Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes: A Pooled Analysis of 9 Trials

doi:10.1161/STROKEAHA.116.013644

Randomized Controlled Trial

. 2016 Sep;47(9):2373-9.

doi: 10.1161/STROKEAHA.116.013644. Epub 2016 Aug 9.

Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes: A Pooled Analysis of 9 Trials

Kennedy R Lees¹, Jonathan Emberson¹, Lisa Blackwell¹, Erich Bluhmki¹, Stephen M Davis¹, Geoffrey A Donnan¹, James C Grotta¹, Markku Kaste¹, Rüdiger von Kummer¹, Maarten G Lansberg¹, Richard I Lindley¹, Patrick Lyden¹, Gordon D Murray¹, Peter A G Sandercock¹, Danilo Toni¹, Kazunori Toyoda¹, Joanna M Wardlaw¹, William N Whiteley¹, Colin Baigent¹, Werner Hacke¹, George Howard²; Stroke Thrombolysis Trialists’ Collaborators Group

Collaborators, Affiliations

Collaborators

Stroke Thrombolysis Trialists’ Collaborators Group:
John Marler, Heather Halls, Lisa Holland, Clare Mathews, Samantha Smith, Kate Wilson, Masatoshi Koga, Gregory Albers, Thomas Brott, Geoffrey Cohen, Masatoshi Koga, Jean Marc Olivot, Mark Parsons, Barbara Tilley, Nils Wahlgren, Gregory J Del Zoppo

Affiliations

¹ From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (K.R.L.); Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, United Kingdom (J.E., L.B., C.B.); Statistics Department, Boehringer Ingelheim, Germany (E.B.); Melbourne Brain Centre, The Royal Melbourne Hospital and University of Melbourne, Australia (S.M.D.); Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia (G.A.D.); Mobile Stroke Unit and Stroke Research Program, Memorial Hermann Hospital, Houston, TX (J.C.G.); Department of Neurology, Helsinki University Hospital and Clinical Neurosciences, University of Helsinki, Finland (M.K.); Department of Neuroradiology, Technische Universität, Dresden, Germany (R.v.K.); Stanford Stroke Center, Palo Alto, CA (M.G.L.); Discipline of Medicine, Westmead Hospital Clinical School, George Institute for Global Health, University of Sydney, NSW, Australia (R.I.L.); Department of Neurology, Cedars-Sinai, Los Angeles, CA (P.L.); Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (G.D.M.); Centre for Clinical Brain Sciences, University of Edinburgh, United Kingdom (P.A.G.S., J.M.W., W.N.W.); Department of Neurology and Psychiatry, Sapienza University of Rome, Italy (D.T.); Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (K.T.); Department of Neurology, University of Heidelberg, Im Neuenheimer Feld, Germany (W.H.); and Department of Biostatistics, UAB School of Public Health, Birmingham, AL (G.H.).
² From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (K.R.L.); Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, United Kingdom (J.E., L.B., C.B.); Statistics Department, Boehringer Ingelheim, Germany (E.B.); Melbourne Brain Centre, The Royal Melbourne Hospital and University of Melbourne, Australia (S.M.D.); Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia (G.A.D.); Mobile Stroke Unit and Stroke Research Program, Memorial Hermann Hospital, Houston, TX (J.C.G.); Department of Neurology, Helsinki University Hospital and Clinical Neurosciences, University of Helsinki, Finland (M.K.); Department of Neuroradiology, Technische Universität, Dresden, Germany (R.v.K.); Stanford Stroke Center, Palo Alto, CA (M.G.L.); Discipline of Medicine, Westmead Hospital Clinical School, George Institute for Global Health, University of Sydney, NSW, Australia (R.I.L.); Department of Neurology, Cedars-Sinai, Los Angeles, CA (P.L.); Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (G.D.M.); Centre for Clinical Brain Sciences, University of Edinburgh, United Kingdom (P.A.G.S., J.M.W., W.N.W.); Department of Neurology and Psychiatry, Sapienza University of Rome, Italy (D.T.); Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (K.T.); Department of Neurology, University of Heidelberg, Im Neuenheimer Feld, Germany (W.H.); and Department of Biostatistics, UAB School of Public Health, Birmingham, AL (G.H.). ghoward@uab.edu.

