The implications of the GALA trial: General Anaesthesia vs Local (regional) Anaesthesia  for Carotid Surgery 3 rd  UK Stro...
The sort of calculation that  one can do in one’s head… <ul><li>For >70% symptomatic stenosis   </li></ul><ul><li>Risk of ...
Interpretation <ul><li>If number-needed-to-operate = 6 patients,  </li></ul><ul><li>to make surgery a ‘better buy’ (reduce...
General (GA) or Local Anaesthesia (LA)  for carotid surgery: pros and cons <ul><li>Advantages to LA </li></ul><ul><li>‘ Aw...
Cochrane Review of LA v GA for carotid  surgery: non-randomised, stroke and death  Rerkasem K, Bond R, Rothwell PM.  Cochr...
Cochrane Review of LA v GA for carotid  surgery: randomised, stroke and death Rerkasem K, Bond R, Rothwell PM.  Cochrane D...
Rationale for GALA <ul><li>Good theoretical reasons to prefer LA over GA for CEA but ….…    “beautiful hypotheses can be d...
What happened next? 1997:  CPW, MJG Steering Committee Protocol MREC Trial Co-ordinator  Funding 1999:   Pilot 20 UK Centr...
Design of GALA  <ul><li>Randomised, partially blinded two arm trial, intention-to–treat analysis </li></ul><ul><li>Uncerta...
<ul><li>Assume 7.5% incidence of primary outcome at 30 days  </li></ul><ul><li>Achieve one third reduction in risk to 5% (...
Eligibility for the GALA Trial <ul><li>Experienced surgeons (>15 carotid endarterectomies per annum) </li></ul><ul><li>Loc...
AUSTRALIA 3526 patients from 95 GALA centres in 24 countries CHINA
99.9% FU 3526 randomised (95 centres, 24 countries) GA 1753 allocated:  1628     GA 31 no anaesthesia - 92 cross-over 2 u...
Baseline data Smoking, peripheral arterial disease, coronary artery disease,  atrial fibrillation, diabetes, blood pressur...
Compliance 6 Patient’s decision 3 Problem with position on table etc 8 Patient deteriorated after local block Conversion a...
Compliance – cross-overs 2 7 Reason unknown 44 29 Patient’s decision 9 15 Administrative issues 20 41 Medical decision Loc...
Primary outcome events Intention-to-treat 70 66 4 9 5 10 0% 1% 2% 3% 4% 5% General 84/1752 (4.8%) Local  80/1771 (4.5%) Ot...
Primary outcome events Intention to treat Stroke 3 (-10 to +16) MI -4 (-8 to +2) Death (any cause) 4 (-3 to +12) Stroke or...
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 22-30 Days since endarterectomy N...
Subgroup analysis on  primary outcome Contralateral carotid  occlusion Favours LA Favours GA
Secondary outcomes <ul><li>No definite differences (GA v LA): </li></ul><ul><li>Length of stay Duration of surgery </li></...
Survival analysis  Free of stroke, MI and death
Limitations of GALA <ul><li>Lack of power  </li></ul><ul><li>Sample size, outcome events  </li></ul><ul><li>Lack of comple...
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 20...
Recruitment in Carotid Surgery Trials 0 500 1000 1500 2000 2500 3000 3500 4000 NASCET ECST ACST   1 GALA Number of Patient...
Limitations of local anaesthesia <ul><li>Unable to tolerate  </li></ul><ul><li>Additional sedation and analgesia </li></ul...
Putting GALA into context  Stroke & death Favours Local Favours General Meta-analysis of 7 earlier RCTs GALA Meta-analysis...
Putting GALA into context  Death Favours Local Favours General Meta-analysis of 7 earlier trials GALA Meta-analysis includ...
Conclusions <ul><li>Little difference in patient outcomes regardless of GA or LA </li></ul><ul><li>Surgical teams should b...
