MACQUARIE NEUROSURGERY JOURNAL CLUB 27/10/16

Dr Michael Mulcahy

MACQUARIE NEUROSURGERYJOURNAL CLUB

P.J. Hutchinson, A.G. Kolias, I.S. Timofeev, E.A. Corteen, M. Czosnyka, J. Timothy, I. Anderson, D.O. Bulters, A. Belli, C.A. Eynon, J. Wadley, A.D. Mendelow, P.M. Mitchell, M.H. Wilson, G. Critchley, J. Sahuquillo, A. Unterberg, F. Servadei,

G.M. Teasdale, J.D. Pickard, D.K. Menon, G.D. Murray, and P.J. Kirkpatrick, for the RESCUEicp Trial Collaborators*

Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension

The New England Journal of Medicine, Sept 2016, volume 375, issue 12, pp1119-30.

Authors

• Chief investigator: Professor Peter Hutchinson, University of Cambridge and Addenbrooke’s hospital

• 22 co-authors and 211 trial collaborators

• 52 centres in 20 countries

Disclosures

• Grant from MRC-NIHR partnership• Evelyn trust• Dr. Hutchinson reports grants from NIHR Efficacy and Mechanism Evaluation Programme, during the conduct of the study; grants from NIHR Health Technology Assessment

(HTA) Programme, outside the submitted work; and being a Director of Technicam (manufacturer of a cranial access device). Dr. Hutchinson reports having participated in a consensus conference on intracranial pressure that was held in Milan on October 5, 2013. The conference was financially supported by Codman (a division of Ethicon Ltd.), with an unconditional grant, though he reports having received no support.

• Dr. Bulters reports grants from Innovate UK, grants from EU FP7, grants from EPSRC, grants from NIHR, grants from Royal College of Surgeons of Edinburgh, grants from Wessex Medical Research, grants from Smile for Wessex, grants and personal fees from ReNeuron, personal fees from Portola, personal fees from Johnson and Johnson, grants from Evgen Pharma, grants from Vasopharm, outside the submitted work.

• Dr. Czosnyka reports personal fees from Cambridge Enterprise Ltd., outside the submitted work.• Dr. Kolias reports grants from NIHR Efficacy and Mechanism Evaluation Programme, during the conduct of the study; grants from NIHR Health Technology Assessment (HTA)

Programme, grants from NIHR Health Technology Assessment (HTA) Programme, outside the submitted work; and The British Neurosurgical Trainee Research Collaborative, which he chaired from 2012-15, has been supported with an educational grant from Codman, UK. Dr. Kolias reports having participated in a consensus conference on intracranial pressure that was held in Milan on October 5, 2013. The conference was financially supported by Codman (a division of Ethicon Ltd.), with an unconditional grant.

• Dr. Mendelow reports non-financial support and other from Newcastle Neurosurgery Foundation Ltd., personal fees from Stryker, personal fees from Draeger, outside the submitted work; and Director of Newcastle Neurosurgery Foundation Ltd.

• Dr. Menon reports grants and non-financial support from GlaxoSmithKline Ltd, personal fees from Pressura Ltd, personal fees from Calico Ltd, personal fees from Glide Pharma Ltd, personal fees from Pfizer Ltd, personal fees from Medicxi Ventures (UK) LLP , personal fees from Lantmännen AB , grants from Brainscope Ltd, personal fees from Ornim Medical, personal fees from Shire Medical, other from IMEC Ltd, grants from National Institute for Health Research UK, outside the submitted work; and help with development of a protocol for a clinical trial of ciclosporin in TBI sponsored by Neurovive. The project did not come to fruition.

• Dr. Pickard reports grants from NIHR Efficacy and Mechanism Evaluation Programme, during the conduct of the study; grants from NIHR Senior Investigator Award, grants from NIHR Brain Injury Healthcare Technology Co-operative, grants from NIHR Cambridge Biomedical Research Centre (Brain injury theme), personal fees and non-financial support from Medtronic , personal fees and non-financial support from Codman (Johnson and Johnson), outside the submitted work; and Director, Medicam and Technicam (no financial remuneration) .