PMID: 27507856
PMCID: PMC5024752
DOI: 10.1161/STROKEAHA.116.013644

Randomized Controlled Trial

Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes: A Pooled Analysis of 9 Trials

Kennedy R Lees et al. Stroke. 2016 Sep.

. 2016 Sep;47(9):2373-9.

doi: 10.1161/STROKEAHA.116.013644. Epub 2016 Aug 9.

Authors

Collaborators

Stroke Thrombolysis Trialists’ Collaborators Group:
John Marler, Heather Halls, Lisa Holland, Clare Mathews, Samantha Smith, Kate Wilson, Masatoshi Koga, Gregory Albers, Thomas Brott, Geoffrey Cohen, Masatoshi Koga, Jean Marc Olivot, Mark Parsons, Barbara Tilley, Nils Wahlgren, Gregory J Del Zoppo

Affiliations

¹ From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (K.R.L.); Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, United Kingdom (J.E., L.B., C.B.); Statistics Department, Boehringer Ingelheim, Germany (E.B.); Melbourne Brain Centre, The Royal Melbourne Hospital and University of Melbourne, Australia (S.M.D.); Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia (G.A.D.); Mobile Stroke Unit and Stroke Research Program, Memorial Hermann Hospital, Houston, TX (J.C.G.); Department of Neurology, Helsinki University Hospital and Clinical Neurosciences, University of Helsinki, Finland (M.K.); Department of Neuroradiology, Technische Universität, Dresden, Germany (R.v.K.); Stanford Stroke Center, Palo Alto, CA (M.G.L.); Discipline of Medicine, Westmead Hospital Clinical School, George Institute for Global Health, University of Sydney, NSW, Australia (R.I.L.); Department of Neurology, Cedars-Sinai, Los Angeles, CA (P.L.); Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (G.D.M.); Centre for Clinical Brain Sciences, University of Edinburgh, United Kingdom (P.A.G.S., J.M.W., W.N.W.); Department of Neurology and Psychiatry, Sapienza University of Rome, Italy (D.T.); Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (K.T.); Department of Neurology, University of Heidelberg, Im Neuenheimer Feld, Germany (W.H.); and Department of Biostatistics, UAB School of Public Health, Birmingham, AL (G.H.).
² From the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (K.R.L.); Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, United Kingdom (J.E., L.B., C.B.); Statistics Department, Boehringer Ingelheim, Germany (E.B.); Melbourne Brain Centre, The Royal Melbourne Hospital and University of Melbourne, Australia (S.M.D.); Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia (G.A.D.); Mobile Stroke Unit and Stroke Research Program, Memorial Hermann Hospital, Houston, TX (J.C.G.); Department of Neurology, Helsinki University Hospital and Clinical Neurosciences, University of Helsinki, Finland (M.K.); Department of Neuroradiology, Technische Universität, Dresden, Germany (R.v.K.); Stanford Stroke Center, Palo Alto, CA (M.G.L.); Discipline of Medicine, Westmead Hospital Clinical School, George Institute for Global Health, University of Sydney, NSW, Australia (R.I.L.); Department of Neurology, Cedars-Sinai, Los Angeles, CA (P.L.); Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (G.D.M.); Centre for Clinical Brain Sciences, University of Edinburgh, United Kingdom (P.A.G.S., J.M.W., W.N.W.); Department of Neurology and Psychiatry, Sapienza University of Rome, Italy (D.T.); Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (K.T.); Department of Neurology, University of Heidelberg, Im Neuenheimer Feld, Germany (W.H.); and Department of Biostatistics, UAB School of Public Health, Birmingham, AL (G.H.). ghoward@uab.edu.

