PRIORITY PAPER EVALUATION For reprint orders, please contact: [email protected]
Novel lytics, novel imaging: a new treatment strategy in stroke? Evaluation of: Parsons M, Spratt N, Bivard A et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N. Engl. J. Med. 366(12), 1099–1107 (2012). Intravenous thrombolysis with alteplase is one of the few evidence-based acute ischemic stroke treatments. Efficacy is time dependent and not all patients treated within the 4.5 h license derive benefit. The lytic agent tenecteplase has theoretical benefits. In the Phase II study by Parsons and colleagues, tenecteplase was superior to alteplase across imaging and safety outcomes for patients selected using specific imaging criteria. We review the evidence for thrombolysis, experience with tenecteplase and compare this study with others that have used similar designs for the investigation of novel stroke lytic agents. Keywords: alteplase n ischemic penumbra n stroke n tenecteplase n thrombolytic
Terence J Quinn*1,2 & Jesse Dawson1 Institute of Cardiovascular & Medical Sciences, School of Medicine, University of Glasgow, Glasgow, UK 2 Academic Geriatric Medicine, Walton Building, Glasgow Royal Infirmary, Glasgow, G4 0SF, UK *Author for correspondence: Tel.: +44 141 211 4976 Fax: +44 141 211 4033 [email protected] 1
The burden of stroke
Impacting on the burden of stroke is a global health priority. Stroke remains one of the top three causes of death and is the most common cause of adult disability across industrialized countries. Although age-standardized incidence is falling in certain countries, with an aging population absolute numbers of incident stroke and stroke survivors continues to increase [1] . Driven by direct medical and indirect societal costs, the economic consequence of stroke is substantial, with stroke care estimated to consume approximately 5% of many countries’ healthcare budget [2] . Thus, any intervention that improves stroke outcomes is welcome. Parsons and colleagues report a Phase IIB randomized controlled trial of intravenous thrombolytic agents for acute ischemic stroke [3] . Methods & results
In this study subjects were randomized to thrombolytic treatment using either the conventional and licensed agent, alteplase (tissue plasminogen activator [tPA]; Actilyse®, Boehringer Ingelheim) or an alternative, tenecteplase (TNK; Metalyse [EU]; TNKase [USA], Genentech). TNK was delivered using two dosing schedules, with subjects randomized to a high and low dose. The participants had suffered an ischemic stroke within the previous 6 h and it was required that occlusion of a large cerebral vessel be demonstrated on noninvasive angiography. Participants were further selected based on the presence of radiological evidence of a mismatch between an infarcted brain and a cerebrovascular perfusion deficit. The use of these radiological inclusion criteria formed the basis for the decision to randomize participants out to 6 h, beyond the conventional treatment window of 4.5 h for thrombolytic therapy. Thus, the study provides data concerning both the use of imaging-based selection and the novel lytic TNK. The study included 75 subjects, 25 in each treatment arm. Stroke severity was at least modestly severe with a mean NIH Stroke Scale score of 14.4 (± 2.6). Participants were treated late compared with previous tPA trials, although most were still treated within the current alteplase license time window (time to treatment: 2.9 [± 0.8 h]. A number of end points were assessed with both a radiological (angiographic evidence
10.2217/CER.12.32 © 2012 Future Medicine Ltd
1(4), 311–314 (2012)
part of
ISSN 2042-6305
311
priority paper evaluation
Quinn & Dawson
of arterial reperfusion) and clinical (change in NIH Stroke Scale score at 24 h) measure serving as a coprimary end point. Both high- and lowdose TNK demonstrated improved outcomes compared with alteplase, with the higher dose superior to the lower dose for all prespecified outcomes. Safety outcomes, including intracerebral hemorrhage, were equivalent between groups. The authors described a prespecified secondary analysis of functional outcome (modified Rankin Scale) at 90 days. Modified Rankin is the end point traditionally used in Phase III thrombolysis studies and was used in the pivotal alteplase trials. Again, TNK demonstrated superiority. Overall, those in the high-dose TNK group demonstrated 72% excellent clinical recovery, compared with 42% in the alteplase group. Discussion ■■ Alteplase in ischemic stroke
