1. Mr X, 79 years old Admitted on 5/5/00 to WGH stroke unit Dense (0/5) right arm and leg paresis Aphasic CT scan excluded a bleed Given trial treatment (IST-3) Dramatic recovery 4-5/5 power, now talking

2. How does thrombolysis work? Blood clots are a common cause of ischaemic stroke They are made up of fibrin polymers cross linked by factor X111 (end result of intrinsic and extrinsic coagulation pathway) Plasminogen activators Streptokinase recombinant tissue-type plasminogen activator PLASMINOGENPLASMIN FIBRIN Fibrin degradation products

3. Thrombolysis for acute ischaemic stroke Not routine therapy in Edinburgh (or most of UK) Why not? To help you understand why not, I will: Present the world data on thrombolysis Compare the situation with myocardial infarction Explain why it could be too expensive to deliver What we are doing about it

4. Acute brain attack Exclude: fits/migraine Hypo-hyperglycaemia Other metabolic causes CT Scan Exclude tumour /structural lesion Non-stroke pathology Confirmed ischaemic brain attack PICH, SAH, Subdural Exclude: intracranial bleed

5. Confirmed ischaemic brain attack TIA Are the symptoms/signs resolving rapidly? Yes No Are the symptoms/signs disabling? No Treat like TIA Yes Consider more intensive treatment

6. Thrombolysis: Acute Ischaemic Stroke Relatively short history - RCTs mid 80’s. Early decisions about agent and dose. NEJM 1995;333:1581-1587. rt-PA approved in North America for selected patients within 3 hours of stroke onset. Not approved in Europe. rt-PA use remains quite limited. ? administrative & organisational barriers. ? evidence not as persuasive as for AMI.

7. Thrombolytic Time Window: Acute MI Systematic review of 9 large RCTs involving 58,000 patients. Fibrinolytic Therapy Trialists’ Group. Lancet 1994;343:311-322 Sufficient statistical power to provide reliable estimates of: DURATION of time window. DECLINE in benefit over time.

8. Thrombolytic Time Window: Acute MI Fibrinolytic Therapy Trialists’ Group. Lancet 1994;343:311-322

9. Data: Thrombolysis vs control ThrombolyticNumber of Number of Agent RCTs patients IV tPA 8 2889 (56%) IV SK 4 1292 (25%) IV UK 3 743 (14%) IA Pro-UK 2 220 (5%) Total 17 5144* *9% of available MI data; data on 72 patients from ATLANTIS B not yet available.

10. Symptomatic ICH (fatal & non-fatal) All trials: –2.5% control versus 9.5% treatment. –70 additional ICHs for every 1000 treated (95% CI 58 - 83; 2p<0.000001) rt-PA trials only: –3% control versus 10% treatment. –73 additional ICHs for every 1000 treated (95% CI 55 - 90; 2p<0.000001) No significant heterogeneity noted.

11. Dead or dependent at end of follow-up All trials: –59% control vs 55% treatment (2p=0.003). –44 more patients alive and independent for every 1000 patients treated (95% CI 15 - 73). rt-PA trials: –57% control vs 51% treatment (2p=0.002). –57 more patients alive and independent for every 1000 patients treated (95% CI 20 - 93). Significant heterogeneity noted...

12. Dead or dependent at follow-up: randomisation within 3 hours IV SK vs control IV tPA vs control NINDS ECASS 1 ECASS 2 subtotal IV SK+asp vs asp TOTAL 0.1 0.58 1 10 thrombolysis better thrombolysis worse 7 trials; 1168 patients

13. Absolute effect of thrombolysis for every 1000 patients treated: rt-PA Outcome 0 - 6 hours 0 - 3 hours ICH 55 - 99 more (data not available) Dead 7 fewer - 43 more 61 fewer - 38 more Dead or 20 - 93 fewer 77 - 203 fewer dependent figures are 95% CI

14. Thrombolysis and living with unproven treatments Definite evidence of risk. Evidence of benefit - but which patients benefit most and which patients are most likely to be harmed? Answering this question may allow more patients to be effectively treated with increased certainty.

15. What remains unproven? The upper age limit. The latest time for effective treatment. The role of aspirin. The influence of stroke severity. The influence of CT scan appearance. The generalisability of thrombolysis and the organisation of acute stroke services in non- specialist centres. Long-term effect of thrombolysis.

16. The Third International Stroke Trial (IST-3) Main features Streamlined trial (to encourage participation) Time window of <6 hours from onset (realistic and evidence based) Recruitment started in the Western General Hospital and six other UK hospitals

17. Stroke IS an Emergency!  Stroke is a “Brain Attack”  Stroke is an emergency  “Time is Brain”

18. Future Stroke Treatment? 999 Nurse led Stroke Management process - Evaluation and Triage Within 3-6 Hrs?

19. The Stroke Team Ambulance Service Casualty Dept & ICU/ASU Radiology/Neuroradiology/ Physicians/Radiographers Neurology & Neurosurgery Pharmacy & Laboratory Rehabilitation Admissions Administration Public Relations/Community Education