Questions about authorisation of alteplase for ischaemic stroke

Abstract

Stroke thrombolysis can cause potentially fatal intracerebral haemorrhage, but advocates claim the potential reduction in disability justifies this risk. Alteplase was authorised following the National Institute of Neurological Disorders and Stroke (NINDS) trial.1The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study GroupTissue plasminogen activator for acute ischemic stroke.N Engl J Med. 1995; 333: 1581-1587Crossref PubMed Scopus (10021) Google Scholar A 2004 review2O'Fallon M Asplund K Goldfrank LR et al.Report of the t-PA Review Committee.http://stroke.nih.gov/resources/t-pa-review-committee.htmDate: 2004Google Scholar raised concerns over the trial data. Outcomes across the centres differed considerably. Bias could explain the observation that the plot of outcome (modified Rankin score 0–1) against number of patients recruited does not resemble the expected symmetrical funnel (figure). The review2O'Fallon M Asplund K Goldfrank LR et al.Report of the t-PA Review Committee.http://stroke.nih.gov/resources/t-pa-review-committee.htmDate: 2004Google Scholar highlights concerns with local randomisation resulting in imbalance of stroke severity between the two study groups. 50% of patients within the 0–90 min window were reportedly randomised between 89 and 90 min. The poor prognosis of placebo patients recruited between 91 and 133 min resulted in exceptionally high odds for a favourable outcome. When the imbalance was considered, the estimated benefits were substantially reduced.3Hoffman JR Schriger DL A graphic reanalysis of the NINDS trial.Ann Emerg Med. 2009; 54: 329-336Summary Full Text Full Text PDF PubMed Scopus (55) Google Scholar Unbalanced randomisation might explain why 30-day mortality was improved in NINDS but not replicated elsewhere. For blood pressure, “non-compliance with the defined protocol was substantial, and persistent, throughout the study”.2O'Fallon M Asplund K Goldfrank LR et al.Report of the t-PA Review Committee.http://stroke.nih.gov/resources/t-pa-review-committee.htmDate: 2004Google Scholar The review2O'Fallon M Asplund K Goldfrank LR et al.Report of the t-PA Review Committee.http://stroke.nih.gov/resources/t-pa-review-committee.htmDate: 2004Google Scholar clarified that in some instances pharmacological monitoring was done by representatives (nurses) of the sponsoring pharmaceutical firm.Incomplete blinding in alteplase trials could also produce bias.4Wardlaw JM Murray V Berge E Del Zoppo GJ Thrombolysis for acute ischaemic stroke.Cochrane Database Syst Rev. 2009; 4 (CD000213.)Google Scholar First, treatment very often causes visible bleeding. Second, the possibility that investigators could have distinguished either the freeze-dried or the initially frothy reconstituted alteplase from matching placebo has not been openly examined and reported. Third, observers monitoring outcomes potentially had knowledge of events around randomisation. Three industry sponsored trials (ECASS, ECASS II, and ECASS III), each of more than 500 participants, only improved post-stroke independence by 6%, 8%, and 5% respectively, with a fourth (ATLANTIS) reporting a 4% deficit.4Wardlaw JM Murray V Berge E Del Zoppo GJ Thrombolysis for acute ischaemic stroke.Cochrane Database Syst Rev. 2009; 4 (CD000213.)Google Scholar 30-day mortality was similar in two studies, and 5% worse in two. The one positive trial of these four (ECASS III) had randomised 14·1% of patients with a history of stroke to placebo and 7·7% to alteplase (p=0·003).5Hacke W Kaste M Bluhmki E et al.for the European Cooperative Acute Stroke Study (ECASS) investigatorsAlteplase compared with placebo within 3 to 4.5 hours for acute ischemic stroke.N Engl J Med. 2008; 359: 1317-1329Crossref PubMed Scopus (4905) Google Scholar The authors of a Cochrane review4Wardlaw JM Murray V Berge E Del Zoppo GJ Thrombolysis for acute ischaemic stroke.Cochrane Database Syst Rev. 2009; 4 (CD000213.)Google Scholar conclude by suggesting that cautious physicians “may choose not to use the treatment at all”.In two pooled analyses promoting the benefit of alteplase within 4·5 h, the questionable quality of the raw data received no comment.6The ATLANTIS ECASSNINDS rt-PA Study Group InvestigatorsAssociation of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials.Lancet. 