Intravenous thrombolysis with alteplase has transformed acute stroke care in the last two decades. Along with early antiplatelet administration and admission to a dedicated stroke unit, alteplase is one of the few evidence-based therapies available for acute ischemic stroke [4] . The rationale for use of a thrombolytic is based on the concept of the ‘ischemic penumbra’; an area of brain that has limited blood perfusion, is functionally quiescent and at risk of cell death but is not yet irreversibly damaged. If blood flow can be restored through lysis of clot, this penumbra should be ‘salvaged’, which will limit the immediate cerebral damage and reduce disability in the longer term. The efficacy of this approach has been confirmed in large clinical trials [5] although benefit in unselected patients is confined to the first 4.5 h after symptom onset. Within this time period benefits are also highly time dependent with odds of favorable outcome estimated at 2.8 (95% CI: 1.8–9.5) for treatment within 90 min and 1.6 (95% CI: 1.1–2.2) for treatment between 91 and 180 min [5] . The third European Cooperative Acute Stroke Study (n = 821) confirmed efficacy of alteplase up to 4.5 h, although odds of favorable outcome were less (1.34; 95% CI: 1.02–01.76) [6] . Delivering thrombolytic therapy within this narrow therapeutic window remains a clinical and public health challenge. Even when administered, thrombolytic therapy with alteplase does not deliver universal benefit. There is a risk of intracerebral bleeding, although rates of clinically significant hemorrhage are modest in real-world
312
J. Compar. Effect. Res. (2012) 1(4)
case series [7] . Furthermore, not all patients derive benefit from treatment with radiological reperfusion seen in only approximately half of all subjects treated [8] . To convey this in easy-to-understand numbers, for every 100 patients treated in the 0–3 h window, 32 will show some improvement in disability scoring, three will be harmed and for the remaining 65, alteplase will show no effect [5] . A new thrombolytic agent would hopefully afford a higher rate of arterial reperfusion and a lower risk of hemorrhage and thereby, through improvement in the risk–benefit ratio, allow the timescale to be prolonged. ■■ Tenecteplase
TNK is one of a variety of intravenous lytic agents to have been studied in acute stroke. It is a genetically engineered mutant tPA and has theoretical advantages to alteplase. TNK has been engineered for greater fibrin specificity and improved resistance to inactivation by endogenous plasminogen activator inhibitor-1. This gives reduced systemic clearance rates relative to alteplase and a longer half-life allowing rapid bolus administration, as compared with the infusion required for alteplase [9] . TNK is an established treatment for myo cardial infarction. The thrombolysis in myocardial infarction family of studies suggested a efficacy of tenecteplase, that was confirmed in the Phase III randomized controlled trial (n = 16,949). The ASSENT trial compared TNK with alteplase and although there was no significant difference in primary outcomes, apparent advantages were seen in subjects receiving later treatment and there was a suggestion of reduced bleeding complications, both of which would be important properties for a stroke treatment [10] . TNK has been previously studied in stroke with initial promising results in a dose–escalation study, followed by an attempt at an adequately powered definitive study, which was terminated early owing to poor recruitment rates [9] . ■■ Improving patient selection
A further interesting aspect of the Parsons study is the imaging-based inclusion criteria. As the benefit of thrombolytic therapy is based on salvage of ischemic penumbra, intuitively those most likely to benefit from lysis will have a small area of irreversibly damaged cerebral tissue relative to the area of disordered cerebral perfusion. These areas can be imaged and quantified with MRI or computed tomography. Patients with no
future science group
Novel lytics, novel imaging: a new treatment strategy in stroke?
