The sort of calculation that one can do in one’s head…

1. The implications of the GALA trial:General Anaesthesia vs Local (regional) Anaesthesia for Carotid Surgery3rd UK Stroke Forum Conference, Harrogate, December 2008 Michael Gough, Leeds and Charles Warlow, Edinburgh for the GALA collaborators

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. What happened next? 1997: CPW, MJG Steering Committee Protocol MREC Trial Co-ordinator Funding 1999: Pilot 20 UK Centres 2003: Main Trial

9. 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

10. Why 5000 patients? • 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

11. 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

12. 3526 patients from 95 GALA centres in 24 countries CHINA AUSTRALIA

13. 99.9% FU

14. Baseline data Smoking, peripheral arterial disease, coronary artery disease, atrial fibrillation, diabetes, blood pressure all equal

15. Compliance

16. Compliance – cross-overs

17. 5% 10 5 4 4% 9 Other deaths 3% MI (fatal or non-fatal) 2% 70 66 Stroke (fatal or non-fatal) 1% 0% General 84/1752 (4.8%) Local 80/1771 (4.5%) Primary outcome eventsIntention-to-treat

18. 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) -20 -10 0 10 20 Events prevented/1000 (95% CI) Favours General Favours Local Primary outcome events Intention to treat

19. 80 infarct haemorrhage unknown 70 60 50 Number of patients . 40 30 20 10 0 Pre- 0 1 2 3 4 5-7 8-14 15-21 22-30 Days since endarterectomy op Strokes within 30 days of CEA

20. Subgroup analysis on primary outcome Contralateral carotid occlusion Favours LA Favours GA

21. 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

22. Survival analysis Free of stroke, MI and death

23. 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

24. Non UK UK UK and Non UK Centres Number of patients randomised/year 900 800 700 600 500 Patients 400 300 200 100 0 1999 2000 2001 2002 2003 2004 2005 2006 2007

25. 4000 3526 3500 3120 3024 3000 2267 2500 2000 Number of Patients 1500 1000 500 0 NASCET ECST ACST1 GALA Recruitment in Carotid Surgery Trials

26. 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

27. OR (95% CI) 0.62 (0.24 to 1.59) 0.88 (0.64 to 1.23) 0.85 (0.63 to 1.16) Meta-analysis of 7 earlier RCTs GALA Meta-analysis including GALA Favours Local Favours General Putting GALA into context Stroke & death

28. Putting GALA into context Death OR (95% CI) 0.23 (0.05 - 1.01) 0.72 (0.40 - 1.30) 0.62 (0.36 – 1.07) Meta-analysis of 7 earlier trials GALA Meta-analysis including GALA Favours Local Favours General

29. 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

30. Healthcare Foundation The GALA Trial A collaboration Vascular Surgeons throughout Europe