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Snake venom, vampire bat saliva, or rt-PA: time matters
Comment
Snake venom, vampire bat saliva, or rt-PA: time matters
www.thelancet.com Vol 368 November 25, 2006
analysis suggested that a time window could be longer than 3 h for recanalisation therapy,8 and the Desmoteplase in Acute Ischemic Stroke Trial (DIAS) and Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS) trials verified that point.8,9 DIAS and DEDAS, with a 3–9 h window, used desmoteplase, which is identical to a protein in the saliva of the vampire bat, Desmodus rotundus. Both studies8,9 showed that it is possible to improve the outcome of stroke patients with drug-induced recanalisation after 3 h from the onset of symptoms. Although desmoteplase has higher fibrinogen specificity and longer terminal half-life than rt-PA, these properties cannot alone explain the significant benefits of the trials. Modern MRI technology was essential for the benefits in DIAS and DEDAS. Perfusion and diffusion mismatch revealed by MRI was used in these trials to select those patients who still have ischaemic penumbra after 3 h and thus have a chance to benefit from recanalisation. However, for most stroke patients, the time for recanalisation is probably shorter, as the results of the pooled analysis7 and ESTAT tell. Basilar artery occlusion seems to be an exception to this rule.10 When the European Medicines Agency (EMEA) approved alteplase for the treatment of acute ischaemic stroke in a 3 h time window, the approval was conditional. All patients treated should be included in the SITS-MOST (Safety Implementation of Thrombolysis in Stroke: a Multinational Multicentre Monitoring Study of Safety and Efficacy of Thrombolysis in Stroke) register so that EMEA could monitor safety, even outside randomised trials. The SITS-MOST register showed that thrombolysis can be safely provided in routine clinical care. Our results
See Articles page 1871
The printed journal includes an image merely for illustration
Science Photo Library
In today’s Lancet, Michael Hennerici and colleagues1 report on the European Stroke Treatment with Ancrod Trial (ESTAT), which assessed the effects of a purified fraction of venom from the Malaysian pit viper versus placebo in acute ischaemic stroke. In the active treatment group there were more symptomatic intracerebral haemorrhages, neurological recovery was worse, and the 90-day mortality was higher than in the placebo group. However, Hennerici and colleagues are to be congratulated for a well-executed trial. Although the study was unsuccessful, it delivers an important message: that time from onset of symptoms to treatment matters, and in ESTAT it was too long. The study also highlights how important it is to publish unsuccessful trials. Such trials often include valuable pieces of information, which can guide future studies. Furthermore, it is unethical not to publish the results of all well-designed and executed trials just because they fail to reach their targets. Why did ESTAT not show a difference with 1222 patients enrolled, while the sister study, the Stroke Treatment with Ancrod Trial (STAT),2 with an almost identical design and only 500 patients, showed a significant difference? There is one major difference between the two designs. The time window in STAT was 3 h, but in ESTAT it was 6 h. ESTAT and STAT delivered the same message that the National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue-plasminogen Activator (NINDS rt-PA) Stroke Study3 versus the European Cooperative Acute Stroke Study (ECASS) studies did.4,5 The NINDS rt-PA study in acute stroke had a 3 h window and half of the patients treated within 90 min showed an effect; however, the ECASS and ECASS II5 studies with a 6 h window did not show an outcome difference. The most probable reason for the failure was too long a window when no functional neuroimaging was used in patient selection. As time goes on, there is less and less ischaemic penumbra—ie, ischaemic but not yet dead brain tissue to be saved by timely recanalisation and reperfusion. The fact that early treatment is the key for good outcome was suggested by the post-hoc analysis of NINDS6 and verified by the results of the pooled analysis of the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS), ECASS, ECASS II, and NINDS trials.7 There are stroke patients who benefit from recanalisation and reperfusion after the 3 h window. The pooled
Malaysian pit viper
1845
Comment
in the register show that the number of patients treated within 90 min and earlier can be increased and thereby the number of patients with good outcome can be increased.11 Early treatment requires continuous education, practice, and training of the whole chain in stroke care. If doubts remain that time matters, ESTAT should abolish them. To accelerate the improvement in stroke care, an American consensus conference on improving the chain of recovery in your community, organised by the National Institute of Neurological Disorders and Stroke in 2002,12 and a European Consensus Conference updating the Helsingborg Declaration in 2006 both recommend that all people involved in acute stroke care should organise their services to make early admission and treatment possible. If success is awaited, one only has to look in the mirror to see the major reason for the slow improvement.
