Evaluating Treatments for Acute Ischaemic Stroke - What Works and What Doesn't?

1. Evidence based stroke medicine. Evaluating treatments for acute ischaemic stroke -what works and what doesn’t? Professor Peter Sandercock

2. 85% of strokes are ischaemic, and related to blockage of an artery by a blood clot, so potential treatments to improve the circulation might be: • Thrombolytic (clot-dissolving): eg Streptokinase, TPA. Breaks up clot by splitting fibrin • Anticoagulant (Clot preventing): prevents formation of fibrin, prevents spreading of clot & formation of new clot • Antiplatelet (clot preventing): prevents platelets sticking together prevents spreading of clot & formation of new clot.

3. Does treatment X do more good than harm? • Benefits of the treatment (eg reduced disability)? • Risks (eg fatal bleeding)? ?

4. What is the balance of RISK and BENEFIT? RISK BENEFIT

5. Getting reliable evidence on new treatments (in animals and patients) • Minimise selection bias - RANDOM ALLOCATION • Minimise observer bias - BLIND ASSESSMENT of outcome • Minimise random error - LARGE SAMPLE • Choose appropriate measure of outcome - use COMMON SENSE

6. OK, how to design appropriate randomised trial? • Large, simple • What to use as primary measure of outcome? • vessel patency • volume of brain damaged on scan? • disability • handicap? • Quality of life • death? • what about side effects (eg bleeding?) • Highly selected patients or a broad range?

7. Effects of treatment X on death in a small trial Difference = 2% or 20 deaths avoided per 1000 treated, but not statistically significant. Would need a trial with over 10,000 subjects to confirm or refute a benefit of this size.

8. Thrombolysis in AMI: accumulating the evidence Antman & Lau. JAMA 1992; 268: 240-8

9. By the 1980’s, what did we know about thrombolysis for heart attacks (AMI)? • 23 small randomised trials completed, including a total of about 6000 patients, showing: • It can unblock arteries after heart attacks, but bleeding could be a side-effect (sometimes fatal) • trials were too small reliably to answer the question ‘does thrombolysis save lives in patients with heart attacks?’ , but suggested the benefit might be about 20 lives saved per 1000 patients treated • Doctors not convinced: treatment not used • 2 Mega- trials, each with 20,000 patients then completed (ISIS-2 and GISSI), showing thrombolysis reduced risk of death after MI by about a fifth: clotbusters save lives

10. Publication of large-scale MI trials followed by increased use in UK Trent region (Ketley and Woods Lancet 1993: 342: 891-4)

11. What is the best sort of evidence? BEST • Up-to date systematic review of all relevant randomised trials • Narrative review article • Textbook WORST

12. What is a systematic review? • Defined aim • Defined methods • defined search strategy • criteria to include studies • type of study (eg strictly randomised) • type of patient • type of outcome • Estimate of overall treatment effect

13. Where can you find systematic reviews and RCT’s? • MEDLINE: but only about 50% of relevant RCT’s can be found here • Cochrane Library: in many hospital libraries on CD ROM, or Internet (Abstracts at: http://www.update-software.com/ccweb/cochrane/revabstr/abidx.htm)

14. Cochrane systematic review of the evidence for thrombolytic therapy in acute ischaemic stroke Joanna Wardlaw abstract available free at: www.dcn.ed.ac.uk/csrg or on CDROM The Cochrane Library

15. Fatal intracerebral haemorrhage (ICH) with thrombolysis for ischaemic stroke

16. ICH after thrombolysis for ischaemic stroke • Fatal ICH increased from 1% to 5%. • five fold increase (p<0.00001) • 50 extra fatal ICH per 1000 treated • Fatal or non-fatal symptomatic ICH increased from 3% to 10%. • three fold increase (p<0.00001) • 70 extra haemorrhages per 1000 treated • Similar proportional increase in ICH with different thrombolytic agents