penumbra have little potential to benefit from reperfusion and could be spared the risks, while those with substantial penumbra may benefit from reperfusion even if treated beyond the conventional treatment-time window. The use of imaging parameters to select those patients who may benefit from ‘late’ thrombo lysis has been supported by nonrandomized studies and randomized studies such as EPITHET and DEFUSE [11,12] . Definitive data are however still lacking, although Parson’s data provides further indirect support. ■■ Desmoteplase déjà vu
This imaging based approach has been used before with another novel fibrinolytic. Desmoteplase is a lytic agent similar in structure to tPA but with distinct pharmacology. The DIAS family of trials studied the thrombolytic drug desmoteplase in subjects selected on the basis of MRI evidence of salvageable brain tissue. Two Phase II trials of desmoteplase suggested benefit based on improved reperfusion rates [13,14] . However, the Phase III DIAS-2 study (n = 186) was neutral [15] . There are differences between Parsons’ study and DIAS-2; DIAS-2 included strokes with minor neurological deficit, smaller areas of infarct core, smaller radiological mismatch and a few had vessel occlusion. It seems likely that the DIAS-2 population were too ‘mild’ to demonstrate a treatment effect. Indeed, post hoc analysis limited to those patients with cerebral vessel occlusion suggested a benefit of desmoteplase. Conclusion
In selected patients, intravenous TNK may have benefits over standard alteplase treatment. Although these data are promising, we must remember that this was a Phase IIB study and further evidence is required before we adopt TNK as the lytic of choice in stroke. It is telling that of 2768 subjects assessed, only 75 were included in the final study, emphasizing the
priority paper evaluation
need for ‘real-world’ studies, complemented by registry data. Future perspective
Intravenous alteplase is a highly efficacious therapy for acute ischemic stroke. As clinicians have gained familiarity with alteplase it is increasingly being used in groups for whom thrombolysis was previously thought to be unsafe, including older adults and those at extremes of impairment. The third International Stroke Trial will soon present data that may support or challenge this approach [101] . Intravenous thrombolysis will remain an important component of therapy in stroke for many years. In coronary artery disease, percutaneous intervention is increasingly used in favor of intravenous lysis. However, results to date with percutaneous intervention for stroke have been mixed with no compelling evidence of efficacy, although trials are ongoing. Despite its many benefits, alteplase is limited by its narrow time window and unpredictable reperfusion rates. The paper by Parsons suggests two possible interventions that may improve utility of intravenous lysis. The use of imaging to define regions of salvageable brain is intuitive, and based on these and other data, increasing use of these technologies seems warranted. The potential for TNK to deliver improved outcomes compared with alteplase is also strongly supported by Parson’s data, but adequately powered head-to-head trials will still be required. We must remember that recent stroke research has been characterized by agents that have shown considerable promise in preclinical and earlyphase trials, only to show a neutral effect in larger scale clinical studies. Financial & competing interests disclosure J Dawson has received speaker fees for lectures on management of stroke from Pfizer, Boeringher Ingheim and Bristol Myers Squibb. TJ Quinn has received speaker fees for
Executive summary Intravenous thrombolysis with alteplase is an effective treatment for acute ischemic stroke. Efficacy of alteplase is limited by the narrow therapeutic window for administration, safety concerns and frequent nonreperfusion. ■■ The genetically engineered agent tenecteplase (TNK) has theoretical benefits over alteplase and has shown efficacy in other clinical areas. ■■ Parsons and colleagues demonstrate superiority of TNK to alteplase across various outcomes in a highly selected population. ■■ The trialists used nonroutine imaging criteria to target selection. ■■ There is now strong evidence for larger scale trials of TNK against alteplase in routine clinical settings. ■■ ■■
future science group
www.futuremedicine.com
313
priority paper evaluation
Quinn & Dawson
lectures on management of stroke from Bristol Myers Squibb and Merck. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the
References 1
Rich DQ, Gaziano JM, Kurth T. Geographic patterns in overall and specific cardiovascular disease incidence in apparently healthy men in the United States. Stroke 38, 2221–2227 (2007).
2
Quinn TJ, Dawson J. Acute ‘strokenomics’ efficacy and economic analyses of alteplase for acute ischemic stroke. Expert Rev. Pharmacoecon. Outcomes Res. 9(6), 513–522 (2009).