• Dr. Servadei reports grants and personal fees from Codman Company , grants and personal fees from Finceramica , personal fees from Baxter Company , outside the submitted work

Study Relevance

• At the time of trial design (>10yrs ago) there were many studies on the role of decompressive craniectomy in TBI, with a wide range of outcomes

• Concerns that DC simply increases the amount of patients in a vegetative state

• Important to resolve the role of this treatment for a condition with profound social and economic consequences

Relevance/Originality

• ICP >20mmHg for more than 15min within a 1 hr period, despite optimised first tier therapy.

• Significant decrease in ICP in Sx group; mortality was similar (Sx 19% v. non-Sx 18%); GOS-E scores at 6 months were worse (p=0.03). Contradictory to the literature at the time.

• Concluded that the findings were unlikely to be due to a shift from survival to vegetative state (due to similar mortality), but rather that DC changes outcome from favourable to unfavourable.

Relevance/Originality

Criticism

• protocol was not reflective of clinical practice

• high number of exclusions (only 4.5% of screened patients were enrolled)

• significant imbalances in baseline characteristics, esp. fixed pupils

Trial Design

• International, multi-centre randomised controlled trial

• Two arm, parallel group study

• Pragmatic

• All hospitals provided acute neuroscience care for severe TBI and had 24

hour neurosurgical service

Study Protocol

Acta Neurochirurgica Supplement 2006

Trial Design

Hypotheses

1. Decompressive craniectomy results in an improvement in the Extended Glasgow

Outcome Score compared to optimal medical treatment

2. Decompressive craniectomy results in an improvement in surrogate endpoint

measures (including specific outcome measures [SF-36 questionnaire], control of

ICP, time in intensive care, and time to discharge from the neurosurgical unit)

compared to optimal medical treatment

Trial Design

Outcomes

• Primary outcome is GOS-E score at 6 months

• Secondary outcomes:

- GOS-E at 12 and 24 months (after randomisation)

- Mortality at 6, 12, and 24 months (after randomisation)

- QOL at 6, 12, and 24 months (after randomisation)

- GCS at discharge from hospital

- assessment of ICP control

- time in ICU

- time to discharge from hospital

- health-economic evaluation

• Adverse events will be recorded

Trial Design

How to assess ICP control?

- mean ICP (after randomisation)

- number of hours with ICP>25mmHg (after randomisation)

- the intracranial hypertension index 20

- the intracranial hypertension index 25

- cerebral hypoperfusion index

Trial Design

Original protocol flowchart:

Trial Design

Statistical Analysis Plan

• power calculation: 400 patients required for a 15% difference in outcome

(favourable outcome from 45% to 60%) (power 80%, p=0.05)

• modified intention to treat analysis (excluded patients lost to follow up or who

withdrew consent)

• pre-specified that they would pool ‘upper-good recovery’ and ‘lower good

recovery’

• sensitivity analysis- the proportion of patients achieving a ‘favourable’ outcome

(i.e. upper severe disability or better)

• covariate adjustment (age; GCS motor score; pupils; last pre-randomised

Marshall CT class)

Trial Design

Primary-outcome measure: GOS-E

Trial Design

Results

CONSORT diagram:

Results

Results

Interventions:

Results

Primary outcome:

• ordinal analysis based on proportional odds model

• the goodness of fit of this model was tested with a likelihood-ratio test; this was rejected,

indicating a difference in the distribution of the GOS-E scores in the two groups (at 5%

significance level)

• then, as pre-specified, the groups were compared with a chi-squared test

Results

Primary outcome:

• ordinal analysis based on proportional odds model

• the goodness of fit of this model was tested with likelihood-ratio test and was rejected,

indicating a difference in the distribution of the GOS-E scores in the two groups (at 5%

significance level)

• then, as pre-specified, the groups were compared with unordered chi-squared test

