1. Thrombolysis for acute ischaemic stroke Clinical www.cochranejournalclub.com

2. 2 Clinical question In what, if any circumstances, is thrombolytic therapy a safe and effective treatment for acute ischaemic stroke? Source: Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD000213. DOI: 10.1002/14651858.CD000213.pub3. www.cochranejournalclub.com

3. 3 Context Acute ischaemic stroke is a major cause of death and disability worldwide. Most strokes are due to blockage of an artery in the brain by a blood clot (ischaemic stroke). Thrombolytic drugs dissolve blood clots and may reduce brain damage from a stroke by restoring the blood flow, if given rapidly enough after stroke, but may also cause serious bleeding in the brain. Earlier systematic reviews of this topic have left many questions unanswered. www.cochranejournalclub.com

4. 4 Methods Eligible studies were sought from the specialized register of the Cochrane Stroke Group and the two bibliographic databases, MEDLINE and EMBASE. Relevant journals and conference proceedings were handsearched for studies reported up to early 2014, and researchers and manufacturers were contacted for details of published and unpublished studies. Odds ratios (ORs) and absolute numbers of events avoided (or caused) per 1000 patients treated were calculated. www.cochranejournalclub.com

5. 5 PICO(S) to assess eligible studies Participants: adults with a definite acute ischaemic stroke. Intervention: any thrombolytic drug, in any dose, by the intravenous or intra-arterial route. Comparison: placebo or open control (without a thrombolytic drug). Primary outcomes: death or dependency, death at the end of follow-up; and symptomatic intracranial haemorrhage. Studies: Randomised trials. www.cochranejournalclub.com

6. 6 Description of included studies 27 trials (total: 10,239 participants) were included, with data available for 10,187 participants. Most data are from trials that started treatment up to six hours after stroke. About two-thirds of the participants were in trials of intravenous recombinant tissue plasminogen activator (rt-PA). Four trials used intra-arterial administration. The others used the intravenous route. 16% of participants were over 80 years of age. www.cochranejournalclub.com

7. 7 Results - overall Thrombolytic therapy significantly reduced the proportion of participants who were dead or dependent at 3-6 months after stroke (OR: 0.85, 95% CI: 0.78 to 0.93). However, thrombolytic therapy increased the risk of symptomatic intracranial haemorrhage (OR: 3.75, 95% CI: 3.11 to 4.51), early death (OR: 1.69, 95% CI 1.44 to 1.98) and death by 3-6 months after stroke (OR: 1.18, 95% CI: 1.06 to 1.30). www.cochranejournalclub.com

8. 8 Results – subgroups Therapy within 3 hours of stroke was more effective in reducing death or dependency (OR: 0.66, 95% CI: 0.56 to 0.79), without any increase in death (OR: 0.99, 95% CI: 0.82 to 1.21; 11 trials, 2187 participants). rt-PA significantly reduced death or dependency with treatment up to six hours (OR: 0.84, 95% CI: 0.77 to 0.93, 8 trials, 6729 participants) Participants over 80 benefited equally to younger patients, particularly if treated within three hours. www.cochranejournalclub.com

9. 9 Implications for practice Thrombolysis in the acute phase of ischaemic stroke reduces the proportion of patients who are dead or dependent at the end of follow-up, but there are harms associated with this treatment. Faster treatment is more beneficial. People over 80 derive as much benefit as those under 80, especially if treated within three hours. Current evidence supports configuration of stroke services that can treat as many people as possible as fast as possible with rt-PA, including those over 80. www.cochranejournalclub.com

10. 10 Implications for research Further large-scale randomised trials are needed: To identify means of minimising the harms without reducing the benefit, e.g. lower dose, avoiding people with specific characteristics (yet to be determined) or combinations of characteristics (e.g. elderly, severe stroke and some imaging feature), slower administration of the rt-PA bolus, different drug with lower haemorrhage risk, etc. To identify the latest time window for treatment. To identify benefits or harms in mild stroke. To investigate quality of life and cost effectiveness. www.cochranejournalclub.com

11. 11 Useful links www.cochranejournalclub.com Cochrane Journal Club discussion points Thrombolysis for acute ischaemic stroke