Funding: Health Foundation, ESVS The implications of the GALA trial: General Anaesthesia vs Local (regional) Anaesthesia for Carotid Surgery 3 rd UK Stroke

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


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


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


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


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


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


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


What happened next?

1997: CPW, MJG

Steering Committee

Protocol

MREC

Trial Co-ordinator

Funding

1999: Pilot 20 UK Centres

2003:Main Trial


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


• 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?


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


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


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


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


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


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)


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


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


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


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


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


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


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


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


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


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)


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)


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


The GALA Trial

A collaboration

Vascular Surgeons throughout Europe

HealthcareFoundation

Documents

Funding: Health Foundation, ESVS The implications of the GALA trial: General Anaesthesia vs Local (regional) Anaesthesia for Carotid Surgery 3 rd UK Stroke