1
2
3
4
5
6
7
8
Markku Kaste Department of Neurology, Helsinki University Central Hospital, University of Helsinki, 00029HUS Helsinki, Finland markku.kaste@hus.fi I served on the steering committees of ECASS, ECASS II, ATLANTIS, DIAS, and DIAS II. My travel expenses for steering committee meetings plus honoraria were paid by Boehringer Ingelheim, PAION GmbH, and Forest Research Laboratories Inc. While visiting professor in the USA, I proposed and drafted the STAT trial, which later was done by American colleagues. I am a consultant for Neurobiological Technologies and H Lundbeck; both companies have an interest in recanalisation therapies in acute ischaemic stroke.
9 10 11 12
Hennerici M, Kay R, Bogousslausky J, et al, for the ESTAT investigators. Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: a randomised, controlled trial. Lancet 2006; 368: 1871–78. Sherman DG, Atkinson RP, Chippendale T, for the STAT participants. Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial. JAMA 2000; 283: 2395–403. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333: 1581–87. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274: 1017–25. Hacke W, Kaste M, Fieschi C, for the Second European-Australian Acute Stroke Study. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998; 352: 1245–51. Marler JR, Tilley BC, Lu M, for the NINDS rt-PA Stroke Study Group. Early stroke treatment associated with better outcome: the NINDS rt-PA Stroke Study. Neurology 2000; 55: 1649–55. Hacke W, Donnan G, Fieschi C, for the ATLANTIS Trial Investigators, ECASS Trials Investigators and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363: 768–74. Hacke W, Albers G, Al-Rawi Y, for the DIAS Study Group. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005; 36: 66–73. Furlan AJ, Eyding D, Albers GW, for the DEDAS Investigators. Dose escalation of desmoteplase for acute ischemic stroke (DEDAS). Stroke 2006; 37: 1227–31. Lindsberg PJ, Soinne L, Tatlisumak T, et al. Long-term outcome after intravenous thrombolysis of basilar artery occlusion. JAMA 2004; 292: 1862–86. Kaste M. Evidence, education and practice. Cerebrovasc Dis 2006; 22: 342–49. National Institute of Neurological Disorders and Stroke. Task Force Report: improving the chain of recovery in your community. April 13, 2005: http://www.ninds.nih.gov/news_and_events/proceedings/acute_stroke_ workshop.htm (accessed Aug 3, 2006).
England’s national Teenage Pregnancy Strategy See Articles page 1879
1846
Declines in teenage childbearing in the UK and similar industrialised countries are well documented.1,2 Still, the UK continues to struggle with the highest teenage birthrate in western Europe.3 In today’s Lancet, Paul Wilkinson and colleagues4 describe England’s Teenage Pregnancy Strategy, and assess the programme’s preliminary effect on teenage conceptions, births, and abortions. Developed countries with the lowest rates of births to teenage mothers are characterised by school-based sex education, broad availability of contraception including postcoital methods, and access to abortion services.5 With this knowledge, an ambitious strategy to halve the UK’s teenage pregnancy rate by 2010 and increase the number of teenage parents in education, training, or employment was funded in 1999. The strategy has four major components: a national media campaign, joint action to ensure national and local coordination,
improved education about sex and relationships and increased access to services, and support for teen parents to return to education, training, or employment. Rates of teenage conceptions peaked in England in 1998, and then fell. By 1999–2003, rates of conceptions had fallen by 3·2%, abortion rates had increased by 7·5%, and birthrates had been reduced by 10·6%. The average annual decrease in conceptions from 1998 to 2003 was 2·0%. Except for service quality (which, contrary to expectation, was negatively associated with decline in conceptions), individual components of the strategy showed no association with change in teenage conceptions. However, level of expenditure, a proxy measure of extent and quality of local implementation of the strategy, was associated with fewer conceptions and births in both unadjusted and adjusted analyses. Notably, greater expenditures were associated with significantly larger declines in teenage conceptions in www.thelancet.com Vol 368 November 25, 2006
Snake venom, vampire bat saliva, or rt-PA: time matters
www.thelancet.com Vol 368 November 25, 2006
