct or thrombo* or emboli* or occlus* or hypoxi*)):ti,ab
#11.	MeSH descriptor: [Brain Ischemia] explode all trees
#12.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or crescendo or transient or lacunar) near/3 isch?emi):ti,ab
#13.	MeSH descriptor: [Ischemic Attack, Transient] this term only
#14.	(isch?emi* near/2 attack*):ti,ab
#15.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or crescendo or transient or lacunar) near/3 (oedema or edema* or swell* or swollen or enlarg*)):ti,ab
#16.	TIA:ti,ab
#17.	(or #1-#16)
#18.	MeSH descriptor: [Decompression, Surgical] this term only
#19.	MeSH descriptor: [Neurosurgical Procedures] this term only
#20.	MeSH descriptor: [Craniotomy] this term only
#21.	MeSH descriptor: [Trephining] explode all trees
#22.	(decompress* or craniectom* or craniotom* or hemi-craniect* or hemicraniect* or trepa* or treph*):ti,ab
#23.	(hippocampectom* or lobectom* or strokectom*):ti,ab
#24.	(or #18-#23)
#25.	#17 and #24

Table 10Database date parameters and filters used

Database

Dates searched

Search filter used

Medline

01 January 2007 – 06 August 2018

Exclusions

Health economics studies

Embase

01 January 2007 – 06 August 2018

Exclusions

Health economics studies

Centre for Research and Dissemination (CRD)

HTA - 01 January 2007 – 10 November 2017

NHSEED - 01 January 2007 – March 2015

None

Medline (Ovid) search terms

1.	exp Stroke/
2.	(stroke or strokes).ti,ab.
3.	((cerebro* or cerebral) adj2 (accident or apoplexy)).ti,ab.
4.	(CVA or poststroke or poststrokes).ti,ab.
5.	exp Intracranial Hemorrhages/
6.	(brain adj2 (attack1 or hemorrhag or haemorrhag* or bleed* or infarct*)).ti,ab.
7.	((intracerebral or intracranial or cerebral* or cerebro* or cerebrum or cerebellum or subarachnoid* or choroidal or basal ganglia or subdural) adj3 (hemorrhag* or haemorrhag* or bleed*)).ti,ab.
8.	exp Brain infarction/
9.	exp Carotid Artery Thrombosis/
10.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or transient or lacunar) adj3 (infarct or thrombo* or emboli* or occlus* or hypoxi*)).ti,ab.
11.	exp Brain Ischemia/
12.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or crescendo or transient or lacunar) adj3 isch?emi).ti,ab.
13.	Ischemic Attack, Transient/
14.	(isch?emi* adj2 attack*).ti,ab.
15.	TIA.ti,ab.
16.	or/1-15
17.	letter/
18.	editorial/
19.	news/
20.	exp historical article/
21.	Anecdotes as Topic/
22.	comment/
23.	case report/
24.	(letter or comment*).ti.
25.	or/17-24
26.	randomized controlled trial/ or random*.ti,ab.
27.	25 not 26
28.	animals/ not humans/
29.	exp Animals, Laboratory/
30.	exp Animal Experimentation/
31.	exp Models, Animal/
32.	exp Rodentia/
33.	(rat or rats or mouse or mice).ti.
34.	or/27-33
35.	16 not 34
36.	limit 35 to English language
37.	(exp child/ or exp pediatrics/ or exp infant/) not (exp adolescent/ or exp adult/ or exp middle age/ or exp aged/)
38.	36 not 37
39.	economics/
40.	value of life/
41.	exp “costs and cost analysis”/
42.	exp Economics, Hospital/
43.	exp Economics, medical/
44.	Economics, nursing/
45.	economics, pharmaceutical/
46.	exp “Fees and Charges”/
47.	exp budgets/
48.	budget*.ti,ab.
49.	cost*.ti.
50.	(economic* or pharmaco?economic*).ti.
51.	(price* or pricing*).ti,ab.
52.	(cost* adj2 (effectiv* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
53.	(financ* or fee or fees).ti,ab.
54.	(value adj2 (money or monetary)).ti,ab.
55.	or/39-54
56.	38 and 55

