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Meta-Analysis
. 2013 May 31;2013(5):CD000514.
doi: 10.1002/14651858.CD000514.pub3.

Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke

Joanna M Wardlaw  1 , Panos Koumellis, Ming Liu
Affiliations
Meta-Analysis

Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke

Joanna M Wardlaw et al. Cochrane Database Syst Rev. .

Abstract

Background: Stroke is a leading cause of death and disability world wide. Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is licensed for treatment of acute ischaemic stroke in the early hours after symptom onset. It has been shown in randomised controlled trials (RCTs) and the 2009 Cochrane review of thrombolysis for acute ischaemic stroke to reduce dependency but at the increased risk of intracranial haemorrhage. Methods to reduce the risk of haemorrhage while retaining or enhancing the benefit could increase the use of thrombolytic treatment. While most available information comes from RCTs of intravenous rt-PA at 0.9 mg/kg, it is possible that other doses, drugs and other routes of administration might increase benefit and reduce the hazard.

Objectives: To assess the risks and benefits of different thrombolytic agents, doses and routes of administration for the treatment of acute ischaemic stroke.

Search methods: We searched the Cochrane Stroke Group Trials Register (May 2012), MEDLINE (1966 to May 2012) and EMBASE (1980 to May 2012). We handsearched journals and conference proceedings, searched ongoing trials registers and contacted pharmaceutical companies and researchers.

Selection criteria: Unconfounded randomised and quasi-randomised trials of different doses of a thrombolytic agent, or different agents, or the same agent given by different routes, in people with confirmed acute ischaemic stroke.

Data collection and analysis: Two review authors independently assessed trial eligibility and quality, and extracted the data using a structured proforma. We cross-checked and resolved discrepancies by discussion to reach consensus. We obtained translations and additional information from study authors where required.

Main results: We included 20 trials involving 2527 patients. Concealment of allocation was poorly described. Different doses (of tissue plasminogen activator, urokinase, desmoteplase or tenecteplase) were compared in 13 trials (N = 1433 patients). Different agents (tissue plasminogen activator versus urokinase, tissue-cultured urokinase versus conventional urokinase, tenecteplase versus tissue plasminogen activator) were compared in five trials (N = 875 patients). Five trials (N = 485) compared different routes of administration. As some trials compared different agents and different doses, some patients contributed to two analyses. There was an approximately three-fold increase in fatal intracranial haemorrhages in patients allocated to higher than to lower doses of the same thrombolytic drug (odds ratio (OR) 2.71, 95% confidence interval (CI) 1.22 to 6.04). There was no difference in the number of patients who were dead or dependent at the end of follow-up between those allocated higher or lower doses of thrombolytic drug (OR 0.86, 95% CI 0.62 to 1.19). Higher versus lower doses of desmoteplase were associated with more deaths at the end of follow-up (OR 3.21, 95% CI 1.23 to 8.39). There was no evidence of any benefit for intra-arterial over intravenous treatment.

Authors' conclusions: These limited data suggest that higher doses of thrombolytic agents may lead to higher rates of bleeding. However, the evidence is inadequate to conclude whether lower doses of thrombolytic agents are more effective than higher doses, or whether one agent is better than another, or which route of administration is the best, for acute ischaemic stroke. At present, intravenous rt-PA at 0.9mg/kg as licensed in many countries appears to represent best practice and other drugs, doses or routes of administration should only be used in randomised controlled trials.

PubMed Disclaimer

Conflict of interest statement

JMW (and other academic colleagues) was awarded grants to perform the Third International Stroke Trial, a multicentre international randomised controlled trial of rt‐PA versus control in acute ischaemic stroke. The funders included the UK Medical Research Council, the Emerging Medicines Evaluation initiative of the National Institutes of Health Research UK, the Stroke Association, and numerous other governmental and charitable funders. These grants were all administered by the University of Edinburgh and funded staff, equipment and consumables. I received no personal salary or other direct funding from any of these.

Many years ago, the University of Edinburgh established a Brain Research Imaging Centre Magnetic Resonance scanner with academic government grants and some collaborative support from industry. The Industry funders were the MR equipment manufacturer Elscint (now taken over by GE) who provided the majority industry investment, Boehringer Ingelheim and Novartis, both of whom provided small contributions worth less than 5% of the total cost of the facility.

PK and ML have no known conflicts of interest.

