Iwona Physio: Time is brain- aim to diagnose

In the UK, stroke is the most common serious neurological disease and a leading cause of death; there are more than 1.2 million stroke survivors, of whom more than 50% have a disability. Improving outcome from stroke is thus a key healthcare priority. About 80% of acute strokes are ischaemic, mainly from large vessel occlusion due to either artery-to-artery embolism or cardiac embolism. Early treatment is critical to rescue potentially salvageable tissue (‘time is brain’): safe, rapid and effective arterial recanalisation to restore blood flow and improve functional outcome remains the primary goal of hyperacute ischaemic stroke management. Until recently, the only licensed treatment for acute ischaemic stroke was intravenous thrombolysis with recombinant tissue-type plasminogen activator (IV r-tPA). However, since November 2014, nine positive randomised controlled trials of mechanical thrombectomy have been published leading to a revolution in the care of patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation (http://pn.bmj.com/content/practneurol/early/2017/06/30/practneurol-2017-001685.full.pdf).

Intravenous recombinant tissue-type plasminogen activator (IV r-tPA) 0.9 mg/kg is licensed for use in the UK up to 4.5 hours post symptom onset. The treatment within 3 hours resulted in good outcome in 9 randomised trials. Rapid delivery of intravenous thrombolysis after stroke onset is crucial: the number needed to treat for an excellent outcome roughly doubles from 5 (for treatment within 90 min) to 9 (when treatment is given at 3- 4.5 hours). However, the relative benefit of IV r-tPA appears to be consistent regardless of age or stroke severity.

Present guidance and marketing authorisation from Europe and elsewhere recommends the routine use of alteplase within 4·5 h of stroke onset but, in the USA, the Food and Drug Administration has approved the use of alteplase only within 3 h of stroke onset. Marketing of alteplase in some European countries is also restricted to patients younger than 80 years (despite clinical guidelines based on observational studies that recommends its use in older patients), whereas no such age restriction applies in many other countries, including the USA.

The another research (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60584-5/fulltext) analysis was to explore the extent to which treatment delay affected the effect of alteplase and to establish whether age or stroke severity affected treatment effects. These analyses assessing potential effect modification are only possible with individual patient data. Key secondary aims included estimating the effect of alteplase on symptomatic intracranial haemorrhage and on 90-day mortality.

The same research provides clear evidence for improved odds of a good stroke outcome when treatment is started within 4·5 h of ischaemic stroke, with earlier treatment resulting in bigger proportional and absolute benefits. The average benefit of alteplase might even extend beyond 4·5 h for some patients. The proportional benefits were similar for patients aged older than 80 years compared with younger patients, and for patients with minor or severe strokes compared with other patients. The results support guidelines that recommend use of alteplase irrespective of age and up to 4·5 h after onset of stroke.

In the past year, six positive trials of endovascular thrombectomy for ischaemic stroke have provided level 1 evidence for improved patient outcome compared with standard care. In most patients, thrombectomy was performed in addition to thrombolysis with intravenous alteplase, but benefits were also reported in patients ineligible for alteplase treatment. Despite differences in the details of eligibility requirements, all these trials required proof of major vessel occlusion on non-invasive imaging and most used some imaging technique to exclude patients with a large area of irreversibly injured brain tissue. The results indicate that modern thrombectomy devices achieve faster and more complete reperfusion than do older devices, leading to improved clinical outcomes compared with intravenous alteplase alone. The number needed to treat to achieve one additional patient with independent functional outcome was in the range of 3·2–7·1 and, in most patients, was in addition to the substantial efficacy of intravenous alteplase. No major safety concerns were noted, with low rates of procedural complications and no increase in symptomatic intracerebral haemorrhage (http://www.thelancet.com/action/showFullTextImages?pii=S1474-4422%2815%2900140-4).

There is little evidence on optimum antithrombotic treatment during and after thrombectomy. Urgent anticoagulation is not generally recommended in acute ischaemic stroke due to the risk of intracranial haemorrhage. Aspirin is not recommended within 24 hours of IV r-tPA but should be started orally (or via nasogastric tube) within 24-48hours after stroke onset. Randomised trials and registries do not give consistent data or recommendations regarding antithrombotic use in mechanical thrombectomy. Some units give a single procedural dose of heparin, but they avoid antiplatelet medication or further anticoagulation for 24 hours from stroke symptom onset, and they suggest follow-up brain imaging with CT or MRI to exclude haemorrhagic complications, but practice varies. If a stent does not deploy, after 24 hours and satisfactory clinical progress and follow-up imaging to exclude significant haemorrhage, then aspirin 300 mg for up to 2weeks is given, followed by long-term secondary prevention. This will depend on stroke mechanism: usually clopidogrel or aspirin for non-cardioembolic and oral anticoagulation for atrial fibrillation or other cardioembolic sources. If deploy a stent, recommendation is acutely starting treatment with aspirin and clopidogrel (or equivalent) dual antiplatelet therapy for at least 3-6months. For stents in patients requiring anticoagulation generally switch to a single antiplatelet agent for long term secondary prevention.