Funding: Health Foundation, ESVS 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

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) Management Leeds: surgical and anaesthetic leadership Edinburgh: trial Management York: 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-op n, 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, ESVS AUSTRALIA 3526 patients from 95 GALA centres in 24 countries CHINA

Funding: Health Foundation, ESVS 3526 randomised (95 centres, 24 countries) GA 1753 allocated: 1628  GA 31 no anaesthesia - 92 cross- over 2 unknown 1752 for primary outcome (No FU = 1, Incomplete = 20) LA 1773 allocated: 1655  LA 41 no anaesthesia - 75 cross- over 2 unknown 1771 for primary outcome (No FU = 2, Incomplete = 19) 99.9% FU

Funding: Health Foundation, ESVS Baseline data GeneralLocal Age70 (sd 9)69 (sd 9) Male1232 (70%)1256 (71%) Asymptomatic stenosis685 (39%)677 (38%) Mean % stenosis81 (sd 11) Contralateral ICA occlusion150 (9%)160 (9%) Smoking, peripheral arterial disease, coronary artery disease, atrial fibrillation, diabetes, blood pressure all equal

Funding: Health Foundation, ESVS Compliance GeneralLocal No anaesthesia Stroke or death before operation22 Carotid artery occlusion88 Too ill (not carotid), Stenosis too mild, stent512 Patient refused Conversion post- anaesthesia, pre-op Patient’s decision6 Problem with position on table etc3 Patient deteriorated after local block8 Conversion after start of surgery Pain, discomfort, anxiety, claustrophobia34 Physiological instability, protracted surgery11 Neurological deterioration on cross-clamping7

Funding: Health Foundation, ESVS Compliance – cross-overs Reasons: General (n=92) Local (n=75) Medical decision4120 Administrative issues159 Patient’s decision2944 Reason unknown72

Funding: Health Foundation, ESVS Primary outcome events Intention-to-treat % 1% 2% 3% 4% 5% General 84/1752 (4.8%) Local 80/1771 (4.5%) Other deaths MI (fatal or non-fatal) Stroke (fatal or non-fatal)

Funding: Health Foundation, ESVS Primary outcome events Stroke3(-10 to +16) MI-4(-8 to +2) Death (any cause)4(-3 to +12) Stroke or death4(-9 to +18) Stroke, MI or death3(-11 to +17) Favours GeneralFavours Local Events prevented/1000 (95% CI) Intention to treat

Funding: Health Foundation, ESVS Strokes within 30 days of CEA Pre- op Days since endarterectomy Number of patients. infarcthaemorrhageunknown

Funding: Health Foundation, ESVS Subgroup analysis on primary outcome Contralateral carotid occlusion Favours LAFavours GA

Funding: Health Foundation, ESVS Secondary outcomes No definite differences (GA v LA): Length of stayDuration of surgery Trainee v consultantAsymptomatic v symptomatic UK v othersCranial nerve injury Wound haematomaChest infection Quality of life at one monthOutcome at one year Cost

Funding: Health Foundation, ESVS Survival analysis Free of stroke, MI and death

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 Patients Non UK UK

Funding: Health Foundation, ESVS Recruitment in Carotid Surgery Trials NASCETECSTACST 1GALA Number of Patients

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 Favours LocalFavours 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 Favours LocalFavours General Meta-analysis of 7 earlier trials GALA Meta-analysis including GALA OR (95% CI) 0.23 ( ) 0.72 ( ) 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 Healthcare Foundation