17. Thrombolysis for ischaemic stroke: dead or dependent

18. Overall, thrombolytic treatment within 6 hours of onset of acute ischaemic stroke significantly improved long-term outcome • At final follow-up, patients treated with thrombolysis had a highly significant 24% reduction in the relative odds of a bad outcome (2p <0.0001) (= 10% relative risk reduction). • For every 1000 patients treated < 6hrs, 65 avoided ‘death or dependence’. • Need to treat 16 to prevent one poor outcome

19. Implications for research. A large randomised trial of thrombolysis with rt-PA in acute ischaemic stroke would help answer: • how wide is the time window beyond 3hours (6,9, 12 hours?) • which patients benefit most? • which patients most likely to be harmed? • is the risk of death reduced or not?

20. IST-3 trial design: • Randomised controlled trial of rT-PA versus placebo in 6,000 patients. • < 6 hours symptom onset with CT scan • Eligibility based on ‘the uncertainty principle’. • Clear indication to treat: TREAT • Clear contraindication: DON’T TREAT • Uncertain: RANDOMISE • Careful characterisation at baseline

21. Cochrane systematic review of the randomised trials of anticoagulants in acute ischaemic stroke (Gubitz et al CDSR 2002)

22. Recurrent ischaemic stroke or intracranial haemorrhage during treatment period 4.1% 4.1% NS p<0.0001 p<0.001

23. Outcome at end of follow-up Dead

24. Summary of effects of anticoagulants (mainly heparin) in acute ischaemic stroke • No net short- or long-term benefit. • No subgroup of patient or anticoagulant regimen associated with clear net benefit. • Significant bleeding risk: 9 extra symptomatic intracranial and 9 major extracranial haemorrhages per 1000 patients treated. • Bleeding risk dose-related: High > Low > Nil • It gives no overall benefit, causes bleeds, is a pain in the leg/arm/abdomen for the patient, costs money (and nurses time); why use it?

25. Indications for early aspirin use in acute ischaemic stroke: a combined analysis of over 40,000 randomised patients from CAST and IST Sandercock PAG, Chen ZM, on behalf of IST and CAST collaborative groups Stroke 2000; 31:1240-49.

26. Design features of CAST & IST • Randomised • Acute ischaemic stroke <48 hours • CT before entry where possible, or soon after • Aspirin dose (scheduled treatment period): • IST: 300mg daily vs open control (2 weeks) • CAST: 160mg daily vs placebo control (4 weeks)

27. Patients included in the trials

28. Recurrent ischaemic stroke or intracranial haemorrhage during treatment period 3.5% 4.0% 2p <0.0001 % % 2p < 0.0001 % % 2p = 0.07

29. Summary of aspirin benefit • For every 1000 patients started < 48 hrs of onset: • < 14 days, 7 avoid recurrent ischaemic stroke • at 6 months, 12 avoid death or dependency, & an extra 10 make a complete recovery • The risk of cerebral haemorrhage is low (1-2 per 1000) and is completely outweighed by the benefits • Early aspirin is of net benefit for a wide range of patients, so prompt treatment should be considered for almost all patients presenting with suspected acute ischaemic stroke.

30. Worldwide benefit each year of a policy of 'give aspirin without delay' in acute stroke • 8 million patients with acute stroke • 5 million with acute ischaemic stroke • 1 million reach medical attention and get aspirin • 10,000 avoid a poor outcome, extra 10,000 make a complete recovery • Lesson: a small benefit in a large number of people adds up to a worthwhile benefit to mankind

31. What have we learned about thrombolysis, anticoagulants and aspirin? • Thrombolysis: promising, but applicable to 1% of all ischaemic strokes? Need much larger-scale trials. • Anticoagulants/heparin: benefits balanced by bleeding risk. No net benefit. • Aspirin. Modest benefits, but applicable to almost all patients. Like thrombolysis for AMI, It needed 40,000 randomised patients to prove it and persuade clinicians to change • Effort and audit needed to ensure ALL patients with acute ischaemic stroke get aspirin • CT has excluded haemorrhage? • patient able to swallow safely? -> oral aspirin • not able to swallow? -> rectally or via NG tube