Results

Primary outcome (sensitivity analysis):

• increase in favourable outcome (8.2%, p=0.12) and unfavourable outcome (no p-value)

Results

Primary outcome:

For every 100 patients treated with surgery rather than medical therapy, there will be 22 more survivors. Of these:- 6 will be in a ‘vegetative state’- 8 will be ‘lower severe disability’- 8 will be independent at home or better

Results

Secondary outcomes:

For every 100 patients treated with surgery rather than medical therapy, there will be 22 more survivors. Of these:- 5 will be in a ‘vegetative state’- 4 will be ‘lower severe disability’- 13 will be independent at home or better

Results

Secondary outcomes:

Sensitivity analysis at 12 months- increase in favourable outcome 13% (p=0.01)

Results

Secondary outcomes:

• Control of intracranial pressure was better in the surgical group in all 5 pre-

specified measures

Results

Secondary outcomes:

• No difference in time to discharge/death from ICU (median about 12 days for both)

• If death is censored, median time to d/c from ICU is 15 v. 21 days (p=0.01)

• Secondary outcomes pending: 24 month GOS-E; QOL analysis; health-economic analysis

• 37 adverse events were reported in 33 patients (surgical group). 32 complications and adverse events were reported in 18 patients (medical group).

Results

A priori subgroup analysis (separate binary logistic regression models for mortality and for

favourable outcome):

Internal Validity

Statistics:

• power calculation was appropriate (80% with p=0.05)

• 15% change in outcome is comparable to the literature

• achieved their recruitment target (400 patients)

Protocol published before trial and it was followed faithfully, except:

• original protocol - hyperventilate to CO2 26-34mmHg; changed to 30-34mmHg

• steroid therapy was in the original protocol; but removed as an option during trial

• initially cooling to 35-36oC was recommend; changed to ‘therapeutic hypothermia’ as an

option

Internal Validity

Randomisation:

• 1:1 allocation with permuted blocks of random size

• Stratified by site

• Blocks were not disclosed to ensure concealment

• Central telephone randomisation service

• Randomisation code was not release until patient had reached stage 3 of the protocol

• Baseline characteristics were similar except: history of drug or alcohol abuse

Blinding:

• clinicians were not blinded

• 2 trial team members reviewed the GOS-E questionnaires independently of each other and were blinded to the group assignment

External Validity

• Representative population

• Relevant inclusion/exclusion criteria

• Modified intention to treat

• The treatment protocol is replicable (keeping in mind pragmatic nature of study)

• Choice of craniectomy technique is replicable

• 12 month follow up and clinically relevant outcomes

• No cranioplasty data

Guidelines for the Management of Severe Traumatic Brain Injury brain trauma foundation

2007: 2016:

External validity- 20 or 25?

Discussion

• Authors’ conclusion:

• At 6 months, DC for severe and refractory intracranial hypertension

after TBI resulted in mortality that was 22 percentage points lower

than that with medical management.

• Surgery also was associated with higher rates of vegetative state,

lower severe disability, and upper severe disability than medical

management.

• The rates of moderate disability and good recovery with surgery were

similar to those with medical management.

Discussion

• Weaknesses:

• dilution of treatment effect given large crossover (37.2%)

• hypothermia used during trial may be harmful (Eurotherm3235)

• steroid use initially an option during the trial

• clinical teams not blinded

• no data on cranioplasty (esp. complications)

• Overall though:

• Clinically relevant and important study

• Well executed a priori protocol

• Robust internal and external validity

Conclusion

• Well-conducted RCT

• DC results in reduced mortality, and can thus be used as a life saving intervention for

refractory raised ICP in TBI. There will be increased number of dependent patients at 6-

12 months, as well as increased favourable outcomes

• Trial of DC v. barbiturates.

• In contrast to DECRA: a more generalisable result (less restrictive entry criteria; more

pragmatic approach to intracranial hypertension; more reflective of clinical practice)

• Future studies should look at 1) cranioplasty data and 2) the 37% medical group who

underwent DC