2004; 363: 768-774Summary Full Text Full Text PDF PubMed Scopus (2169) Google Scholar, 7Lees KR Bluhmki E von Kummer R et al.for the ECASSATLANTISNINDS and EPITHET rt-PA Study Group InvestigatorsTime to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.Lancet. 2010; 375: 1695-1703Summary Full Text Full Text PDF PubMed Scopus (1621) Google Scholar The 2009 Cochrane review,4Wardlaw JM Murray V Berge E Del Zoppo GJ Thrombolysis for acute ischaemic stroke.Cochrane Database Syst Rev. 2009; 4 (CD000213.)Google Scholar echoing the 2004 NINDS review,2O'Fallon M Asplund K Goldfrank LR et al.Report of the t-PA Review Committee.http://stroke.nih.gov/resources/t-pa-review-committee.htmDate: 2004Google Scholar suggests that these data pooling and modelling “may be incorrect”. Although a plausible spread of disability scores in observational stroke cohorts is observed (appendix figures 1 and 2), by contrast the scores from patients in the alteplase trials are unevenly distributed (appendix figures 3, 4, and 5).7Lees KR Bluhmki E von Kummer R et al.for the ECASSATLANTISNINDS and EPITHET rt-PA Study Group InvestigatorsTime to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.Lancet. 2010; 375: 1695-1703Summary Full Text Full Text PDF PubMed Scopus (1621) Google Scholar, 8Wahlgren N Ahmed N Davalos A et al.Thrombolysis with alteplase 3-4·5 h after acute ischaemic stroke (SITS-ISTR): an observational study.Lancet. 2008; 372: 1303-1309Summary Full Text Full Text PDF PubMed Scopus (489) Google Scholar, 9Slot KB Berge E Dorman P Lewis S Dennis M Sandercock P the Oxfordshire Community Stroke Projectthe International Stroke Trial (UK) and the Lothian Stroke RegisterImpact of functional status at six months on long term survival in patients with ischaemic stroke: prospective cohort studies.BMJ. 2008; 336: 376-379Crossref PubMed Scopus (145) Google Scholar The trial data within 180 min are more uneven and come predominantly from NINDS.Furthermore, observational treatment cohorts examining the 3–4·5 h window ignored data available from untreated patients—with a 3% lower mortality rate.7Lees KR Bluhmki E von Kummer R et al.for the ECASSATLANTISNINDS and EPITHET rt-PA Study Group InvestigatorsTime to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.Lancet. 2010; 375: 1695-1703Summary Full Text Full Text PDF PubMed Scopus (1621) Google Scholar, 8Wahlgren N Ahmed N Davalos A et al.Thrombolysis with alteplase 3-4·5 h after acute ischaemic stroke (SITS-ISTR): an observational study.Lancet. 2008; 372: 1303-1309Summary Full Text Full Text PDF PubMed Scopus (489) Google Scholar When these studies compare less than 3 h with 3–4·5 h delays, their strikingly similar outcome profiles undermine the case for early administration (appendix figure 2).8Wahlgren N Ahmed N Davalos A et al.Thrombolysis with alteplase 3-4·5 h after acute ischaemic stroke (SITS-ISTR): an observational study.Lancet. 2008; 372: 1303-1309Summary Full Text Full Text PDF PubMed Scopus (489) Google ScholarConsequently, results from the larger third International Stroke Trial (IST-3) were eagerly awaited.10The IST-3 collaborative groupThe benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar, 11The 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; 12: 768-776Summary Full Text Full Text PDF PubMed Scopus (110) Google Scholar Concerns, however, exist. After initially providing drug and placebo, Boehringer Ingelheim discontinued the supply. A published explanation for this decision is awaited. The double-blind trial then became open—likely yielding positive responses from treated participants. Before the final analysis, the university trial statistician left, a new statistician was recruited externally, and he was granted access to the unmasked data before the statistical analysis plan was finalised.12Sandercock P Lindley R Wardlaw J Whiteley W Murray G the IST-3 collaborative groupStatistical analysis plan for the third International Stroke Trial (IST-3); part of a ‘thread’ of reports of the trial.Int J Stroke. 