3
Parsons M, Spratt N, Bivard A et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N. Engl. J. Med. 366, 1099–1107 (2012).
4
McArthur KS, Quinn TJ, Dawson J, Walters MR. Diagnosis and mangemnet of transient ischemic attack and ischemic stroke in the acute phase. BMJ 342, d1938 (2011).
5
Hacke W, Donnan G, Fieschi C et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 363, 768–774 (2004).
6
314
Hacke W, Kaste M, Bluhmki E et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med. 359, 1317–1329 (2008).
7
8
9
10
11
subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Wahlgren N, Ahmed N, Davalos A et al. Thrombolysis with alteplase for acute ischemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 369, 275–282 (2007).
12 Davis SM, Donnan GA, Parsons MW et al.
Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 38, 967–973 (2007).
13 Furlan AJ, Eyding D, Albers GW et al. Dose
Haley EC, Lyden PD, Johnston KC, Hemmen TM; the TNK in Stroke Investigators. A pilot dose–escalation safety study of tenecteplase in acute ischemic stroke. Stroke 36, 607–612 (2005). Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators; Van De Werf F, Adgey J, Ardissino D et al. Single bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomized trial. Lancet 354, 716–722 (1999). Albers GW, Thijs VN, Wechsler L et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study. Ann. Neurol. 60, 508–517 (2006).
J. Compar. Effect. Res. (2012) 1(4)
Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo controlled randomized trial. Lancet Neurol. 7, 299–309 (2008). Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 37, 1227–1231 (2006). 14
Hacke W, Albers G, Al-Rawi Y et al. The Desmoteplase in Acute Ischemic Stroke trial (DIAS): a Phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 36, 66–73 (2005).
15
Hacke W, Furlan AJ, Al Rawi Y et al. Intravenous desmoteplase in patients with acute ischemic stroke selected by MRI perfusion–diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009(2), 141–150 (2009).
■■ Website 101 The Third International Stroke Trial
(Thrombolysis). www.dcn.ed.ac.uk/ist3
future science group
Novel lytics, novel imaging: a new treatment strategy in stroke? Evaluation of: Parsons M, Spratt N, Bivard A et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N. Engl. J. Med. 366(12), 1099–1107 (2012). Intravenous thrombolysis with alteplase is one of the few evidence-based acute ischemic stroke treatments. Efficacy is time dependent and not all patients treated within the 4.5 h license derive benefit. The lytic agent tenecteplase has theoretical benefits. In the Phase II study by Parsons and colleagues, tenecteplase was superior to alteplase across imaging and safety outcomes for patients selected using specific imaging criteria. We review the evidence for thrombolysis, experience with tenecteplase and compare this study with others that have used similar designs for the investigation of novel stroke lytic agents. Keywords: alteplase n ischemic penumbra n stroke n tenecteplase n thrombolytic
Terence J Quinn*1,2 & Jesse Dawson1 Institute of Cardiovascular & Medical Sciences, School of Medicine, University of Glasgow, Glasgow, UK 2 Academic Geriatric Medicine, Walton Building, Glasgow Royal Infirmary, Glasgow, G4 0SF, UK *Author for correspondence: Tel.: +44 141 211 4976 Fax: +44 141 211 4033 [email protected] 1
The burden of stroke
Impacting on the burden of stroke is a global health priority. Stroke remains one of the top three causes of death and is the most common cause of adult disability across industrialized countries. Although age-standardized incidence is falling in certain countries, with an aging population absolute numbers of incident stroke and stroke survivors continues to increase [1] . Driven by direct medical and indirect societal costs, the economic consequence of stroke is substantial, with stroke care estimated to consume approximately 5% of many countries’ healthcare budget [2] . Thus, any intervention that improves stroke outcomes is welcome. Parsons and colleagues report a Phase IIB randomized controlled trial of intravenous thrombolytic agents for acute ischemic stroke [3] . Methods & results