Figures

1
1
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1 Thrombolysis: higher dose versus lower dose of the same agent, Outcome 1 Death or dependency at end of follow‐up.
1.2
1.2. Analysis
Comparison 1 Thrombolysis: higher dose versus lower dose of the same agent, Outcome 2 Death from all causes within about the first two weeks.
1.3
1.3. Analysis
Comparison 1 Thrombolysis: higher dose versus lower dose of the same agent, Outcome 3 Total deaths from all causes at end of follow‐up.
1.4
1.4. Analysis
Comparison 1 Thrombolysis: higher dose versus lower dose of the same agent, Outcome 4 'Significant' intracranial haemorrhage during follow‐up.
1.5
1.5. Analysis
Comparison 1 Thrombolysis: higher dose versus lower dose of the same agent, Outcome 5 Fatal intracranial haemorrhage during follow‐up.
1.6
1.6. Analysis
Comparison 1 Thrombolysis: higher dose versus lower dose of the same agent, Outcome 6 Total major (including fatal) extracranial haemorrhage during follow‐up.
2.1
2.1. Analysis
Comparison 2 Thrombolysis: one agent versus another, Outcome 1 Death or dependency at the end of follow‐up.
2.2
2.2. Analysis
Comparison 2 Thrombolysis: one agent versus another, Outcome 2 Death from all causes within about the first two weeks.
2.3
2.3. Analysis
Comparison 2 Thrombolysis: one agent versus another, Outcome 3 Total deaths from all causes at end of follow‐up.
2.4
2.4. Analysis
Comparison 2 Thrombolysis: one agent versus another, Outcome 4 'Significant' intracranial haemorrhage during follow‐up.
2.5
2.5. Analysis
Comparison 2 Thrombolysis: one agent versus another, Outcome 5 Fatal intracranial haemorrhage during follow‐up.
2.6
2.6. Analysis
Comparison 2 Thrombolysis: one agent versus another, Outcome 6 Total major (including fatal) extracranial haemorrhage during follow‐up.
3.1
3.1. Analysis
Comparison 3 Thrombolysis: different routes of administration of the same agent, Outcome 1 Death or dependency at end of follow‐up.
3.2
3.2. Analysis
Comparison 3 Thrombolysis: different routes of administration of the same agent, Outcome 2 Death from all causes within about the first two weeks.
3.3
3.3. Analysis
Comparison 3 Thrombolysis: different routes of administration of the same agent, Outcome 3 Total deaths from all causes at end of follow‐up.
3.4
3.4. Analysis
Comparison 3 Thrombolysis: different routes of administration of the same agent, Outcome 4 'Significant' intracranial haemorrhage during follow‐up.
3.5
3.5. Analysis
Comparison 3 Thrombolysis: different routes of administration of the same agent, Outcome 5 Fatal intracranial haemorrhage during follow‐up.
See this image and copyright information in PMC