2012; 7: 186-187Crossref PubMed Scopus (14) Google Scholar Although the plan was prepared without knowledge of the unblinded data, the trial statistician and the authors of the statistical analysis plan were contemporaneously working on the IST-3 steering and writing committees.10The IST-3 collaborative groupThe benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar, 12Sandercock P Lindley R Wardlaw J Whiteley W Murray G the IST-3 collaborative groupStatistical analysis plan for the third International Stroke Trial (IST-3); part of a ‘thread’ of reports of the trial.Int J Stroke. 2012; 7: 186-187Crossref PubMed Scopus (14) Google ScholarIST-3 showed no benefit of alteplase administered within 6 h of onset on the primary outcome of being alive and independent at 6 months.10The IST-3 collaborative groupThe benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar No trend was found relating outcome with delay to treatment. 4% excess early mortality was reflected in the Kaplan-Meier curve (see appendix in reference 10). Treated patients had a 7% higher use of high-dependency beds than did untreated patients. Eventual place of residence, unpublished to date but less prone to responder bias than modified Rankin score, indicated no benefit. Recall bias could explain improvements in the complex ordinal analysis (see table 8 in appendix in reference 11). Finally, the 6–18 month survival curves, predicted to diverge if treated survivors were less disabled, remained inseparable.9Slot KB Berge E Dorman P Lewis S Dennis M Sandercock P the Oxfordshire Community Stroke Projectthe International Stroke Trial (UK) and the Lothian Stroke RegisterImpact of functional status at six months on long term survival in patients with ischaemic stroke: prospective cohort studies.BMJ. 2008; 336: 376-379Crossref PubMed Scopus (145) Google Scholar, 11The 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; 12: 768-776Summary Full Text Full Text PDF PubMed Scopus (110) Google ScholarThese observations and concerns over balanced evaluation suggest that the evidence of benefit is precarious. Comprehensive and coordinated care is effective, but it would be prudent for regulatory bodies to carefully reconsider authorisation for the use of alteplase in ischaemic stroke.I declare no competing interests. I thank physicians in the West Midlands who have helped to stimulate this investigation, and particularly Peter Wilmshurst. Stroke thrombolysis can cause potentially fatal intracerebral haemorrhage, but advocates claim the potential reduction in disability justifies this risk. Alteplase was authorised following the National Institute of Neurological Disorders and Stroke (NINDS) trial.1The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study GroupTissue plasminogen activator for acute ischemic stroke.N Engl J Med. 1995; 333: 1581-1587Crossref PubMed Scopus (10021) Google Scholar A 2004 review2O'Fallon M Asplund K Goldfrank LR et al.Report of the t-PA Review Committee.http://stroke.nih.gov/resources/t-pa-review-committee.htmDate: 2004Google Scholar raised concerns over the trial data. Outcomes across the centres differed considerably. Bias could explain the observation that the plot of outcome (modified Rankin score 0–1) against number of patients recruited does not resemble the expected symmetrical funnel (figure). The review2O'Fallon M Asplund K Goldfrank LR et al.Report of the t-PA Review Committee.http://stroke.nih.gov/resources/t-pa-review-committee.htmDate: 2004Google Scholar highlights concerns with local randomisation resulting in imbalance of stroke severity between the two study groups. 