Alteplase in acute ischaemic stroke: the need for speed
Authors: Michael D Hill, Shelagh B Coutts
Journal: The Lancet (2014)

Doctors treating patients who have had an acute ischaemic stroke must feel the need for speed more feverishly than a racing driver. Stroke does not hurt. There is none of the pain that might be registered on the face of a patient with acute myocardial infarction or the visceral sight of blood in the case of trauma to evoke a sense of immediacy. Yet stroke is exactly like acute myocardial infarction and acute trauma in the need for very fast treatment.In The Lancet, Jonathan Emberson and colleagues present a pre-planned analysis of pooled individual data for 6756 patients from all the major trials of thrombolysis for treatment of stroke.1Emberson J Lees KR Lynden P 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; (published online Aug 6.)http://dx.doi.org/10.1016/S0140-6736(14)60584-5PubMed Google Scholar Overall, thrombolysis with alteplase unequivocally resulted in more patients with an excellent neurological outcome at 3–6 months compared with control. This overall outcome included an increase in the number of early fatal intracerebral haemorrhages, but the result is definitive. Thrombolysis is an effective treatment, especially when given fast.Time is the major modifier of the effect of treatment: faster treatment results in a much greater treatment effect.1Emberson J Lees KR Lynden P 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; (published online Aug 6.)http://dx.doi.org/10.1016/S0140-6736(14)60584-5PubMed Google Scholar In Emberson and colleagues' analysis, treatment within 3 h resulted in a good outcome for about 33% of patients who took alteplase compared with 23% who took control (odds ratio [OR] 1·75, 95% CI 1·35–2·27); delay of more than 3·0 h but less than 4·5 h resulted in good outcome for 35% versus 30% (OR 1·26, 95% CI 1·05–1·51); and delay of more than 4·5 h resulted in good outcome for 33% versus 31% (OR 1·15, 95% CI 0·95–1·40). Age and stroke severity did not modify the effect of treatment; both young and old patients, and those who had both mild and severe strokes, benefitted from thrombolysis.Audits2Fonarow GC Zhao X Smith EE et al.Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative.JAMA. 2014; 311: 1632-1640Crossref PubMed Scopus (377) Google Scholar, 3Canadian Stroke NetworkThe quality of stroke care in Canada.http://www.canadianstrokenetwork.ca/index.php/quality-stroke-care/Date: 2011Google Scholar show that patients with ischaemic stroke are offered thrombolysis too rarely or, if they are offered it, too slowly. Quick treatment requires efficient processes and a team approach. Pre-hospital systems to identify patients and bring them to the appropriate hospitals, emergency department swarming, rapid simple imaging, and use of telemedicine must be harnessed to reduce times to treatment. Strategies to do so will vary by region but it is simply unacceptable not to achieve very fast treatment times. In Berlin, Germany, the use of a CT scanner in the ambulance and point-of-care blood testing combined with a telemedicine link has enabled patients to be given alteplase very quickly, even before they reach the hospital.4Walter S Kostopoulos P Haass A et al.Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial.Lancet Neurol. 2012; 11: 397-404Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar In Helsinki, Finland, quick hospital-based treatment is possible with a median time from door to treatment of 20 min in one study.5Meretoja A Strbian D Mustanoja S Tatlisumak T Lindsberg PJ Kaste M Reducing in-hospital delay to 20 minutes in stroke thrombolysis.Neurology. 2012; 79: 306-313Crossref PubMed Scopus (436) Google Scholar However, in most of the world, patients are rarely treated that fast.Emberson and colleagues show that the treatment benefit is similar for young and old patients, with no evidence to support the use of different approaches for patients of different ages. Clearly, older patients should be considered for thrombolysis. Furthermore, the benefit for patients with mild stroke is notable given the continuing discussion about whether or not to treat patients with mild stroke. The data render obsolete the European licensing label for alteplase—which excludes patients older than 80 years and those with severe stroke. The finding of a small benefit of treatment up to 4·5 h from onset makes the advice of the US Food and Drug Administration and Health Canada to not treat patients after 3 h from onset similarly outdated.The question now is not whether we can extend the window for treatment. Rather, how do we get everyone treated faster and how do we dispel preconceived notions about not treating older patients or those with milder strokes? We must move from the proven science to policy and systems of care.Benchmarks for treatment times should be revised, audited, and enforced. The widely adopted standard of 60 min from door to needle is fine if 95% of patients are treated within 60 min. It is not, however, an acceptable average or guide. A median of 30 min is a better target because it affords an extra 30 min leeway, which still permits a 95th percentile of 60 min overall. Hospitals and teams that can achieve these targets, typically centres that treat many patients,6Bray BD Campbell J Cloud GC et al.Bigger, faster? Associations between hospital thrombolysis volume and speed of thrombolysis administration in acute ischemic stroke.Stroke. 