the sort of calculation that one can do in one’s head…
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The implications of the GALA trial: General Anaesthesia vs Local (regional) Anaesthesia for Carotid Surgery 3 rd UK Stroke Forum Conference, Harrogate, December 2008 Michael Gough, Leeds and Charles Warlow, Edinburgh for the GALA collaborators. - PowerPoint PPT PresentationTRANSCRIPT
Funding: Health Foundation, ESVS
The implications of the GALA trial:General Anaesthesia vs Local (regional) Anaesthesia
for Carotid Surgery
3rd UK Stroke Forum Conference, Harrogate, December 2008
Michael Gough, Leeds and Charles Warlow, Edinburgh for the GALA collaborators
Funding: Health Foundation, ESVS
The sort of calculation that one can do in one’s head…
• For >70% symptomatic stenosis
Risk of surgery: 5% stroke/death within 30 days
Risk of ipsilateral ischaemic stroke without surgery: 20% at two years
Risk of death/another sort of stroke within two years: very low
Risk of ipsilateral ischaemic stroke after successful surgery: “zero”
• Calculation
Absolute risk reduction in stroke from surgery: 15% (20 - 5)
Number-needed-to-operate to prevent a stroke = 6 (100/15)
Therefore 1 in 6 patients benefit from surgery, 5 do not
Funding: Health Foundation, ESVS
Interpretation
• If number-needed-to-operate = 6 patients, to make surgery a ‘better buy’ (reduce number-needed-to-operate):
Identify patients with higher ipsilateral stroke risk without operation
Safer investigation (angiography)
Safer surgery (identify low surgical risk)
Safer anaesthesia: GALA
Funding: Health Foundation, ESVS
General (GA) or Local Anaesthesia (LA) for carotid surgery: pros and cons
• Advantages to LA
‘Awake neurological testing’ during carotid clamping = ↓shunting
Preserves autoregulation
• Potential benefits of LA
? ‘safer’ in high risk elderly ‘vascular’ patients
? less ‘stress’ response to surgery
? better postoperative pain relief
? earlier mobilisation, less traumatic = QOL, less expensive v GA
• Possible disadvantages of LA
More traumatic for the patient and the surgeon
Hurried surgery
Conversions (LA to GA) can be problematic
Patient might prefer GA
Funding: Health Foundation, ESVS
Cochrane Review of LA v GA for carotid surgery: non-randomised, stroke and death
Rerkasem K, Bond R, Rothwell PM. Cochrane Database of Systematic Reviews 2004; 2: CD000126
Funding: Health Foundation, ESVS
Cochrane Review of LA v GA for carotid surgery: randomised, stroke and death
Rerkasem K, Bond R, Rothwell PM. Cochrane Database of Systematic Reviews 2004; 2: CD000126
Funding: Health Foundation, ESVS
Rationale for GALA
• Good theoretical reasons to prefer LA over GA for CEA but ….… “beautiful hypotheses can be destroyed by ugly facts”
(Thomas Huxley)
• Cochrane Review encouraging but… non-randomised studies likely to be biased randomised trials too small ‘stroke and death’ are not the only outcomes of interest
• Variation in practice of carotid surgery over time
• No good evidence for LA vs GA in other forms of surgery
Funding: Health Foundation, ESVS
What happened next?
1997: CPW, MJG
Steering Committee
Protocol
MREC
Trial Co-ordinator
Funding
1999: Pilot 20 UK Centres
2003:Main Trial
Funding: Health Foundation, ESVS
Design of GALA
• Randomised, partially blinded two arm trial, intention-to–treat analysis• Uncertainty principle • Pragmatic non-restrictive protocols (except shunt in LA)
• ManagementLeeds: surgical and anaesthetic leadership Edinburgh: trial ManagementYork: health economics
• Target: 5000 patients
• Follow up at: hospital discharge, 7 days post operative, or death one month: ‘blind’ stroke physician/neurologist (phone if necessary) one month: QOL questionnaire (UK only) one year: questionnaire to patients re stroke/MI
Funding: Health Foundation, ESVS
• Assume 7.5% incidence of primary outcome at 30 days • Achieve one third reduction in risk to 5% (> 90% power at 5%)• Analysis intention-to-treat
• Primary outcome:
Stroke (including retinal infarct), myocardial infarction (MI), death
• Secondary outcomes:
Alive and stroke/MI free at one year
QOL at 30 days (UK only)
Surgical complications (haematoma, re-opn, cranial nerve palsy etc)
Length of stay (intensive care, high dependency, total)
Cost
Why 5000 patients?