Embase (Ovid) search terms

1.	*cerebrovascular accident/ or cardioembolic stroke/ or exp experimental stroke/ or lacunar stroke/
2.	(stroke or strokes).ti,ab.
3.	((cerebro* or cerebral) adj2 (accident or apoplexy)).ti,ab.
4.	(CVA or poststroke or poststrokes).ti,ab.
5.	brain hemorrhage/ or brain ventricle hemorrhage/ or cerebellum hemorrhage/ or subarachnoid hemorrhage/
6.	(brain adj2 (attack1 or hemorrhag or haemorrhag* or bleed* or infarct*)).ti,ab.
7.	((intracerebral or intracranial or cerebral* or cerebro* or cerebrum or cerebellum or subarachnoid* or choroidal or basal ganglia or subdural) adj3 (hemorrhag* or haemorrhag* or bleed*)).ti,ab.
8.	brain infarction/ or brain infarction size/ or brain stem infarction/ or cerebellum infarction/
9.	*Carotid Artery Thrombosis/
10.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or transient or lacunar) adj3 (infarct or thrombo* or emboli* or occlus* or hypoxi*)).ti,ab.
11.	brain ischemia/ or hypoxic ischemic encephalopathy/
12.	((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or crescendo or transient or lacunar) adj3 isch?emi).ti,ab.
13.	*Transient ischemic attack/
14.	(isch?emi* adj2 attack*).ti,ab.
15.	TIA.ti,ab.
16.	or/1-15
17.	letter.pt. or letter/
18.	note.pt.
19.	editorial.pt.
20.	case report/ or case study/
21.	(letter or comment*).ti.
22.	or/17-21
23.	randomized controlled trial/ or random*.ti,ab.
24.	22 not 23
25.	animal/ not human/
26.	nonhuman/
27.	exp Animal Experiment/
28.	exp Experimental Animal/
29.	animal model/
30.	exp Rodent/
31.	(rat or rats or mouse or mice).ti.
32.	or/24-31
33.	16 not 32
34.	(exp child/ or exp pediatrics/) not (exp adult/ or exp adolescent/)
35.	33 not 34
36.	health economics/
37.	exp economic evaluation/
38.	exp health care cost/
39.	exp fee/
40.	budget/
41.	funding/
42.	budget*.ti,ab.
43.	cost*.ti.
44.	(economic* or pharmaco?economic*).ti.
45.	(price* or pricing*).ti,ab.
46.	(cost* adj2 (effectiv* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
47.	(finance* or fee or fees).ti,ab.
48.	(value adj2 (money or monetary)).ti,ab.
49.	or/36-48
50.	35 and 49

NHS EED and HTA (CRD) search terms

#1.	MeSH DESCRIPTOR Stroke EXPLODE 1 2
#2.	((stroke or strokes))
#3.	(((cerebro* or cerebral) adj2 (accident or apoplexy)))
#4.	((CVA or poststroke or poststrokes))
#5.	MeSH DESCRIPTOR Intracranial Hemorrhages EXPLODE ALL TREES
#6.	((brain adj2 (attack1 or hemorrhag or haemorrhag* or bleed* or infarct*)))
#7.	(((intracerebral or intracranial or cerebral* or cerebro* or cerebrum or cerebellum or subarachnoid* or choroidal or basal ganglia or subdural) adj3 (hemorrhag* or haemorrhag* or bleed*)))
#8.	MeSH DESCRIPTOR Brain Infarction EXPLODE ALL TREES
#9.	MeSH DESCRIPTOR Carotid Artery Thrombosis EXPLODE ALL TREES
#10.	(((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or transient or lacunar) adj3 (infarct or thrombo* or emboli* or occlus* or hypoxi*)))
#11.	MeSH DESCRIPTOR Brain Ischemia EXPLODE ALL TREES
#12.	(((brain or brainstem or cerebr* or cerebell* or vertebrobasil* or verte brobasil* or hemisphere* or intracran* or intracerebral or infratentorial or supratentorial or mca1 or anterior circulation or carotid or crescendo or transient or lacunar) adj3 isch?emi))
#13.	MeSH DESCRIPTOR Ischemic Attack, Transient EXPLODE ALL TREES
#14.	((isch?emi* adj2 attack*))
#15.	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14

Figure 1Flow chart of clinical study selection for the review of decompressive hemicraniectomy

Figure 1Mortality at 30 days

Figure 2Mortality at 6 months

Figure 3Mortality at 1 year

Figure 4Functional outcomes, score of 0-3 on mRS scale at 6 months

Figure 5Functional outcomes, score of 0-3 on mRS scale at 1 year

Figure 6Quality of life, SF-36 at 1 year (range: 0-100, high is good outcome)