The GALA Trial A collaboration Vascular Surgeons throughout Europe Healthcare Foundation
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UK Stroke Forum December 2008

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UK Stroke Forum December 2008

  1. 1. 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
  2. 2. The sort of calculation that one can do in one’s head… <ul><li>For >70% symptomatic stenosis </li></ul><ul><li>Risk of surgery: 5% stroke/death within 30 days </li></ul><ul><li>Risk of ipsilateral ischaemic stroke without surgery: 20% at two years </li></ul><ul><li>Risk of death/another sort of stroke within two years: very low </li></ul><ul><li>Risk of ipsilateral ischaemic stroke after successful surgery: “zero” </li></ul><ul><li>Calculation </li></ul><ul><li>Absolute risk reduction in stroke from surgery: 15% (20 - 5) </li></ul><ul><li>Number-needed-to-operate to prevent a stroke = 6 (100/15) </li></ul><ul><li>Therefore 1 in 6 patients benefit from surgery, 5 do not </li></ul>
  3. 3. Interpretation <ul><li>If number-needed-to-operate = 6 patients, </li></ul><ul><li>to make surgery a ‘better buy’ (reduce number-needed-to-operate): </li></ul><ul><li>Identify patients with higher ipsilateral stroke risk without operation </li></ul><ul><li>Safer investigation (angiography) </li></ul><ul><li>Safer surgery (identify low surgical risk) </li></ul><ul><li>Safer anaesthesia: GALA </li></ul>
  4. 4. General (GA) or Local Anaesthesia (LA) for carotid surgery: pros and cons <ul><li>Advantages to LA </li></ul><ul><li>‘ Awake neurological testing’ during carotid clamping = ↓ shunting </li></ul><ul><li>Preserves autoregulation </li></ul><ul><li>Potential benefits of LA </li></ul><ul><li>? ‘safer’ in high risk elderly ‘vascular’ patients </li></ul><ul><li>? less ‘stress’ response to surgery </li></ul><ul><li>? better postoperative pain relief </li></ul><ul><li>? earlier mobilisation, less traumatic =  QOL, less expensive v GA </li></ul><ul><li>Possible disadvantages of LA </li></ul><ul><li>More traumatic for the patient and the surgeon </li></ul><ul><li>Hurried surgery </li></ul><ul><li>Conversions (LA to GA) can be problematic </li></ul><ul><li>Patient might prefer GA </li></ul>
  5. 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. 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. 7. Rationale for GALA <ul><li>Good theoretical reasons to prefer LA over GA for CEA but ….… “beautiful hypotheses can be destroyed by ugly facts” </li></ul><ul><li>(Thomas Huxley) </li></ul><ul><li>Cochrane Review encouraging but… </li></ul><ul><li>non-randomised studies likely to be biased </li></ul><ul><li>randomised trials too small </li></ul><ul><li>‘ stroke and death’ are not the only outcomes of interest </li></ul><ul><li>Variation in practice of carotid surgery over time </li></ul><ul><li>No good evidence for LA vs GA in other forms of surgery </li></ul>
  8. 8. What happened next? 1997: CPW, MJG Steering Committee Protocol MREC Trial Co-ordinator Funding 1999: Pilot 20 UK Centres 2003: Main Trial
  9. 9. Design of GALA <ul><li>Randomised, partially blinded two arm trial, intention-to–treat analysis </li></ul><ul><li>Uncertainty principle </li></ul><ul><li>Pragmatic non-restrictive protocols (except shunt in LA) </li></ul><ul><li>Management </li></ul><ul><li>Leeds: surgical and anaesthetic leadership </li></ul><ul><li>Edinburgh: trial Management </li></ul><ul><li>York: health economics </li></ul><ul><li>Target: 5000 patients </li></ul><ul><li>Follow up at: </li></ul><ul><ul><li>hospital discharge, 7 days post operative, or death </li></ul></ul><ul><ul><li>one month: ‘blind’ stroke physician/neurologist (phone if necessary) </li></ul></ul><ul><ul><li>one month: QOL questionnaire (UK only) </li></ul></ul><ul><ul><li>one year: questionnaire to patients re stroke/MI </li></ul></ul>
  10. 10. <ul><li>Assume 7.5% incidence of primary outcome at 30 days </li></ul><ul><li>Achieve one third reduction in risk to 5% (> 90% power at 5%) </li></ul><ul><li>Analysis intention-to-treat </li></ul><ul><li>Primary outcome: </li></ul><ul><li>Stroke (including retinal infarct), myocardial infarction (MI), death </li></ul><ul><li>Secondary outcomes: </li></ul><ul><li>Alive and stroke/MI free at one year </li></ul><ul><li>QOL at 30 days (UK only) </li></ul><ul><li>Surgical complications (haematoma, re-op n , cranial nerve palsy etc) </li></ul><ul><li>Length of stay (intensive care, high dependency, total) </li></ul><ul><li>Cost </li></ul>Why 5000 patients?