analysis suggested that a time window could be longer than 3 h for recanalisation therapy,8 and the Desmoteplase in Acute Ischemic Stroke Trial (DIAS) and Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS) trials verified that point.8,9 DIAS and DEDAS, with a 3–9 h window, used desmoteplase, which is identical to a protein in the saliva of the vampire bat, Desmodus rotundus. Both studies8,9 showed that it is possible to improve the outcome of stroke patients with drug-induced recanalisation after 3 h from the onset of symptoms. Although desmoteplase has higher fibrinogen specificity and longer terminal half-life than rt-PA, these properties cannot alone explain the significant benefits of the trials. Modern MRI technology was essential for the benefits in DIAS and DEDAS. Perfusion and diffusion mismatch revealed by MRI was used in these trials to select those patients who still have ischaemic penumbra after 3 h and thus have a chance to benefit from recanalisation. However, for most stroke patients, the time for recanalisation is probably shorter, as the results of the pooled analysis7 and ESTAT tell. Basilar artery occlusion seems to be an exception to this rule.10 When the European Medicines Agency (EMEA) approved alteplase for the treatment of acute ischaemic stroke in a 3 h time window, the approval was conditional. All patients treated should be included in the SITS-MOST (Safety Implementation of Thrombolysis in Stroke: a Multinational Multicentre Monitoring Study of Safety and Efficacy of Thrombolysis in Stroke) register so that EMEA could monitor safety, even outside randomised trials. The SITS-MOST register showed that thrombolysis can be safely provided in routine clinical care. Our results
See Articles page 1871
The printed journal includes an image merely for illustration
Science Photo Library
In today’s Lancet, Michael Hennerici and colleagues1 report on the European Stroke Treatment with Ancrod Trial (ESTAT), which assessed the effects of a purified fraction of venom from the Malaysian pit viper versus placebo in acute ischaemic stroke. In the active treatment group there were more symptomatic intracerebral haemorrhages, neurological recovery was worse, and the 90-day mortality was higher than in the placebo group. However, Hennerici and colleagues are to be congratulated for a well-executed trial. Although the study was unsuccessful, it delivers an important message: that time from onset of symptoms to treatment matters, and in ESTAT it was too long. The study also highlights how important it is to publish unsuccessful trials. Such trials often include valuable pieces of information, which can guide future studies. Furthermore, it is unethical not to publish the results of all well-designed and executed trials just because they fail to reach their targets. Why did ESTAT not show a difference with 1222 patients enrolled, while the sister study, the Stroke Treatment with Ancrod Trial (STAT),2 with an almost identical design and only 500 patients, showed a significant difference? There is one major difference between the two designs. The time window in STAT was 3 h, but in ESTAT it was 6 h. ESTAT and STAT delivered the same message that the National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue-plasminogen Activator (NINDS rt-PA) Stroke Study3 versus the European Cooperative Acute Stroke Study (ECASS) studies did.4,5 The NINDS rt-PA study in acute stroke had a 3 h window and half of the patients treated within 90 min showed an effect; however, the ECASS and ECASS II5 studies with a 6 h window did not show an outcome difference. The most probable reason for the failure was too long a window when no functional neuroimaging was used in patient selection. As time goes on, there is less and less ischaemic penumbra—ie, ischaemic but not yet dead brain tissue to be saved by timely recanalisation and reperfusion. The fact that early treatment is the key for good outcome was suggested by the post-hoc analysis of NINDS6 and verified by the results of the pooled analysis of the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS), ECASS, ECASS II, and NINDS trials.7 There are stroke patients who benefit from recanalisation and reperfusion after the 3 h window. The pooled
Malaysian pit viper
1845
Comment
in the register show that the number of patients treated within 90 min and earlier can be increased and thereby the number of patients with good outcome can be increased.11 Early treatment requires continuous education, practice, and training of the whole chain in stroke care. If doubts remain that time matters, ESTAT should abolish them. To accelerate the improvement in stroke care, an American consensus conference on improving the chain of recovery in your community, organised by the National Institute of Neurological Disorders and Stroke in 2002,12 and a European Consensus Conference updating the Helsingborg Declaration in 2006 both recommend that all people involved in acute stroke care should organise their services to make early admission and treatment possible. If success is awaited, one only has to look in the mirror to see the major reason for the slow improvement.