Figure 7Mortality, 6 months

Figure 8Mortality, 1 year

Figure 9Functional outcomes, mRS 0-3 at 6 months

Figure 10Functional outcomes, mRS 0-3, 1 year

Figure 11Quality of life, EQ-5D, index scale (range: −0.205 “dead” to 1.0 “perfect health”), 1 year

Figure 12Quality of Life, EQ-5D, visual analogue scale (range: 0-100, high is good outcome), 1 year

Figure 13mRS distribution at 6 months

Figure 14mRS distribution at 1 year

Table 11Clinical evidence profile: Decompressive hemicraniectomy vs medical treatment for those under 60yrs

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	DHC	Medical Treatment	Relative (95% CI)	Absolute	Quality	Importance
Mortality at 30 days
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹	none	2/17 (11.8%)	53.3%	RR 0.22 (0.06 to 0.88)	416 fewer per 1000 (from 64 fewer to 501 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
Mortality at 6 months
3	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹	none	15/47 (31.9%)	54.54%	RR 0.52 (0.32 to 0.86)	262 fewer per 1000 (from 76 fewer to 371 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
Mortality at 1 year
3	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	15/69 (21.7%)	59.38%	RR 0.34 (0.21 to 0.56)	392 fewer per 1000 (from 261 fewer to 469 fewer)	⨁⨁⨁⨁ HIGH	CRITICAL
Functional outcomes at 6 months, score of 0-3 on mRS scale (range: 0-6, high is poor outcome)
4	randomised trials	Very serious²	no serious inconsistency	no serious indirectness	very serious¹	none	20/64 (31.3%)	28.3%	RR 1.39 (0.76 to 2.56)	110 more per 1000 (from 68 fewer to 441 more)	⨁◯◯◯ VERY LOW	CRITICAL
Functional outcomes at 1 year, score of 0-3 on mRS scale (range: 0-6, high is poor outcome)
3	randomised trials	serious²	no serious inconsistency	no serious indirectness	serious¹	none	126/69 (37.7%)	25%	RR 1.52 (0.9 to 2.57)	130 more per 1000 (from 25 fewer to 392 more)	⨁⨁◯◯ LOW	CRITICAL
Quality of Life, SF-36 mental summary (0-100), high is good outcome (follow-up 1 years)
1	randomised trials	serious²	no serious inconsistency	no serious indirectness	very serious¹	none	23	12	-	MD 2 higher (5.92 lower to 9.92 higher)	⨁◯◯◯ VERY LOW	IMPORTANT
Quality of Life, SF-36 physical summary (0-100), high is good outcome (follow-up 1 years)
1	randomised trials	serious²	no serious inconsistency	no serious indirectness	serious¹	none	23	12	-	MD 7 lower (13.85 to 0.15 lower)	⨁⨁◯◯ LOW	IMPORTANT
Quality of Life, SF-36 VAS (0-100), high is good outcome (follow-up 1 years)
1	randomised trials	serious²	no serious inconsistency	no serious indirectness	serious¹	none	20	12	-	MD 7 lower (27.49 lower to 13.49 higher)	⨁⨁◯◯ LOW	IMPORTANT

1: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs.

2: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.

3: Control arm had zero events.

Table 12Clinical evidence profile: Decompressive hemicraniectomy vs medical treatment for those over 60yrs