50% of patients within the 0–90 min window were reportedly randomised between 89 and 90 min. The poor prognosis of placebo patients recruited between 91 and 133 min resulted in exceptionally high odds for a favourable outcome. When the imbalance was considered, the estimated benefits were substantially reduced.3Hoffman JR Schriger DL A graphic reanalysis of the NINDS trial.Ann Emerg Med. 2009; 54: 329-336Summary Full Text Full Text PDF PubMed Scopus (55) Google Scholar Unbalanced randomisation might explain why 30-day mortality was improved in NINDS but not replicated elsewhere. For blood pressure, “non-compliance with the defined protocol was substantial, and persistent, throughout the study”.2O'Fallon M Asplund K Goldfrank LR et al.Report of the t-PA Review Committee.http://stroke.nih.gov/resources/t-pa-review-committee.htmDate: 2004Google Scholar The review2O'Fallon M Asplund K Goldfrank LR et al.Report of the t-PA Review Committee.http://stroke.nih.gov/resources/t-pa-review-committee.htmDate: 2004Google Scholar clarified that in some instances pharmacological monitoring was done by representatives (nurses) of the sponsoring pharmaceutical firm. Incomplete blinding in alteplase trials could also produce bias.4Wardlaw JM Murray V Berge E Del Zoppo GJ Thrombolysis for acute ischaemic stroke.Cochrane Database Syst Rev. 2009; 4 (CD000213.)Google Scholar First, treatment very often causes visible bleeding. Second, the possibility that investigators could have distinguished either the freeze-dried or the initially frothy reconstituted alteplase from matching placebo has not been openly examined and reported. Third, observers monitoring outcomes potentially had knowledge of events around randomisation. Three industry sponsored trials (ECASS, ECASS II, and ECASS III), each of more than 500 participants, only improved post-stroke independence by 6%, 8%, and 5% respectively, with a fourth (ATLANTIS) reporting a 4% deficit.4Wardlaw JM Murray V Berge E Del Zoppo GJ Thrombolysis for acute ischaemic stroke.Cochrane Database Syst Rev. 2009; 4 (CD000213.)Google Scholar 30-day mortality was similar in two studies, and 5% worse in two. The one positive trial of these four (ECASS III) had randomised 14·1% of patients with a history of stroke to placebo and 7·7% to alteplase (p=0·003).5Hacke W Kaste M Bluhmki E et al.for the European Cooperative Acute Stroke Study (ECASS) investigatorsAlteplase compared with placebo within 3 to 4.5 hours for acute ischemic stroke.N Engl J Med. 2008; 359: 1317-1329Crossref PubMed Scopus (4905) Google Scholar The authors of a Cochrane review4Wardlaw JM Murray V Berge E Del Zoppo GJ Thrombolysis for acute ischaemic stroke.Cochrane Database Syst Rev. 2009; 4 (CD000213.)Google Scholar conclude by suggesting that cautious physicians “may choose not to use the treatment at all”. In two pooled analyses promoting the benefit of alteplase within 4·5 h, the questionable quality of the raw data received no comment.6The ATLANTIS ECASSNINDS rt-PA Study Group InvestigatorsAssociation of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials.Lancet. 2004; 363: 768-774Summary Full Text Full Text PDF PubMed Scopus (2169) Google Scholar, 7Lees KR Bluhmki E von Kummer R et al.for the ECASSATLANTISNINDS and EPITHET rt-PA Study Group InvestigatorsTime to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.Lancet. 2010; 375: 1695-1703Summary Full Text Full Text PDF PubMed Scopus (1621) Google Scholar The 2009 Cochrane review,4Wardlaw JM Murray V Berge E Del Zoppo GJ Thrombolysis for acute ischaemic stroke.Cochrane Database Syst Rev. 2009; 4 (CD000213.)Google Scholar echoing the 2004 NINDS review,2O'Fallon M Asplund K Goldfrank LR et al.Report of the t-PA Review Committee.http://stroke.nih.gov/resources/t-pa-review-committee.htmDate: 2004Google Scholar suggests that these data pooling and modelling “may be incorrect”. Although a plausible spread of disability scores in observational stroke cohorts is observed (appendix figures 1 and 2), by contrast the scores from patients in the alteplase trials are unevenly distributed (appendix figures 3, 4, and 5).7Lees KR Bluhmki E von Kummer R et al.for the ECASSATLANTISNINDS and EPITHET rt-PA Study Group InvestigatorsTime to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.Lancet. 