The Lancet today publishes two papers Online First about the use of alteplase in stroke, timed to coincide with their presentation at the European Stroke Conference in Lisbon, Portugal.
Alteplase (also referred to as recombinant tissue plasminogen activator [rt-PA]) is a protein that aids in the breakdown of blood clots. Thus it can be used in a number of conditions including ischaemic stroke, pulmonary embolism, and heart attacks. However, licensing of the drug is restrictive and use varies widely. For example, it is not licensed to treat stroke in people aged 80 years and over, and there is also a question mark about the exact window of time after a stroke during which alteplase treatment can be given safely and effectively. The issue of age is important since, in a developed country such as the UK, around one third of strokes each year occur in people aged 80 years and over, ie, about 30 000 people per year.
In the first of the two Articles, Professor Peter Sandercock, University of Edinburgh and Western General Hospital, Edinburgh, UK, and colleagues from the IST-3 collaborative group, report the results of the third International Stroke Trial (IST-3) which sought to determine whether a wider range than hitherto of patients treated up to 6 h from stroke onset in clinical trials might benefit (ie, be alive and independent in daily living). Currently, thrombolysis is known to be of net benefit in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4.5 hours of onset.
The trial assessed 3035 patients at 156 hospitals in 12 countries, 1515 receiving alteplase and 1520 in the control group. 1617 patients (53%) were older than 80 years of age. At 6 months, for the primary outcome, 554 (37%) patients in the alteplase group versus 534 (35%) in the control group were alive and independent; for every 1000 patients treated within 6 hrs, 14 more were alive and independent. Measured this way according to the trial's primary endpoint, the effect of alteplase on disability was not statistically significant. However, when patient outcome was assessed on a five point scale ranging from no problems to very severe problems or death, the treatment was shown to have a statistically significant effect: the odds of surviving with less disability were 27% greater for patients treated with alteplase.
Among the patients treated within three hours (some 80% of whom were aged over 80 years) the benefit was much greater; for every 1000 treated, at six months 80 more were alive and able to look after themselves.
Fatal or non-fatal symptomatic haemorrhage within 7 days occurred in 104 (7%) of patients in the alteplase group versus 16 (1%) in the control group. More deaths occurred within 7 days in the alteplase group (163 [11%]) than in the control group (107 [7%]). However, between 7 days and 6 months there were fewer deaths in the alteplase group than in the control group, so that, by 6 months, similar numbers of patients had died in the two groups in aggregate (408 [27%] in the alteplase group vs 407 [27%] in the control group).
The authors say: "For the types of patient recruited in IST-3 (about three quarters of whom were randomised after 3 h, and half of all patients were older than 80 years of age), by 6 months there was evidence that alteplase improved functional outcome. The data also add weight to the policy of treating patients as soon as possible, and justify extending treatment to patients older than 80 years of age. The data do not support any restriction of treatment on the basis of stroke severity or the presence of early ischaemic change on the baseline brain scan."
In the second Article, Professor Joanna Wardlaw (also University of Edinburgh and Western General Hospital, Edinburgh, UK) and colleagues report a meta-analysis combining the IST-3 trial results with other major trials on alteplase.
The data reported for 12 trials involving 7012 patients showed that, for every 1000 patients allocated to intravenous alteplase up to 6 h after stroke, 42 more patients were alive and independent; and 55 more had the better outcome of being alive with a favourable outcome at the end of follow-up. This benefit occurred despite an increase in the number of early symptomatic intracranial haemorrhages and early deaths. These early hazards were offset by a reduction in the number of deaths between 7 days and the end of follow-up, and so, by the end of follow-up at 3-6 months, no effect on deaths from all causes was apparent, and the number of patients who were dependent was reduced.
The data show that earlier treatment is better, leading to an 87 per 1000 increase in the number of patients who were alive with favourable outcomes (the best outcome) and a 90 per 1000 increase in those alive and independent (the next best outcome) with treatment within 3 h of stroke. Among the 1711 patients older than 80 years, the absolute benefits from alteplase were at least as large as for the younger patients, especially with early treatment (for those over 80 treated within 3 hours, 96 patients more per 1000 treated were alive and independent).
The authors say that the exact time window for benefit of alteplase treatment remains unclear. Although net benefit from thrombolysis clearly declines with increasing delay to treatment, these data suggest that benefit probably extends beyond 4.5 h, possibly as late as 6 h in some patients, although the time probably varies with key individual or combined patients' characteristics, which were not possible to identify from this analysis.
The authors conclude: "The evidence indicates that intravenous alteplase increases the proportion of patients who are alive with favourable outcome and alive and independent at final follow-up. The data strengthen previous evidence to treat patients as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke...This study will be important for understanding the true health economic effect of thrombolytic treatment. If small gains in functional ability by 3 months translate into greater long-term survival free of disability, this is likely to reduce health-care costs and increase quality of life and cost effectiveness."
In a linked Comment, Dr Didier Leys and Dr Charlotte Cordonnier, Department of Neurology, Stroke Unit, Roger Salengro Hospital, Lille, France, conclude: "The key message of IST-3 and the updated meta-analysis is that many eligible patients from subgroups excluded by the European licence should now be given alteplase. Every stroke patient should therefore be classed as a candidate for thrombolysis and managed as a medical emergency irrespective of age, severity, and clinical presentation. The default situation for the first health care professional who identifies the stroke patient should be to treat, and the role of stroke and emergency physicians is now not to identify patients who will be given alteplase, but to identify the few who will not."
IST-3 study: Prof Peter Sandercock, University of Edinburgh and Western General Hospital, Edinburgh, UK. T) +44 (0) 7703 342 453 E) Peter.Sandercock@ed.ac.uk
IST-3 study: (Australia) Richard I Lindley, Sydney Medical School – Westmead Hospital and The George Institute for Global Health, University of Sydney, Australia. T) +61 404 866 007 E) richard.lindley@sydney.edu.au
Meta-analysis: Professor Joanna Wardlaw, University of Edinburgh and Western General Hospital, Edinburgh, UK. T) +44 (0) 7766 398659 E) joanna.wardlaw@ed.ac.uk
Additional contact for Profs Sandercock and Wardlaw: Eleanor Cowie, Press & PR Officer, University of Edinburgh. T) +44 (0) 131 650 6514 / +44 (0)7791 355 886 E) eleanor.cowie@ed.ac.uk
Dr Didier Leys, Department of Neurology, Stroke Unit, Roger Salengro Hospital, Lille, France. (please email for interview first) T) +33 680 74 11 67 E) didier.leys@chru-lille.fr
Dr Charlotte Cordonnier, Department of Neurology, Stroke Unit, Roger Salengro Hospital, Lille, France. (please email for interview first) T) +336 26 74 18 93 E) Charlotte.CORDONNIER@CHRU-LILLE.FR
Journal
The Lancet