Correspondence
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Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a metaanalysis of individual patient data from randomised trials. Lancet 2014; 384: 1929–35. IST-3 collaborative group. 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: 2352–63. Kent DM, Price LL, Ringleb P, Hill MD, Selker HP. Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke: a pooled analysis of randomized clinical trials. Stroke 2005; 36: 62–65. Shobha N, Sylaja PN, Kapral MK, Fang J, Hill MD; Investigators of the Registry of the Canadian Stroke Network. Differences in stroke outcome based on sex. Neurology 2010; 74: 767–71. Lorenzano S, Ahmed N, Falcou A, et al. Does sex influence the response to intravenous thrombolysis in ischemic stroke? Answers from safe implementation of treatments in Stroke-International Stroke Thrombolysis Register. Stroke 2013; 44: 3401–06. Santalucia P, Pezzella FR, Sessa M, et al. Sex differences in clinical presentation, severity and outcome of stroke: results from a hospitalbased registry. Eur J Intern Med 2013; 24: 167–71.
Authors’ reply We thank the correspondents for their interest in our meta-analysis of individual patient data from trials of alteplase for patients with acute ischaemic stroke.1 In this study of 6756 patients in nine trials, we found that alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of the onset of acute ischaemic stroke, with earlier treatment resulting in bigger proportional benefits, irrespective of age or stroke severity. Alteplase increased the absolute risk of fatal intracranial haemorrhage within the first week after stroke by about 2%, but had no significant effect on other early causes of death, nor on later causes of death.1 Consequently, absolute mortality at 90 days was still about 2% higher in patients treated with alteplase and, as pointed out by Peter Appelros and Andreas Terént, this risk must be balanced against any reduction in disability among surviving patients at 3–6 months 1396
(on average, a 10% absolute risk reduction for patients treated within 3 h after stroke and 5% for patients treated 3–4·5 h after stroke).1 Alteplase should be given as early as possible since the expected benefit diminishes with increasing treatment delay. However, the estimates provided by Mattias Brunstöm and Bo Carlberg do not take account of differences in age or stroke severity between patients treated within 3 h or later and are therefore less reliable than the estimates in our study,1,2 which were adjusted for treatment allocation, treatment delay, age, stroke severity, and, where relevant, for interactions between treatment allocation and these characteristics. We used a trial-stratified regression method in our meta-analysis and not a pooled analysis, as suggested by David Newman. In our statistical analysis plan, 2 we specifically recognised that the overall average effect of alteplase on a good stroke outcome (ie, modified Rankin score of 0–1) would probably be misleading because it would vary by treatment delay (and perhaps also by age or stroke severity). Our analysis, which preserved the randomised comparisons within each trial, allowed not only for this source of effect modification (ie, heterogeneity) to be accounted for but also allowed for any potential effect modification by age or stroke severity to be identified and characterised. Further potential effect modifiers, including sex, were pre-specified for future analyses.2 There was no sex-dependent difference in the proportional effect of alteplase on a good stroke outcome (heterogeneity between men and women in treatment within 3 h, p=0·95; treatment within 3·1–4·5 h, p=0·53), symptomatic intracranial haemorrhage (type-2 parenchymal haemorrhage definition: p=0·82; SITS-MOST definition: p=0·84), or fatal intracranial haemorrhage within 7 days (p=0·50).
CB is involved in clinical trials funded by grants from Merck, Pfizer, and Novartis to the University of Oxford. KRL declares speaker fees from and has served on the data monitoring committee of trials for Boehringer Ingelheim and declares research grant support from Genentech. PS declares honoraria for lectures from Boehringer Ingelheim. WH declares research grant support, speaker fees, and fees for consultancy and advisory board membership from Boehringer Ingelheim. JE and PL declare no competing interests.
Jonathan Emberson, Kennedy R Lees, Patrick Lyden, *Colin Baigent, Peter Sandercock, Werner Hacke, on behalf of the Stroke Treatment Trialists’ Collaboration [email protected] Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK (JE, CB); University of Glasgow, Glasgow, UK (KRL); Department of Neurology, Cedars-Sinai, Los Angeles, CA, USA (PL); University of Edinburgh, Edinburgh, UK (PS); and University of Heidelberg, Heidelberg, Germany (WH) 1
2
Emberson J, Lees K, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a metaanalysis of individual patient data from randomised trials. Lancet 2014; 384: 1929–35. The Stroke Thrombolysis Trialists’ Collaboration. Details of a prospective protocol for a collaborative meta-analysis of individual participant data from all randomized trials on intravenous rt-PA vs. control: statistical analysis plan for the Stroke Thrombolysis Trialists’ Collaborative metaanalysis. Int J Stroke 2013; 8: 278–83.
Department of Error Cuzick J. Radiotherapy for breast cancer, the TARGIT-A trial. Lancet 2014; 383: 1716—In this Letter (May 17), Jack Cuzick’s disclosure should have read: “I was chairman of the Data Monitoring Committee for the TARGIT-A trial, but this was disbanded before I could formally resign.” This correction has been made to the online version as of April 10, 2015. Behringer K, Goergen H, Hitz F, et al. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin’s lymphoma (GHSG HD13): an openlabel, randomised, non-inferiority trial. Lancet 2015; 385: 1418–27—In this Article (Dec 22, 2014) the groups added after the author names should read “on behalf of the German Hodgkin Study Group, the Swiss Group for Clinical Cancer Research, and the Arbeitsgemeinschaft Medikamentöse Tumortherapie”. These corrections have been made to the online version as of April 10, 2015, and the printed Article is correct.