2010; 375: 1695-1703Summary Full Text Full Text PDF PubMed Scopus (1621) Google Scholar, 8Wahlgren N Ahmed N Davalos A et al.Thrombolysis with alteplase 3-4·5 h after acute ischaemic stroke (SITS-ISTR): an observational study.Lancet. 2008; 372: 1303-1309Summary Full Text Full Text PDF PubMed Scopus (489) Google Scholar, 9Slot KB Berge E Dorman P Lewis S Dennis M Sandercock P the Oxfordshire Community Stroke Projectthe International Stroke Trial (UK) and the Lothian Stroke RegisterImpact of functional status at six months on long term survival in patients with ischaemic stroke: prospective cohort studies.BMJ. 2008; 336: 376-379Crossref PubMed Scopus (145) Google Scholar The trial data within 180 min are more uneven and come predominantly from NINDS. Furthermore, observational treatment cohorts examining the 3–4·5 h window ignored data available from untreated patients—with a 3% lower mortality rate.7Lees KR Bluhmki E von Kummer R et al.for the ECASSATLANTISNINDS and EPITHET rt-PA Study Group InvestigatorsTime to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.Lancet. 2010; 375: 1695-1703Summary Full Text Full Text PDF PubMed Scopus (1621) Google Scholar, 8Wahlgren N Ahmed N Davalos A et al.Thrombolysis with alteplase 3-4·5 h after acute ischaemic stroke (SITS-ISTR): an observational study.Lancet. 2008; 372: 1303-1309Summary Full Text Full Text PDF PubMed Scopus (489) Google Scholar When these studies compare less than 3 h with 3–4·5 h delays, their strikingly similar outcome profiles undermine the case for early administration (appendix figure 2).8Wahlgren N Ahmed N Davalos A et al.Thrombolysis with alteplase 3-4·5 h after acute ischaemic stroke (SITS-ISTR): an observational study.Lancet. 2008; 372: 1303-1309Summary Full Text Full Text PDF PubMed Scopus (489) Google Scholar Consequently, results from the larger third International Stroke Trial (IST-3) were eagerly awaited.10The IST-3 collaborative groupThe benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar, 11The 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; 12: 768-776Summary Full Text Full Text PDF PubMed Scopus (110) Google Scholar Concerns, however, exist. After initially providing drug and placebo, Boehringer Ingelheim discontinued the supply. A published explanation for this decision is awaited. The double-blind trial then became open—likely yielding positive responses from treated participants. Before the final analysis, the university trial statistician left, a new statistician was recruited externally, and he was granted access to the unmasked data before the statistical analysis plan was finalised.12Sandercock P Lindley R Wardlaw J Whiteley W Murray G the IST-3 collaborative groupStatistical analysis plan for the third International Stroke Trial (IST-3); part of a ‘thread’ of reports of the trial.Int J Stroke. 2012; 7: 186-187Crossref PubMed Scopus (14) Google Scholar Although the plan was prepared without knowledge of the unblinded data, the trial statistician and the authors of the statistical analysis plan were contemporaneously working on the IST-3 steering and writing committees.10The IST-3 collaborative groupThe benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar, 12Sandercock P Lindley R Wardlaw J Whiteley W Murray G the IST-3 collaborative groupStatistical analysis plan for the third International Stroke Trial (IST-3); part of a ‘thread’ of reports of the trial.Int J Stroke. 2012; 7: 186-187Crossref PubMed Scopus (14) Google Scholar IST-3 showed no benefit of alteplase administered within 6 h of onset on the primary outcome of being alive and independent at 6 months.10The IST-3 collaborative groupThe benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomised controlled trial.Lancet. 2012; 379: 2352-2363Summary Full Text Full Text PDF PubMed Scopus (929) Google Scholar No trend was found relating outcome with delay to treatment. 