PMID: 27507856
PMCID: PMC5024752
DOI: 10.1161/STROKEAHA.116.013644

Abstract

Background: Thrombolytic therapy with intravenous alteplase within 4.5 hours of ischemic stroke onset increases the overall likelihood of an excellent outcome (no, or nondisabling, symptoms). Any improvement in functional outcome distribution has value, and herein we provide an assessment of the effect of alteplase on the distribution of the functional level by treatment delay, age, and stroke severity.

Methods: Prespecified pooled analysis of 6756 patients from 9 randomized trials comparing alteplase versus placebo/open control. Ordinal logistic regression models assessed treatment differences after adjustment for treatment delay, age, stroke severity, and relevant interaction term(s).

Results: Treatment with alteplase was beneficial for a delay in treatment extending to 4.5 hours after stroke onset, with a greater benefit with earlier treatment. Neither age nor stroke severity significantly influenced the slope of the relationship between benefit and time to treatment initiation. For the observed case mix of patients treated within 4.5 hours of stroke onset (mean 3 hours and 20 minutes), the net absolute benefit from alteplase (ie, the difference between those who would do better if given alteplase and those who would do worse) was 55 patients per 1000 treated (95% confidence interval, 13-91; P=0.004).

Conclusions: Treatment with intravenous alteplase initiated within 4.5 hours of stroke onset increases the chance of achieving an improved level of function for all patients across the age spectrum, including the over 80s and across all severities of stroke studied (top versus bottom fifth means: 22 versus 4); the earlier that treatment is initiated, the greater the benefit.

Keywords: United States; confidence interval; odds ratio; stroke; thrombolytic therapy.

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Conflict of interest statement

KL reports fees or expenses from American Stroke Association, Applied Clinical Intelligence, Atrium, Boehringer Ingelheim, EVER NeuroPharma, Hilicon, Nestle, Novartis, Stroke Academic Industry Roundtable, University of Lancaster; and research funding to the University of Glasgow and to the Virtual International Stroke Trials Archive from Genentech. CB, LB, and JE have not accepted fees, honoraria, or paid consultancies but are involved in clinical trials of lipid-modifying treatment funded by Merck to the University of Oxford, with the University the trial sponsor in all cases. EB is employed by Boehringer Ingelheim. SD has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Medtronic and Pfizer. GD is co-principal investigator for the EXTEND trial using alteplase and has received honoraria from Boehringer Ingelheim, Bayer, Pfizer, Sanofi and Merk Sharp & Dohme. JG has acted as a consultant for Frazer Ltd and Stryker, has received grant support from the American Heart Association, Genentech, and Behring, and has received grant support within the past 3 years from Haemonetics and Medtronics. MK reports fees and expenses from Lundbeck A/S, Mitsubishi Pharma Europe, Siemens AG. RvK reports fees from H. Lundbeck A/S, Boehringer Ingelheim, Covidien, Brainsgate, Synarc, and Penumbra, Inc. RIL has received honoraria from Boehringer Ingelheim, Covidien and Pfizer for lectures given in the past 3 years. PS has received honoraria for lectures which were paid to the department from Boehringer Ingelheim. DT reports honoraria from Boehringer Ingelheim, Bayer and Pfizer. KT has received research grant support from the Japan Agency for Medical Research and Development, and fees from Mitsubishi Tanabe Pharma. JW declares trial funding from the Medical Research Council, Efficacy and Mechanism Evaluation Programme, Stroke Association and Health Foundation. WNW is funded by a Medical Research Council Clinician Scientist Fellowship (G0902303). WH reports honoraria from Boehringer Ingelheim, Daiichi Sankyo and Bayer, receipt of an unrestricted research grant from Boehringer Ingelheim to perform the ECASS 4 EXTEND trial, and past chairmanship of the ECASS 1-3 thrombolysis trials. GH, MKa, ML and GM declare no conflicts of interest.

Figures

**Figure 1. Relative odds of a good stroke outcome with alteplase, for each alternative definition of 'good' outcome, among all randomized patients.**
* Estimated from a logistic regression model stratified by trial and adjusted only for treatment allocation. ** Primary pre−specified mRS comparison. IST−3 applied the Oxford Handicap Scale to patients at 6 months’ follow−up. We have used mortality and functional outcome at 6 months for IST−3 patients but at 3 months for all other trials’ patients.