1
2
3
4
5
6
7
8
Markku Kaste Department of Neurology, Helsinki University Central Hospital, University of Helsinki, 00029HUS Helsinki, Finland markku.kaste@hus.fi I served on the steering committees of ECASS, ECASS II, ATLANTIS, DIAS, and DIAS II. My travel expenses for steering committee meetings plus honoraria were paid by Boehringer Ingelheim, PAION GmbH, and Forest Research Laboratories Inc. While visiting professor in the USA, I proposed and drafted the STAT trial, which later was done by American colleagues. I am a consultant for Neurobiological Technologies and H Lundbeck; both companies have an interest in recanalisation therapies in acute ischaemic stroke.
9 10 11 12
Hennerici M, Kay R, Bogousslausky J, et al, for the ESTAT investigators. Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: a randomised, controlled trial. Lancet 2006; 368: 1871–78. Sherman DG, Atkinson RP, Chippendale T, for the STAT participants. Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial. JAMA 2000; 283: 2395–403. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333: 1581–87. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274: 1017–25. Hacke W, Kaste M, Fieschi C, for the Second European-Australian Acute Stroke Study. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998; 352: 1245–51. Marler JR, Tilley BC, Lu M, for the NINDS rt-PA Stroke Study Group. Early stroke treatment associated with better outcome: the NINDS rt-PA Stroke Study. Neurology 2000; 55: 1649–55. Hacke W, Donnan G, Fieschi C, for the ATLANTIS Trial Investigators, ECASS Trials Investigators and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363: 768–74. Hacke W, Albers G, Al-Rawi Y, for the DIAS Study Group. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005; 36: 66–73. Furlan AJ, Eyding D, Albers GW, for the DEDAS Investigators. Dose escalation of desmoteplase for acute ischemic stroke (DEDAS). Stroke 2006; 37: 1227–31. Lindsberg PJ, Soinne L, Tatlisumak T, et al. Long-term outcome after intravenous thrombolysis of basilar artery occlusion. JAMA 2004; 292: 1862–86. Kaste M. Evidence, education and practice. Cerebrovasc Dis 2006; 22: 342–49. National Institute of Neurological Disorders and Stroke. Task Force Report: improving the chain of recovery in your community. April 13, 2005: http://www.ninds.nih.gov/news_and_events/proceedings/acute_stroke_ workshop.htm (accessed Aug 3, 2006).
England’s national Teenage Pregnancy Strategy See Articles page 1879
1846
Declines in teenage childbearing in the UK and similar industrialised countries are well documented.1,2 Still, the UK continues to struggle with the highest teenage birthrate in western Europe.3 In today’s Lancet, Paul Wilkinson and colleagues4 describe England’s Teenage Pregnancy Strategy, and assess the programme’s preliminary effect on teenage conceptions, births, and abortions. Developed countries with the lowest rates of births to teenage mothers are characterised by school-based sex education, broad availability of contraception including postcoital methods, and access to abortion services.5 With this knowledge, an ambitious strategy to halve the UK’s teenage pregnancy rate by 2010 and increase the number of teenage parents in education, training, or employment was funded in 1999. The strategy has four major components: a national media campaign, joint action to ensure national and local coordination,
improved education about sex and relationships and increased access to services, and support for teen parents to return to education, training, or employment. Rates of teenage conceptions peaked in England in 1998, and then fell. By 1999–2003, rates of conceptions had fallen by 3·2%, abortion rates had increased by 7·5%, and birthrates had been reduced by 10·6%. The average annual decrease in conceptions from 1998 to 2003 was 2·0%. Except for service quality (which, contrary to expectation, was negatively associated with decline in conceptions), individual components of the strategy showed no association with change in teenage conceptions. However, level of expenditure, a proxy measure of extent and quality of local implementation of the strategy, was associated with fewer conceptions and births in both unadjusted and adjusted analyses. Notably, greater expenditures were associated with significantly larger declines in teenage conceptions in www.thelancet.com Vol 368 November 25, 2006