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Decompressive Hemicraniectomy	Medical Treatment	Relative (95% CI)	Absolute	Quality	Importance
Mortality, 6 months
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹	none	2/16 (12.5%)	60.9%	RR 0.20 (0.05 to 0.8)	487 fewer per 1000 (from 122 fewer to 579 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
Mortality, 1 year
3	randomised trials	no serious risk of bias	no serious inconsistency	serious²	no serious imprecision	none	29/74 (39.2%)	75.8%	RR 0.52 (0.39 to 0.7)	364 fewer per 1000 (from 227 fewer to 462 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
Functional outcomes, 6 months, score of 0-3 on mRS scale (range: 0-6, high is poor outcome)
2	randomised trials	serious³	no serious inconsistency	no serious indirectness	very serious¹	none	5/65 (7.7%)	2/76 (2.6%)	RR 2.45 (0.55 to 10.91)	23 more per 1000 (from 7 fewer to 159 more)	⨁◯◯◯ VERY LOW	CRITICAL
2	randomised trials	serious³	no serious inconsistency	no serious indirectness	very serious¹	none			RR 2.45 (0.55 to 10.91)	23 more per 1000 (from 7 fewer to 159 more)	⨁◯◯◯ VERY LOW	CRITICAL
Functional outcomes, 1 year, score of 0-3 on mRS scale (range: 0-6, high is poor outcome)
3	randomised trials	serious³	no serious inconsistency	no serious indirectness	serious¹	none	10/76 (13.2%)	3/89 (3.4%)	RR 3.18 (1.03 to 9.83)	100 more per 1000 (from 10 more to 180 more)⁴	⨁⨁◯◯ LOW	CRITICAL
3	randomised trials	serious³	no serious inconsistency	no serious indirectness	serious¹	none			RR 3.18 (1.03 to 9.83)	100 more per 1000 (from 10 more to 180 more)⁴	⨁⨁◯◯ LOW	CRITICAL
Quality of Life, 1 year, EQ-5D (Better indicated by higher values)
1	randomised trials	serious³	no serious inconsistency	no serious indirectness	serious¹	none	42	58	-	MD 0.10 higher (0 to 0.2 higher)	⨁⨁◯◯ LOW	IMPORTANT
Quality of Life, 1 year, EQ-5D, visual analogue scale (0-100; Better indicated by higher values)
1	randomised trials	serious³	no serious inconsistency	no serious indirectness	serious¹	none	42	57	-	MD 16.40 higher (6.54 to 26.26 higher)	⨁⨁◯◯ LOW	IMPORTANT

1: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs.

2: Downgraded by 1 or 2 increments because the majority of the evidence included an indirect or very indirect population respectively.

3: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.

4: Calculated from risk difference.

Figure 15Flow chart of health economic study selection for the guideline

* Non-relevant population, intervention, comparison, design or setting; non-English language

Table 13Studies excluded from the clinical review

Study	Exclusion reason
Alexander 2016¹	Incorrect study design. Systematic review with references checked.
Ayling 2018²	Incorrect study design. Systematic review with no RCTs.
Back 2015³	Meta-analysis with references checked.
Cho 2003⁵	Incorrect comparison.
Delgado-López 2004⁹	Not in English.
Dhand 2014¹⁰	Inappropriate comparison. Incorrect interventions. Correspondence.
Elsawaf 2018¹¹	Incorrect comparison
Georgiadis 2002¹³	Incorrect interventions
Geurts 2013¹⁴	Follow up study
Gupta 2004¹⁵	Incorrect interventions. Inappropriate comparison. Systematic review: study designs inappropriate.
Hofmeijer 2008¹⁶	Abstract only
Inamasu 2013¹⁹	Incorrect study design. Retrospective.
Juttler 2011²⁰	Incomplete study. Awaiting their results.
Kamran 2017²³	Incorrect study design. Retrospective.
Khoozestan 2012²⁴	Incorrect study design. Protocol.
Li 2017²⁵	Incorrect study design. Systematic review.
Lin 2016²⁶	Incorrect study design. NRS.
Lu 2014²⁷	Incorrect study design. Systematic Review.
Lucas 2012²⁸	Incorrect study design. Observational.
Macleod 2006²⁹	Incorrect study design. Protocol.
McKenna 2012³⁰	Inappropriate comparison.
Mohan Rajwani 2017³¹	Incorrect study design. Systematic review
Neugebauer 2012³³	Incorrect study design. Protocol.
Omay 2013³⁴	Incorrect study design. RCTs obtained.
Pledl 2016³⁶	Incorrect study design. Retrospective.
Schwab 1995³⁸	Not in English.
Sengeze 2014³⁹	Incorrect study design. NRS.
Streib 2016⁴¹	Meta-analysis with references checked.
Vahedi 2004⁴³	Incorrect study design. Trial record
Vahedi 2005⁴⁵	Incorrect study design. Abstract
Vahedi 2007⁴⁴	Meta-analysis with references checked.
Vahedi 2009⁴²	Incorrect study design. Review
Van Middelaar 2015⁴⁷	Incorrect study design. Systematic review with not solely RCTs.
Vibbert 2010⁴⁸	Incorrect study design. Review
Worp 2006⁴⁹	Incorrect study design. Protocol
Yang 2015⁵⁰	Systematic review with references checked.