In this study subjects were randomized to thrombolytic treatment using either the conventional and licensed agent, alteplase (tissue plasminogen activator [tPA]; Actilyse®, Boehringer Ingelheim) or an alternative, tenecteplase (TNK; Metalyse [EU]; TNKase [USA], Genentech). TNK was delivered using two dosing schedules, with subjects randomized to a high and low dose. The participants had suffered an ischemic stroke within the previous 6 h and it was required that occlusion of a large cerebral vessel be demonstrated on noninvasive angiography. Participants were further selected based on the presence of radiological evidence of a mismatch between an infarcted brain and a cerebrovascular perfusion deficit. The use of these radiological inclusion criteria formed the basis for the decision to randomize participants out to 6 h, beyond the conventional treatment window of 4.5 h for thrombolytic therapy. Thus, the study provides data concerning both the use of imaging-based selection and the novel lytic TNK. The study included 75 subjects, 25 in each treatment arm. Stroke severity was at least modestly severe with a mean NIH Stroke Scale score of 14.4 (± 2.6). Participants were treated late compared with previous tPA trials, although most were still treated within the current alteplase license time window (time to treatment: 2.9 [± 0.8 h]. A number of end points were assessed with both a radiological (angiographic evidence
10.2217/CER.12.32 © 2012 Future Medicine Ltd
1(4), 311–314 (2012)
part of
ISSN 2042-6305
311
priority paper evaluation
Quinn & Dawson
of arterial reperfusion) and clinical (change in NIH Stroke Scale score at 24 h) measure serving as a coprimary end point. Both high- and lowdose TNK demonstrated improved outcomes compared with alteplase, with the higher dose superior to the lower dose for all prespecified outcomes. Safety outcomes, including intracerebral hemorrhage, were equivalent between groups. The authors described a prespecified secondary analysis of functional outcome (modified Rankin Scale) at 90 days. Modified Rankin is the end point traditionally used in Phase III thrombolysis studies and was used in the pivotal alteplase trials. Again, TNK demonstrated superiority. Overall, those in the high-dose TNK group demonstrated 72% excellent clinical recovery, compared with 42% in the alteplase group. Discussion ■■ Alteplase in ischemic stroke
Intravenous thrombolysis with alteplase has transformed acute stroke care in the last two decades. Along with early antiplatelet administration and admission to a dedicated stroke unit, alteplase is one of the few evidence-based therapies available for acute ischemic stroke [4] . The rationale for use of a thrombolytic is based on the concept of the ‘ischemic penumbra’; an area of brain that has limited blood perfusion, is functionally quiescent and at risk of cell death but is not yet irreversibly damaged. If blood flow can be restored through lysis of clot, this penumbra should be ‘salvaged’, which will limit the immediate cerebral damage and reduce disability in the longer term. The efficacy of this approach has been confirmed in large clinical trials [5] although benefit in unselected patients is confined to the first 4.5 h after symptom onset. Within this time period benefits are also highly time dependent with odds of favorable outcome estimated at 2.8 (95% CI: 1.8–9.5) for treatment within 90 min and 1.6 (95% CI: 1.1–2.2) for treatment between 91 and 180 min [5] . The third European Cooperative Acute Stroke Study (n = 821) confirmed efficacy of alteplase up to 4.5 h, although odds of favorable outcome were less (1.34; 95% CI: 1.02–01.76) [6] . Delivering thrombolytic therapy within this narrow therapeutic window remains a clinical and public health challenge. Even when administered, thrombolytic therapy with alteplase does not deliver universal benefit. There is a risk of intracerebral bleeding, although rates of clinically significant hemorrhage are modest in real-world
312
J. Compar. Effect. Res. (2012) 1(4)
case series [7] . Furthermore, not all patients derive benefit from treatment with radiological reperfusion seen in only approximately half of all subjects treated [8] . To convey this in easy-to-understand numbers, for every 100 patients treated in the 0–3 h window, 32 will show some improvement in disability scoring, three will be harmed and for the remaining 65, alteplase will show no effect [5] . A new thrombolytic agent would hopefully afford a higher rate of arterial reperfusion and a lower risk of hemorrhage and thereby, through improvement in the risk–benefit ratio, allow the timescale to be prolonged. ■■ Tenecteplase