**Figure 2. Relative odds of a good stroke outcome with alteplase by time to treatment, for each alternative definition of 'good' outcome**
In each panel the solid line represents the best linear fit between the log odds ratio for each mRS outcome among patients given alteplase compared with patients given control (vertical axis) and treatment delay (horizontal axis). Estimates are derived from a regression model in which alteplase, time to treatment, age and stroke severity (handled in a quadratic manner) are included as main effects but the only treatment interaction included is with time to treatment.

**Figure 3. Effect of alteplase on any upwards shift in mRS, by treatment delay**
The solid line represents the best linear fit between the log odds ratio for an improved stroke outcome among patients given alteplase compared with patients given control (vertical axis) and treatment delay (horizontal axis). Estimates are derived from a regression model in which alteplase, time to treatment, age and stroke severity (handled in a quadratic manner) are included as main effects but the only treatment interaction included is with time to treatment. Only 198 patients (159 of whom were from IST−3) had a time from stroke onset to treatment of more than 6 hours. The point at which the estimated treatment effect crosses 1 is therefore an extrapolation from the data.

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References

1. Bath PMW, Lees KR, Schellinger PD, Altman H, Bland M, Hogg C, et al. for the European Stroke Organisation Outcomes Working Group Statistical Analysis of the Primary Outcome in Acute Stroke Trials. Stroke. 2012;43:1171–1178. - PubMed
1. Emberson J, Lees KR, Lyden P, Albers G, Bluhmki E, Brott T, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;379:2352–2363. - PMC - PubMed
1. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375:1695–1703. - PubMed
1. Gage BF, Cardinalli AB, Owens DK. The effect of stroke and stroke prophylaxis with aspirin or warfarin on quality of life. Arch Int Med. 1996;156:1829–1836. - PubMed
1. Hong KS, Saver JL. Quantifying the value of stroke disability outcomes: WHO global burden of disease project disability weights for each level of the modified Rankin Scale. Stroke. 2009;40:3828–3833. - PMC - PubMed

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[1] Bath PMW, Lees KR, Schellinger PD, Altman H, Bland M, Hogg C, et al. for the European Stroke Organisation Outcomes Working Group Statistical Analysis of the Primary Outcome in Acute Stroke Trials. Stroke. 2012;43:1171–1178. - PubMed

[2] Bath PMW, Lees KR, Schellinger PD, Altman H, Bland M, Hogg C, et al. for the European Stroke Organisation Outcomes Working Group Statistical Analysis of the Primary Outcome in Acute Stroke Trials. Stroke. 2012;43:1171–1178. - PubMed

[3] Emberson J, Lees KR, Lyden P, Albers G, Bluhmki E, Brott T, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;379:2352–2363. - PMC - PubMed

[4] Emberson J, Lees KR, Lyden P, Albers G, Bluhmki E, Brott T, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;379:2352–2363. - PMC - PubMed

[5] Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375:1695–1703. - PubMed

[6] Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375:1695–1703. - PubMed

[7] Gage BF, Cardinalli AB, Owens DK. The effect of stroke and stroke prophylaxis with aspirin or warfarin on quality of life. Arch Int Med. 1996;156:1829–1836. - PubMed

[8] Gage BF, Cardinalli AB, Owens DK. The effect of stroke and stroke prophylaxis with aspirin or warfarin on quality of life. Arch Int Med. 1996;156:1829–1836. - PubMed

[9] Hong KS, Saver JL. Quantifying the value of stroke disability outcomes: WHO global burden of disease project disability weights for each level of the modified Rankin Scale. Stroke. 2009;40:3828–3833. - PMC - PubMed

[10] Hong KS, Saver JL. Quantifying the value of stroke disability outcomes: WHO global burden of disease project disability weights for each level of the modified Rankin Scale. Stroke. 2009;40:3828–3833. - PMC - PubMed

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Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes: A Pooled Analysis of 9 Trials

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Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes: A Pooled Analysis of 9 Trials

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