Funding: Health Foundation, ESVS
Eligibility for the GALA Trial
• Experienced surgeons (>15 carotid endarterectomies per annum)
• Local ethics committee approval
• Any patient requiring carotid surgery (symptomatic or asymptomatic stenosis)
• Usual management, except shunts during LA only if indicated by awake testing
• Uncertainty
• No patient preference
Funding: Health Foundation, ESVSAUSTRALIA3526 patients from 95 GALA centres in 24 countries
CHINA
Funding: Health Foundation, ESVS
3526 randomised(95 centres, 24 countries)
GA1753 allocated: 1628 GA
31 no anaesthesia - 92 cross-over2 unknown
LA1773 allocated: 1655 LA
41 no anaesthesia - 75 cross-over2 unknown
1752 for primary outcome (No FU = 1, Incomplete = 20)
1771 for primary outcome (No FU = 2, Incomplete = 19)
99.9% FU
Funding: Health Foundation, ESVS
Baseline data
General Local
Age 70 (sd 9) 69 (sd 9)
Male 1232 (70%) 1256 (71%)
Asymptomatic stenosis 685 (39%) 677 (38%)
Mean % stenosis 81 (sd 11) 81 (sd 11)
Contralateral ICA occlusion 150 (9%) 160 (9%)
Smoking, peripheral arterial disease, coronary artery disease, atrial fibrillation, diabetes, blood pressure all equal
Funding: Health Foundation, ESVS
Compliance
General Local
No anaesthesia
Stroke or death before operation 2 2
Carotid artery occlusion 8 8
Too ill (not carotid), Stenosis too mild, stent 5 12
Patient refused 9 31 13 41
Conversion post- anaesthesia, pre-op
Patient’s decision 6
Problem with position on table etc 3
Patient deteriorated after local block 8
Conversion after start of surgery
Pain, discomfort, anxiety, claustrophobia 34
Physiological instability, protracted surgery 11
Neurological deterioration on cross-clamping 7
Funding: Health Foundation, ESVS
Compliance – cross-overs
Reasons:General (n=92)
Local (n=75)
Medical decision 41 20
Administrative issues 15 9
Patient’s decision 29 44
Reason unknown 7 2
Funding: Health Foundation, ESVS
Primary outcome eventsIntention-to-treat
70 66
4 9510
0%
1%
2%
3%
4%
5%
General
84/1752 (4.8%)
Local
80/1771 (4.5%)
Other deaths
MI (fatal ornon-fatal)
Stroke (fatalor non-fatal)
Funding: Health Foundation, ESVS
Primary outcome events
Stroke 3 (-10 to +16)
MI -4(-8 to +2)
Death (any cause) 4 (-3 to +12)
Stroke or death 4 (-9 to +18)
Stroke, MI or death 3 (-11 to +17)
Favours General Favours Local
Events prevented/1000 (95% CI)
-20 -10 0 10 20
Intention to treat
Funding: Health Foundation, ESVS
Strokes within 30 days of CEA
0
10
20
30
40
50
60
70
80
Pre-op
0 1 2 3 4 5-7 8-14 15-21 22-30Days since endarterectomy
Num
ber
of p
atie
nts
.
infarct haemorrhage unknown
Funding: Health Foundation, ESVS
Subgroup analysis on primary outcome
Subgroup General Local P(% ) (% )
Contralateral carotid Yes 10.0% 5.0% 0.098occlusion No 4.3% 4.5%
Age (years) >75 5.3% 4.6% 0.741<=75 4.6% 4.5%
Baseline surgical High 4.1% 4.6% 0.933risk Medium 5.1% 4.9%
Low 4.7% 4.2%
Favours LA Favours GA
Odds ratio and 95% Confidence interval
0.1 1 10
Contralateral carotid occlusion
Favours LA Favours GA
Funding: Health Foundation, ESVS
Secondary outcomes
No definite differences (GA v LA):
Length of stay Duration of surgery
Trainee v consultant Asymptomatic v symptomatic
UK v others Cranial nerve injury
Wound haematoma Chest infection
Quality of life at one month Outcome at one year
Cost
Funding: Health Foundation, ESVS
Survival analysis Free of stroke, MI and death
0%
2%
4%
6%
8%
10%
12%
14%
0 6 12Months since randomisation
% o
f pat
ient
s w
ith e
vent
.
General
Local
Number at risk: General Local
1752 1241 736 1771 1269 751
P=0.094
Funding: Health Foundation, ESVS
Limitations of GALA
• Lack of power
Sample size, outcome events
• Lack of complete blinding
• Cross-overs pre-op (5%), conversions LA GA (4%)
• Lack of standardisation of anaesthetic and surgical protocols
BP in the GA group, Patching: 42% LA v 50% GA
• The surgical risk model did not work
• Took too long, would have failed without the non-UK centres
Funding: Health Foundation, ESVS
UK and Non UK Centres
Number of patients randomised/year
0
100
200
300
400
500
600
700
800
900
1999 2000 2001 2002 2003 2004 2005 2006 2007
Pat
ien
ts
Non UKUK
Funding: Health Foundation, ESVS
Recruitment inCarotid Surgery Trials
0
500
1000
1500
2000
2500
3000
3500
4000
NASCET ECST ACST 1 GALA
Num
ber
of P
atie
nts
2267
3024 3120
3526
Funding: Health Foundation, ESVS
Limitations of local anaesthesia
• Unable to tolerate
• Additional sedation and analgesia
• Conversion to GA
• Stress & anxiety may cardiac events
• Injury to surrounding structures
• More peri-operative strokes may be due to embolism
• Modern GA safer/less stressful
Funding: Health Foundation, ESVS
Putting GALA into context Stroke & death
0.1 1 10
Favours Local Favours General
Meta-analysis of 7 earlier RCTs
GALA
Meta-analysis including GALA
OR (95% CI)
0.62 (0.24 to 1.59)
0.88 (0.64 to 1.23)
0.85 (0.63 to 1.16)
Funding: Health Foundation, ESVS
Putting GALA into context Death
0.01 0.1 1 10 100
Favours Local Favours General
Meta-analysis of 7 earlier trials
GALA
Meta-analysis including GALA
OR (95% CI)
0.23 (0.05 - 1.01)
0.72 (0.40 - 1.30)
0.62 (0.36 – 1.07)
Funding: Health Foundation, ESVS
Conclusions
• Little difference in patient outcomes regardless of GA or LA
• Surgical teams should be able to offer both LA & GA
• The individual choice should be determined by the patient’s medical need and personal preference
• Trials like GALA could and should be done more quickly, but will have to be multinational
• Regulations make trials increasingly difficult to do, and more expensive
• The cost-effectiveness of carotid endarterectomy would be improved more dramatically by shortening the time from symptoms to surgery
Funding: Health Foundation, ESVS
The GALA Trial
A collaboration
Vascular Surgeons throughout Europe
HealthcareFoundation