TNK is one of a variety of intravenous lytic agents to have been studied in acute stroke. It is a genetically engineered mutant tPA and has theoretical advantages to alteplase. TNK has been engineered for greater fibrin specificity and improved resistance to inactivation by endogenous plasminogen activator inhibitor-1. This gives reduced systemic clearance rates relative to alteplase and a longer half-life allowing rapid bolus administration, as compared with the infusion required for alteplase [9] . TNK is an established treatment for myo cardial infarction. The thrombolysis in myocardial infarction family of studies suggested a efficacy of tenecteplase, that was confirmed in the Phase III randomized controlled trial (n = 16,949). The ASSENT trial compared TNK with alteplase and although there was no significant difference in primary outcomes, apparent advantages were seen in subjects receiving later treatment and there was a suggestion of reduced bleeding complications, both of which would be important properties for a stroke treatment [10] . TNK has been previously studied in stroke with initial promising results in a dose–escalation study, followed by an attempt at an adequately powered definitive study, which was terminated early owing to poor recruitment rates [9] . ■■ Improving patient selection
A further interesting aspect of the Parsons study is the imaging-based inclusion criteria. As the benefit of thrombolytic therapy is based on salvage of ischemic penumbra, intuitively those most likely to benefit from lysis will have a small area of irreversibly damaged cerebral tissue relative to the area of disordered cerebral perfusion. These areas can be imaged and quantified with MRI or computed tomography. Patients with no
future science group
Novel lytics, novel imaging: a new treatment strategy in stroke?
penumbra have little potential to benefit from reperfusion and could be spared the risks, while those with substantial penumbra may benefit from reperfusion even if treated beyond the conventional treatment-time window. The use of imaging parameters to select those patients who may benefit from ‘late’ thrombo lysis has been supported by nonrandomized studies and randomized studies such as EPITHET and DEFUSE [11,12] . Definitive data are however still lacking, although Parson’s data provides further indirect support. ■■ Desmoteplase déjà vu
This imaging based approach has been used before with another novel fibrinolytic. Desmoteplase is a lytic agent similar in structure to tPA but with distinct pharmacology. The DIAS family of trials studied the thrombolytic drug desmoteplase in subjects selected on the basis of MRI evidence of salvageable brain tissue. Two Phase II trials of desmoteplase suggested benefit based on improved reperfusion rates [13,14] . However, the Phase III DIAS-2 study (n = 186) was neutral [15] . There are differences between Parsons’ study and DIAS-2; DIAS-2 included strokes with minor neurological deficit, smaller areas of infarct core, smaller radiological mismatch and a few had vessel occlusion. It seems likely that the DIAS-2 population were too ‘mild’ to demonstrate a treatment effect. Indeed, post hoc analysis limited to those patients with cerebral vessel occlusion suggested a benefit of desmoteplase. Conclusion
In selected patients, intravenous TNK may have benefits over standard alteplase treatment. Although these data are promising, we must remember that this was a Phase IIB study and further evidence is required before we adopt TNK as the lytic of choice in stroke. It is telling that of 2768 subjects assessed, only 75 were included in the final study, emphasizing the
priority paper evaluation
need for ‘real-world’ studies, complemented by registry data. Future perspective
Intravenous alteplase is a highly efficacious therapy for acute ischemic stroke. As clinicians have gained familiarity with alteplase it is increasingly being used in groups for whom thrombolysis was previously thought to be unsafe, including older adults and those at extremes of impairment. The third International Stroke Trial will soon present data that may support or challenge this approach [101] . Intravenous thrombolysis will remain an important component of therapy in stroke for many years. In coronary artery disease, percutaneous intervention is increasingly used in favor of intravenous lysis. However, results to date with percutaneous intervention for stroke have been mixed with no compelling evidence of