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

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.

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

What is the balance of RISK and BENEFIT? RISKBENEFIT

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

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.

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?

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

By 1980, what did we know about thrombolysis for heart attacks? It unblocks arteries in dogs with experimental heart attacks: 23 small randomised trials completed, including a total of about 6000 patients, showing: –It can unblock arteries after heart attacks –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

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

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

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

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: software.com/ccweb/cochrane/revabstr/ abidx.htm)

What is in the April 2000 edition of the Cochrane Library? Cochrane Database of Systematic Reviews: 795 Reviews Database of Abstracts of Reviews of Effectiveness: 2433 Review abstracts Cochrane Controlled Trials Register: 264,000 References to RCTs and CCTs

Cochrane systematic review of the evidence for thrombolytic therapy in acute ischaemic stroke Joanna Wardlaw abstract available free at: or on CDROM The Cochrane Library

Fatal intracerebral haemorrhage (ICH) with thrombolysis for ischaemic stroke

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

Thrombolysis for ischaemic stroke: long-term outcome

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

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?

Suggested trial design: Randomised controlled trial of rT-PA versus placebo in 5,000 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

Cochrane systematic review of the randomised trials of anticoagulants in acute ischaemic stroke (Gubitz et al CDSR 1999)

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

Outcome at end of follow-up Dead

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?

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

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)

Patients included in the trials

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

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.

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

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 swalow? -> rectally or via NG tube