4% excess early mortality was reflected in the Kaplan-Meier curve (see appendix in reference 10). Treated patients had a 7% higher use of high-dependency beds than did untreated patients. Eventual place of residence, unpublished to date but less prone to responder bias than modified Rankin score, indicated no benefit. Recall bias could explain improvements in the complex ordinal analysis (see table 8 in appendix in reference 11). Finally, the 6–18 month survival curves, predicted to diverge if treated survivors were less disabled, remained inseparable.9Slot KB Berge E Dorman P Lewis S Dennis M Sandercock P the Oxfordshire Community Stroke Projectthe International Stroke Trial (UK) and the Lothian Stroke RegisterImpact of functional status at six months on long term survival in patients with ischaemic stroke: prospective cohort studies.BMJ. 2008; 336: 376-379Crossref PubMed Scopus (145) Google Scholar, 11The 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; 12: 768-776Summary Full Text Full Text PDF PubMed Scopus (110) Google Scholar These observations and concerns over balanced evaluation suggest that the evidence of benefit is precarious. Comprehensive and coordinated care is effective, but it would be prudent for regulatory bodies to carefully reconsider authorisation for the use of alteplase in ischaemic stroke. I declare no competing interests. I thank physicians in the West Midlands who have helped to stimulate this investigation, and particularly Peter Wilmshurst. Supplementary Material Download .pdf (.18 MB) Help with pdf files Supplementary appendix Download .pdf (.18 MB) Help with pdf files Supplementary appendix Evidence and doubt in the translation of research into careIf patients, health systems, and societies are to benefit from research, then research findings need to be incorporated into practice. That this has not yet happened widely for the treatment of acute ischaemic stroke, despite its increasing incidence in ageing populations, the ruinous sequelae without treatment, and a licensed medical intervention proven to improve outcomes, raises serious questions about the extent to which patients are actually benefiting from evidence. Full-Text PDF Alteplase for ischaemic stroke—responsesIn his Correspondence Roger Shinton raises concerns about the benefits of alteplase to treat acute ischaemic stroke. He refers to the Cochrane review of thrombolysis in acute ischaemic stroke,1 published in 2009, with data for 3977 patients treated with alteplase in randomised controlled trials (RCTs). Since then, the Third International Stroke Trial (IST-3) and an updated systematic review of all alteplase trials (7012 patients) have been published,2,3 an individual patient data meta-analysis of alteplase trials has been done by independent statisticians,4 and a complete update of all RCTs of all thrombolytic agents in acute ischaemic stroke (10 187 patients) in the Cochrane Database of Systematic Reviews has been very recently published. Full-Text PDF Alteplase for ischaemic strokeRoger Shinton's Correspondence (Aug 23, p 659)1 called into question the evidence supporting the safe use of alteplase in patients with acute ischaemic stroke.1 Ian Hudson, of the Medicines and Healthcare Products Regulatory Agency (MHRA), responded to this Correspondence by convening an expert working group to review the benefits and risks of this drug.2 A review of reports of spontaneous adverse drug reactions (ADR) should inform this query, but a substantial level of under-reporting might restrict its use. Full-Text PDF Alteplase for ischaemic stroke—responsesRoger Shinton's Correspondence contains numerous factual inaccuracies and statements that are not consistent with the text of the cited references, and do not in our opinion merit a reconsideration of the authorisation of alteplase in acute ischaemic stroke. Full-Text PDF Alteplase for ischaemic stroke—responsesIn his Correspondence Roger Shinton expresses his concerns regarding the balance of benefits and risks of alteplase in the treatment of acute ischaemic stroke and calls for a review by regulators. Full-Text PDF