efficacy, although trials are ongoing. Despite its many benefits, alteplase is limited by its narrow time window and unpredictable reperfusion rates. The paper by Parsons suggests two possible interventions that may improve utility of intravenous lysis. The use of imaging to define regions of salvageable brain is intuitive, and based on these and other data, increasing use of these technologies seems warranted. The potential for TNK to deliver improved outcomes compared with alteplase is also strongly supported by Parson’s data, but adequately powered head-to-head trials will still be required. We must remember that recent stroke research has been characterized by agents that have shown considerable promise in preclinical and earlyphase trials, only to show a neutral effect in larger scale clinical studies. Financial & competing interests disclosure J Dawson has received speaker fees for lectures on management of stroke from Pfizer, Boeringher Ingheim and Bristol Myers Squibb. TJ Quinn has received speaker fees for
Executive summary Intravenous thrombolysis with alteplase is an effective treatment for acute ischemic stroke. Efficacy of alteplase is limited by the narrow therapeutic window for administration, safety concerns and frequent nonreperfusion. ■■ The genetically engineered agent tenecteplase (TNK) has theoretical benefits over alteplase and has shown efficacy in other clinical areas. ■■ Parsons and colleagues demonstrate superiority of TNK to alteplase across various outcomes in a highly selected population. ■■ The trialists used nonroutine imaging criteria to target selection. ■■ There is now strong evidence for larger scale trials of TNK against alteplase in routine clinical settings. ■■ ■■
future science group
www.futuremedicine.com
313
priority paper evaluation
Quinn & Dawson
lectures on management of stroke from Bristol Myers Squibb and Merck. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the
References 1
Rich DQ, Gaziano JM, Kurth T. Geographic patterns in overall and specific cardiovascular disease incidence in apparently healthy men in the United States. Stroke 38, 2221–2227 (2007).
2
Quinn TJ, Dawson J. Acute ‘strokenomics’ efficacy and economic analyses of alteplase for acute ischemic stroke. Expert Rev. Pharmacoecon. Outcomes Res. 9(6), 513–522 (2009).
3
Parsons M, Spratt N, Bivard A et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N. Engl. J. Med. 366, 1099–1107 (2012).
4
McArthur KS, Quinn TJ, Dawson J, Walters MR. Diagnosis and mangemnet of transient ischemic attack and ischemic stroke in the acute phase. BMJ 342, d1938 (2011).
5
Hacke W, Donnan G, Fieschi C et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 363, 768–774 (2004).
6
314
Hacke W, Kaste M, Bluhmki E et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med. 359, 1317–1329 (2008).
7
8
9
10
11
subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Wahlgren N, Ahmed N, Davalos A et al. Thrombolysis with alteplase for acute ischemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 369, 275–282 (2007).
12 Davis SM, Donnan GA, Parsons MW et al.
Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 38, 967–973 (2007).
13 Furlan AJ, Eyding D, Albers GW et al. Dose
Haley EC, Lyden PD, Johnston KC, Hemmen TM; the TNK in Stroke Investigators. A pilot dose–escalation safety study of tenecteplase in acute ischemic stroke. Stroke 36, 607–612 (2005). Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators; Van De Werf F, Adgey J, Ardissino D et al. Single bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomized trial. Lancet 354, 716–722 (1999). Albers GW, Thijs VN, Wechsler L et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study. Ann. Neurol. 60, 508–517 (2006).
J. Compar. Effect. Res. (2012) 1(4)
Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo controlled randomized trial. Lancet Neurol. 7, 299–309 (2008). Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 37, 1227–1231 (2006). 14
Hacke W, Albers G, Al-Rawi Y et al. The Desmoteplase in Acute Ischemic Stroke trial (DIAS): a Phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 36, 66–73 (2005).
15
Hacke W, Furlan AJ, Al Rawi Y et al. Intravenous desmoteplase in patients with acute ischemic stroke selected by MRI perfusion–diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009(2), 141–150 (2009).
■■ Website 101 The Third International Stroke Trial
(Thrombolysis). www.dcn.ed.ac.uk/ist3
future science group
