Thrombolysis with alteplase after stroke: extending outcomes
Authors: Craig Anderson
Journal: The Lancet Neurology (2013)

In their first report1The IST-3 collaborative groupEffect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial.Lancet Neurol. 2013; (published online June 21.)http://dx.doi.org/10.1016/S1474-4422(13)70130-3Google Scholar since publication of the main results,2Sandercock P Wardlaw JM Lindley RI et al.The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (950) Google Scholar, 3Wardlaw JM Murray V Berge E et al.Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis.Lancet. 2012; 379: 2364-2372Summary Full Text Full Text PDF PubMed Scopus (787) Google Scholar the third International Stroke Trial (IST-3) investigators provide new data on the effects of alteplase on health outcomes after stroke, and so re-ignite debate about the best time and method to assess recovery. 90 days is the gold standard time for assessing the effects of treatment in acute stroke trials. This window provides a compromise between timely assessment of adverse effects and physical recovery and avoidance of the additional costs and logistic difficulties of longer follow-up. 18 month follow-up in the IST-3 study has several benefits. First, finding no difference in overall mortality (35%) between the groups provides reassurance that alteplase has no long-term adverse consequences related to restenosis of incompletely recanalised intracerebral arterioles. However, the data also suggest that any reduced neurological deficit from treatment did not translate into a net improvement in medium-term survival. Second, at 18 months, the proportion of patients who were alive and independent was significantly higher in the alteplase group compared with the control group (adjusted odds ratio [OR] 1·28, 95% CI 1·03–1·57; p=0·024). This difference was not evident in either the full cohort (1·13, 0·95–1·35; p=0·181)2Sandercock P Wardlaw JM Lindley RI et al.The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (950) Google Scholar or at 6 months in the participants who were followed up for 18 months (1·18, 0·97–1·45; p=0·10).1The IST-3 collaborative groupEffect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial.Lancet Neurol. 2013; (published online June 21.)http://dx.doi.org/10.1016/S1474-4422(13)70130-3Google Scholar The consistent between-group distribution of scores on the Oxford handicap scale at 6 months and 18 months suggests that the treatment effect was stable but also shows some limitations to the approach. The Oxford handicap scale score is based on several broad, ordered levels and so it is somewhat insensitive to change over time, can exhibit ceiling or floor effects, and is limited in its assessment of the functional consequences of stroke on the lives of those affected. As a result, health-related quality of life measures are recognised as valid and useful additional endpoints in randomised controlled trials, particularly for treatments that target chronic or disabling diseases. Indeed, medical decision-making increasingly focuses on health-related quality of life as an important variable because many treatments do not cure disease and patients often have an active role in their medical care and are particularly interested in the non-clinical aspects of treatment and their future requirement for care. EuroQoL is a popular generic, preference-based, measure of health-related quality of life because it is simple, concise, and efficient; it is also able to convert health effects into quality-adjusted life-years for evaluations of cost-effectiveness. The large sample size in the IST-3 study (2348 patients assessed at 18 months) overcomes potential biases introduced through the use of proxies (in 54% of patients) to assess health-related quality of life. The findings from the EuroQoL instrument are therefore not only robust, but also offer separate confirmation of the functional benefits of alteplase besides the results of the Oxford handicap scale score. Additionally, they show that recovery from ischaemic stroke continues beyond 6 months—in the patients followed up at 18 months, only ability to self-care and ability to do usual activities were significantly improved at 6 months in the alteplase group. The difference between groups in overall health utility score also increased between 6 months and 18 months (from 0·04 to 0·06). Although this change is small, scores ranging from as little as −0·01 to 1·4 are still clinically meaningful.4Crosby RD Kolotkin RL Williams GR Defining clinically meaningful change in health-related quality of life.J Clin Epidemiol. 2003; 56: 395-407Summary Full Text Full Text PDF PubMed Scopus (963) Google Scholar, 5Walters SJ BrazierComparison of the minimally important difference for two health state utility measures: EQ-5D and SF-6D.Qual Life Res. 2005; 14: 1523-1532Crossref PubMed Scopus (1005) Google Scholar Finally, half of all participants reported at least a moderate degree of depression or anxiety during follow-up, emphasising the importance of this comorbidity in adjusting to the effects of stroke.6Haley WE Roth DL Kissela B Perkins M Howard G Quality of life after stroke: a prospective longitudinal study.Qual Life Res. 2011; 20: 799-806Crossref PubMed Scopus (89) Google Scholar, 7Ayerbe L Ayis S Crichton S Wolfe CDA Rudd AG The natural history of depression up to 15 years after stroke: the South London stroke register.Stroke. 2013; 44: 1105-1110Crossref PubMed Scopus (145) Google Scholar I commend the IST-3 investigators for providing a more comprehensive, patient-centred approach to assessment of the effects of alteplase on quality of life than has previously been done. As shown in INTERACT2,8Anderson CS Heeley E Huang Y et al.Rapid blood pressure lowering in acute intracerebral hemorrhage.New Engl J Med. 2013; (published May 29.)https://doi.org/10.1056/NEJMoa1214609Crossref Scopus (1095) Google Scholar assessment of health-related quality of life helps the interpretation of outcomes and is an important part of decision-making about efficacy of treatment that accounts for the patients' perspective. Peter Sandercock is a member of the data safety monitoring board for a trial that I lead. I collaborate with Richard Lindley, who also has an appointment at the George Institute. Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trialIST-3 provides evidence that thrombolysis with intravenous alteplase for acute ischaemic stroke does not affect survival, but does lead to statistically significant, clinically relevant improvements in functional outcome and health-related quality of life that are sustained for at least 18 months. Full-Text PDF Open Access