2013; 44: 3129-3135Crossref PubMed Scopus (51) Google Scholar can be accredited as acute stroke centres. Those that cannot should allow stroke care to be centralised to those centres that can.Licensing bodies might consider changes. Accreditation bodies should update their targets and enact them as policy. Funding typically follows accreditation and this will be a crucial incentive for (and a means to) the achievement of fast treatment times. Further analyses of the trial data analysed by Emberson and colleagues will help us to understand the nuances of stroke, such as the effects of CT scan appearance (as assessed by the ASPECTS score),7Barber PA Hill MD Eliasziw M et al.Imaging of the brain in acute ischaemic stroke: comparison of computed tomography and magnetic resonance diffusion-weighted imaging.J Neurol Neurosurg Psychiatry. 2005; 76: 1528-1533Crossref PubMed Scopus (273) Google Scholar, 8Barber PA Demchuk AM Zhang J Buchan AM for the ASPECTS Study GroupValidity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy.Lancet. 2000; 355: 1670-1674Summary Full Text Full Text PDF PubMed Scopus (1659) Google Scholar blood pressure, blood glucose concentration,9Demchuk AM Morgenstern LB Krieger DW et al.Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke.Stroke. 1999; 30: 34-39Crossref PubMed Scopus (336) Google Scholar, 10Poppe AY Hill MD Hyperglycemia in thrombolysed acute ischemic stroke patients.Int J Stroke. 2011; 6: 278Crossref PubMed Scopus (2) Google Scholar even why women have greater relative benefit than men.11Kent 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: 62-65Crossref PubMed Scopus (197) Google Scholar But the biology of stroke is clear and immutable: patients must be treated with extraordinary speed. Delayed treatment is the same as no treatment. We have to adapt our systems of care to the biology of the disease because we cannot adapt the biology to our systems. Drivers, start your engines.MDH has received funding for research from Covidien. SBC has received drugs for a study from Hoffmann-La Roche Canada. Doctors treating patients who have had an acute ischaemic stroke must feel the need for speed more feverishly than a racing driver. Stroke does not hurt. There is none of the pain that might be registered on the face of a patient with acute myocardial infarction or the visceral sight of blood in the case of trauma to evoke a sense of immediacy. Yet stroke is exactly like acute myocardial infarction and acute trauma in the need for very fast treatment. In The Lancet, Jonathan Emberson and colleagues present a pre-planned analysis of pooled individual data for 6756 patients from all the major trials of thrombolysis for treatment of stroke.1Emberson J Lees KR Lynden P 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; (published online Aug 6.)http://dx.doi.org/10.1016/S0140-6736(14)60584-5PubMed Google Scholar Overall, thrombolysis with alteplase unequivocally resulted in more patients with an excellent neurological outcome at 3–6 months compared with control. This overall outcome included an increase in the number of early fatal intracerebral haemorrhages, but the result is definitive. Thrombolysis is an effective treatment, especially when given fast. Time is the major modifier of the effect of treatment: faster treatment results in a much greater treatment effect.1Emberson J Lees KR Lynden P 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; (published online Aug 6.)http://dx.doi.org/10.1016/S0140-6736(14)60584-5PubMed Google Scholar In Emberson and colleagues' analysis, treatment within 3 h resulted in a good outcome for about 33% of patients who took alteplase compared with 23% who took control (odds ratio [OR] 1·75, 95% CI 1·35–2·27); delay of more than 3·0 h but less than 4·5 h resulted in good outcome for 35% versus 30% (OR 1·26, 95% CI 1·05–1·51); and delay of more than 4·5 h resulted in good outcome for 33% versus 31% (OR 1·15, 95% CI 0·95–1·40). Age and stroke severity did not modify the effect of treatment; both young and old patients, and those who had both mild and severe strokes, benefitted from thrombolysis. Audits2Fonarow GC Zhao X Smith EE et al.Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative.JAMA. 2014; 311: 1632-1640Crossref PubMed Scopus (377) Google Scholar, 3Canadian Stroke NetworkThe quality of stroke care in Canada.http://www.canadianstrokenetwork.ca/index.php/quality-stroke-care/Date: 2011Google Scholar show that patients with ischaemic stroke are offered thrombolysis too rarely or, if they are offered it, too slowly. Quick treatment requires efficient processes and a team approach. Pre-hospital systems to identify patients and bring them to the appropriate hospitals, emergency department swarming, rapid simple imaging, and use of telemedicine must be harnessed to reduce times to treatment. Strategies to do so will vary by region but it is simply unacceptable not to achieve very fast treatment times. In Berlin, Germany, the use of a CT scanner in the ambulance and point-of-care blood testing combined with a telemedicine link has enabled patients to be given alteplase very quickly, even before they reach the hospital.4Walter S Kostopoulos P Haass A et al.Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial.Lancet Neurol. 2012; 11: 397-404Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar In Helsinki, Finland, quick hospital-based treatment is possible with a median time from door to treatment of 20 min in one study.5Meretoja A Strbian D Mustanoja S Tatlisumak T Lindsberg PJ Kaste M Reducing in-hospital delay to 20 minutes in stroke thrombolysis.Neurology. 2012; 79: 306-313Crossref PubMed Scopus (436) Google Scholar However, in most of the world, patients are rarely treated that fast. Emberson and colleagues show that the treatment benefit is similar for young and old patients, with no evidence to support the use of different approaches for patients of different ages. Clearly, older patients should be considered for thrombolysis. Furthermore, the benefit for patients with mild stroke is notable given the continuing discussion about whether or not to treat patients with mild stroke. The data render obsolete the European licensing label for alteplase—which excludes patients older than 80 years and those with severe stroke. The finding of a small benefit of treatment up to 4·5 h from onset makes the advice of the US Food and Drug Administration and Health Canada to not treat patients after 3 h from onset similarly outdated. The question now is not whether we can extend the window for treatment. Rather, how do we get everyone treated faster and how do we dispel preconceived notions about not treating older patients or those with milder strokes? We must move from the proven science to policy and systems of care. Benchmarks for treatment times should be revised, audited, and enforced. The widely adopted standard of 60 min from door to needle is fine if 95% of patients are treated within 60 min. It is not, however, an acceptable average or guide. A median of 30 min is a better target because it affords an extra 30 min leeway, which still permits a 95th percentile of 60 min overall. Hospitals and teams that can achieve these targets, typically centres that treat many patients,6Bray BD Campbell J Cloud GC et al.Bigger, faster? Associations between hospital thrombolysis volume and speed of thrombolysis administration in acute ischemic stroke.Stroke. 2013; 44: 3129-3135Crossref PubMed Scopus (51) Google Scholar can be accredited as acute stroke centres. Those that cannot should allow stroke care to be centralised to those centres that can. Licensing bodies might consider changes. Accreditation bodies should update their targets and enact them as policy. Funding typically follows accreditation and this will be a crucial incentive for (and a means to) the achievement of fast treatment times. Further analyses of the trial data analysed by Emberson and colleagues will help us to understand the nuances of stroke, such as the effects of CT scan appearance (as assessed by the ASPECTS score),7Barber PA Hill MD Eliasziw M et al.Imaging of the brain in acute ischaemic stroke: comparison of computed tomography and magnetic resonance diffusion-weighted imaging.J Neurol Neurosurg Psychiatry. 2005; 76: 1528-1533Crossref PubMed Scopus (273) Google Scholar, 8Barber PA Demchuk AM Zhang J Buchan AM for the ASPECTS Study GroupValidity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy.Lancet. 2000; 355: 1670-1674Summary Full Text Full Text PDF PubMed Scopus (1659) Google Scholar blood pressure, blood glucose concentration,9Demchuk AM Morgenstern LB Krieger DW et al.Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke.Stroke. 1999; 30: 34-39Crossref PubMed Scopus (336) Google Scholar, 10Poppe AY Hill MD Hyperglycemia in thrombolysed acute ischemic stroke patients.Int J Stroke. 2011; 6: 278Crossref PubMed Scopus (2) Google Scholar even why women have greater relative benefit than men.11Kent 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: 62-65Crossref PubMed Scopus (197) Google Scholar But the biology of stroke is clear and immutable: patients must be treated with extraordinary speed. Delayed treatment is the same as no treatment. We have to adapt our systems of care to the biology of the disease because we cannot adapt the biology to our systems. Drivers, start your engines. MDH has received funding for research from Covidien. SBC has received drugs for a study from Hoffmann-La Roche Canada. 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 trialsIrrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. Full-Text PDF Open Access