www.thelancet.com Vol 385 April 11, 2015
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Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a metaanalysis of individual patient data from randomised trials. Lancet 2014; 384: 1929–35. IST-3 collaborative group. 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: 2352–63. Kent DM, Price LL, Ringleb P, Hill MD, Selker HP. Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke: a pooled analysis of randomized clinical trials. Stroke 2005; 36: 62–65. Shobha N, Sylaja PN, Kapral MK, Fang J, Hill MD; Investigators of the Registry of the Canadian Stroke Network. Differences in stroke outcome based on sex. Neurology 2010; 74: 767–71. Lorenzano S, Ahmed N, Falcou A, et al. Does sex influence the response to intravenous thrombolysis in ischemic stroke? Answers from safe implementation of treatments in Stroke-International Stroke Thrombolysis Register. Stroke 2013; 44: 3401–06. Santalucia P, Pezzella FR, Sessa M, et al. Sex differences in clinical presentation, severity and outcome of stroke: results from a hospitalbased registry. Eur J Intern Med 2013; 24: 167–71.
Authors’ reply We thank the correspondents for their interest in our meta-analysis of individual patient data from trials of alteplase for patients with acute ischaemic stroke.1 In this study of 6756 patients in nine trials, we found that alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of the onset of acute ischaemic stroke, with earlier treatment resulting in bigger proportional benefits, irrespective of age or stroke severity. Alteplase increased the absolute risk of fatal intracranial haemorrhage within the first week after stroke by about 2%, but had no significant effect on other early causes of death, nor on later causes of death.1 Consequently, absolute mortality at 90 days was still about 2% higher in patients treated with alteplase and, as pointed out by Peter Appelros and Andreas Terént, this risk must be balanced against any reduction in disability among surviving patients at 3–6 months 1396
(on average, a 10% absolute risk reduction for patients treated within 3 h after stroke and 5% for patients treated 3–4·5 h after stroke).1 Alteplase should be given as early as possible since the expected benefit diminishes with increasing treatment delay. However, the estimates provided by Mattias Brunstöm and Bo Carlberg do not take account of differences in age or stroke severity between patients treated within 3 h or later and are therefore less reliable than the estimates in our study,1,2 which were adjusted for treatment allocation, treatment delay, age, stroke severity, and, where relevant, for interactions between treatment allocation and these characteristics. We used a trial-stratified regression method in our meta-analysis and not a pooled analysis, as suggested by David Newman. In our statistical analysis plan, 2 we specifically recognised that the overall average effect of alteplase on a good stroke outcome (ie, modified Rankin score of 0–1) would probably be misleading because it would vary by treatment delay (and perhaps also by age or stroke severity). Our analysis, which preserved the randomised comparisons within each trial, allowed not only for this source of effect modification (ie, heterogeneity) to be accounted for but also allowed for any potential effect modification by age or stroke severity to be identified and characterised. Further potential effect modifiers, including sex, were pre-specified for future analyses.2 There was no sex-dependent difference in the proportional effect of alteplase on a good stroke outcome (heterogeneity between men and women in treatment within 3 h, p=0·95; treatment within 3·1–4·5 h, p=0·53), symptomatic intracranial haemorrhage (type-2 parenchymal haemorrhage definition: p=0·82; SITS-MOST definition: p=0·84), or fatal intracranial haemorrhage within 7 days (p=0·50).
CB is involved in clinical trials funded by grants from Merck, Pfizer, and Novartis to the University of Oxford. KRL declares speaker fees from and has served on the data monitoring committee of trials for Boehringer Ingelheim and declares research grant support from Genentech. PS declares honoraria for lectures from Boehringer Ingelheim. WH declares research grant support, speaker fees, and fees for consultancy and advisory board membership from Boehringer Ingelheim. JE and PL declare no competing interests.
Jonathan Emberson, Kennedy R Lees, Patrick Lyden, *Colin Baigent, Peter Sandercock, Werner Hacke, on behalf of the Stroke Treatment Trialists’ Collaboration [email protected] Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK (JE, CB); University of Glasgow, Glasgow, UK (KRL); Department of Neurology, Cedars-Sinai, Los Angeles, CA, USA (PL); University of Edinburgh, Edinburgh, UK (PS); and University of Heidelberg, Heidelberg, Germany (WH) 1
2
Emberson J, Lees K, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a metaanalysis of individual patient data from randomised trials. Lancet 2014; 384: 1929–35. The Stroke Thrombolysis Trialists’ Collaboration. Details of a prospective protocol for a collaborative meta-analysis of individual participant data from all randomized trials on intravenous rt-PA vs. control: statistical analysis plan for the Stroke Thrombolysis Trialists’ Collaborative metaanalysis. Int J Stroke 2013; 8: 278–83.
Department of Error Cuzick J. Radiotherapy for breast cancer, the TARGIT-A trial. Lancet 2014; 383: 1716—In this Letter (May 17), Jack Cuzick’s disclosure should have read: “I was chairman of the Data Monitoring Committee for the TARGIT-A trial, but this was disbanded before I could formally resign.” This correction has been made to the online version as of April 10, 2015. Behringer K, Goergen H, Hitz F, et al. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin’s lymphoma (GHSG HD13): an openlabel, randomised, non-inferiority trial. Lancet 2015; 385: 1418–27—In this Article (Dec 22, 2014) the groups added after the author names should read “on behalf of the German Hodgkin Study Group, the Swiss Group for Clinical Cancer Research, and the Arbeitsgemeinschaft Medikamentöse Tumortherapie”. These corrections have been made to the online version as of April 10, 2015, and the printed Article is correct.
www.thelancet.com Vol 385 April 11, 2015