  11. 11. Eligibility for the GALA Trial <ul><li>Experienced surgeons (>15 carotid endarterectomies per annum) </li></ul><ul><li>Local ethics committee approval </li></ul><ul><li>Any patient requiring carotid surgery (symptomatic or asymptomatic stenosis) </li></ul><ul><li>Usual management, except shunts during LA only if indicated by awake testing </li></ul><ul><li>Uncertainty </li></ul><ul><li>No patient preference </li></ul>
  12. 12. AUSTRALIA 3526 patients from 95 GALA centres in 24 countries CHINA
  13. 13. 99.9% FU 3526 randomised (95 centres, 24 countries) GA 1753 allocated: 1628  GA 31 no anaesthesia - 92 cross-over 2 unknown LA 1773 allocated: 1655  LA 41 no anaesthesia - 75 cross-over 2 unknown 1752 for primary outcome (No FU = 1, Incomplete = 20) 1771 for primary outcome (No FU = 2, Incomplete = 19)
  14. 14. Baseline data Smoking, peripheral arterial disease, coronary artery disease, atrial fibrillation, diabetes, blood pressure all equal 69 (sd 9) 70 (sd 9) Age 1256 (71%) 1232 (70%) Male 160 (9%) 150 (9%) Contralateral ICA occlusion 81 (sd 11) 81 (sd 11) Mean % stenosis 677 (38%) 685 (39%) Asymptomatic stenosis Local General
  15. 15. Compliance 6 Patient’s decision 3 Problem with position on table etc 8 Patient deteriorated after local block Conversion after start of surgery 34 Pain, discomfort, anxiety, claustrophobia 11 Physiological instability, protracted surgery 7 Neurological deterioration on cross-clamping Conversion post- anaesthesia, pre-op 13 41 9 31 Patient refused 12 5 Too ill (not carotid), Stenosis too mild, stent 8 8 Carotid artery occlusion 2 2 Stroke or death before operation No anaesthesia Local General
  16. 16. Compliance – cross-overs 2 7 Reason unknown 44 29 Patient’s decision 9 15 Administrative issues 20 41 Medical decision Local (n=75) General (n=92) Reasons:
  17. 17. Primary outcome events Intention-to-treat 70 66 4 9 5 10 0% 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)
  18. 18. Primary outcome events Intention to treat 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
  19. 19. 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 22-30 Days since endarterectomy Number of patients . infarct haemorrhage unknown
  20. 20. Subgroup analysis on primary outcome Contralateral carotid occlusion Favours LA Favours GA
  21. 21. Secondary outcomes <ul><li>No definite differences (GA v LA): </li></ul><ul><li>Length of stay Duration of surgery </li></ul><ul><li>Trainee v consultant Asymptomatic v symptomatic </li></ul><ul><li>UK v others Cranial nerve injury </li></ul><ul><li>Wound haematoma Chest infection </li></ul><ul><li>Quality of life at one month Outcome at one year </li></ul><ul><li>Cost </li></ul>
  22. 22. Survival analysis Free of stroke, MI and death
  23. 23. Limitations of GALA <ul><li>Lack of power </li></ul><ul><li>Sample size, outcome events </li></ul><ul><li>Lack of complete blinding </li></ul><ul><li>Cross-overs pre-op (5%), conversions LA  GA (4%) </li></ul><ul><li>Lack of standardisation of anaesthetic and surgical protocols </li></ul><ul><li> BP in the GA group, Patching: 42% LA v 50% GA </li></ul><ul><li>The surgical risk model did not work </li></ul><ul><li>Took too long, would have failed without the non-UK centres </li></ul>
  24. 24. 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 Patients Non UK UK
  25. 25. Recruitment in Carotid Surgery Trials 0 500 1000 1500 2000 2500 3000 3500 4000 NASCET ECST ACST 1 GALA Number of Patients 2267 3024 3120 3526
  26. 26. Limitations of local anaesthesia <ul><li>Unable to tolerate </li></ul><ul><li>Additional sedation and analgesia </li></ul><ul><li>Conversion to GA </li></ul><ul><li>Stress & anxiety may  cardiac events </li></ul><ul><li>Injury to surrounding structures </li></ul><ul><li>More peri-operative strokes may be due to embolism </li></ul><ul><li>Modern GA safer/less stressful </li></ul>
  27. 27. Putting GALA into context Stroke & death 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)
  28. 28. Putting GALA into context Death 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)
  29. 29. Conclusions <ul><li>Little difference in patient outcomes regardless of GA or LA </li></ul><ul><li>Surgical teams should be able to offer both LA & GA </li></ul><ul><li>The individual choice should be determined by the patient’s medical need and personal preference </li></ul><ul><li>Trials like GALA could and should be done more quickly, but will have to be multinational </li></ul><ul><li>Regulations make trials increasingly difficult to do, and more expensive </li></ul><ul><li>The cost-effectiveness of carotid endarterectomy would be improved more dramatically by shortening the time from symptoms to surgery </li></ul>
  30. 30. The GALA Trial A collaboration Vascular Surgeons throughout Europe Healthcare Foundation

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