Update of

Comment in

References

References to studies included in this review

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Abciximab 2001 {published data only}
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ARTIS {published data only}
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CARNEROS‐1 {unpublished data only}
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Christoforidis 2008 {unpublished data only}
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Dong 2003 {published data only}
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Konta 1996 {published data only}
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Lavallee 2007 {published data only}
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Liu 2000b {published data only}
    1. Liu X, Zhan G, Zheng Z. The clinical efficacy and safety of thrombolytic therapy with urokinase in patients with acute cerebral infarction. Chinese Journal of Geriatric Cardiovascular and Cerebrovascular Diseases 2000;2(3):177‐9.
Luo 1997 {published data only}
    1. Luo HW, Geng J, Liu YH. Clinical analysis of treating 50 patients with cerebral infarction by drugs through carotid artery. Chinese Journal of Practical Internal Medicine (Zhongguo shi yong nei ke za zhi) 1997;17(6):376.
Lyden 2003 {published data only}
    1. Lyden P. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke. Stroke Trials Registry, Internet Stroke Center: www.strokecenter.org/trials/ 2003. - PMC - PubMed
Lyden 2003a {published data only}
    1. Haley EC. Pilot study of TNK‐TPA in acute ischemic stroke. CRISP Database (accessed 12 December 2002).
    1. 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 2005;36:607‐12. - PubMed
    1. Lyden P, on behalf of the TNK for Stroke Investigators. Pilot study of tenecteplase (TNK) in acute ischemic stroke: preliminary report. Stroke 2003;34:246.
Macleod 2005 {published data only}
    1. Macleod MR, Davis SM, Mitchell PJ, Gerraty RP, Fitt G, Hankey GJ, et al. Results of a multicentre, randomised controlled trial of intra‐arterial urokinase in the treatment of acute posterior circulation ischaemic stroke. Cerebrovascular Diseases 2005;20(1):12‐7. - PubMed
MELT {published data only}
    1. Ogawa A, Mori E, MinematsuK, Taki W, Takahashi A, Nemoto S, et al. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke. The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) Japan. Stroke 2007;38:2633‐9. - PubMed
MITI‐IV {published data only}
    1. Thijs VN, Peeters A, Vosko M, Aichner F, Schellinger PD, Schneider D, et al. Randomized, placebo‐controlled, dose‐ranging clinical trial of intravenous microplasmin in patients with acute ischemic stroke. Stroke 2009;40(12):3789‐95. - PubMed
Morris 2003 {published data only}
    1. Morris DC, Mitsias P, Silver B, Zhang L, Daley S, Lewandowski C, et al. Abciximab and rt‐PA in acute ischaemic stroke treatment. Proceedings of the 28th AHA International Stroke Conference; February 13‐15 2003; USA, Phoenix, Arizona: The American Stroke Association. Abstract CTP16. 2003.
Qiang 2001 {published data only}
    1. Qiang D. The dynamic study of stroke MRI in hyperacute stroke patients with thrombolysis. Hong Kong Medical Journal 2001;7(4):16.
Qureshi 2002 {published data only}
    1. Qureshi AI. Safety and efficacy of intra‐arterial reteplase and intravenous abciximab in patients with acute ischaemic stroke. www.strokecenter.org 2002. - PubMed
Qureshi 2006 {published data only}
    1. Qureshi AI, Harris‐Lane P, Kirmani JF, Janjua N, Divani AA, Mohammad YM, et al. Intra‐arterial reteplase and intravenous abciximab in patients with acute ischemic stroke: an open‐label, dose‐ranging, phase I study. Neurosurgery 2006;59:789‐97. - PubMed
ReoPro Retavase MRI {published data only}
    1. Patient Recruitment and Public Liaison Office. ReoPro Retavase Reperfusion of Stroke Safety Study ‐ Imaging Evaluation. www.strokecenter.org (Internet Stroke Center) 2002.
Riedel 1996 {unpublished data only}
    1. Riedel A. Phase II pilot study of pro‐urokinase (Saruplase) in acute stroke with angiographically‐proven occlusion of the middle cerebral artery. Unpublished.
Sakamoto 1996 {published data only}
    1. Sakamoto T, Harimoto K, Inoue S, Konishi A. Clinical effects of urokinase and sodium ozagrel in patients with acute symptomatic lacunar infarction. Brain and Nerve/No To Shinkei 1996;48(9):805‐9. - PubMed
Seitz 2004 {published data only}
    1. Seitz RJ, Meisel S, Moll M, Wittsack H‐J, Junghans U, Siebler M. The effect of combined thrombolysis with rtPA and tirofiban on ischemic brain lesions. Neurology 2004;62:2110‐2. - PubMed
Song 2000 {published data only}
    1. Song JY, Zhang Y, Zhan JS, et al. A comparison of efficacy of carotid artery thrombolysis and venous thrombolysis with urokinase in acute cerebral infarction. Chinese Journal of Critical Care Medicine ‐ Zhongguo Ji Jiu Yi Xue 2000;12(5):287‐9.
Song 2003 {published data only}
    1. Song X, Xu G, Zhu R, Yu M, Wu X, Yu S, et al. Intracarotid thrombolysis in treatment of acute cerebral infarction. Proceedings of the 4th International Conference on Research Advances in Cerebrovascular Disease; 13‐15 October 2003; China, Chengdu: 2003:171‐3. 2003.
TASS {published data only}
    1. Haley EC. Pilot study of TNK‐TPA in acute ischaemic stroke, treated within 3 hours. CRISP Database (electronic), also Internet Stroke Trials Directory www.strokecenter.org 2002.
    1. Lyden P, on behalf of the TNK for Stroke Investigators. Pilot study of tenecteplase (TNK) in acute ischaemic stroke: preliminary report. Stroke 2003;34:246.
Tazaki 1987 {published data only}
    1. Tazaki Y, Kobayashi S, Togi H, Ohtomo E, Goto F, Araki G, et al. Therapeutic effect of thrombin inhibitor MD‐805 in cerebral thrombosis ‐ double blinded comparative study with tissue cultured urokinase. Igaku no Ayumi 1987;141:499‐515.
TNK‐TPA {published data only}
    1. Molina CA, Ribo M, Rubiera M, Santamarina E, Delgado‐Mederos R, Maisterra O, et al. TNK induces faster MCA recanalization and leads to better short‐ and long‐term clinical outcomes than native tPA. The TNK‐TPA reperfusion stroke study. Stroke 2008;39(2):563.
Tsuchiya 1989 {published data only}
    1. Tsuchiya T, Fujikake K, Oku K. Effects of urokinase and heparin on hemorrhagic infarction, recanalization, recurrence ‐ analysis of 111 cases with middle cerebral artery occlusion on an acute stage in a prospective controlled trial. Japanese Journal of Stroke 1989;11:500‐10.
Tsuchiya 1990 {published data only}
    1. Tsuchiya T, Fujikake K, Oku K. A study on clinical effects of the combinated therapy of urokinase and heparin for acute lacunar infarcts in a prospective controlled trial. Japanese Journal of Stroke 1990;11:177‐84.
TTT‐AIS {published data only}
    1. Chao AC, Hsu HY, Chung CP, Liu CH, Chen CH, Teng MM, et al. Outcomes of thrombolytic therapy for acute ischemic stroke in Chinese patients: the Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT‐AIS) study. Stroke 2010;41(5):885‐90. - PubMed
URICO‐ICTUS {published data only}
    1. Amaro S, Canovas D, Castellanos M, Gallego J, Marti‐Fabregas J, Segura T, et al. The URICO‐ICTUS study, a phase 3 study of combined treatment with uric acid and rtPA administered intravenously in acute ischaemic stroke patients within the first 4.5 hours of onset of symptoms. International Journal of Stroke 2010;5:325‐8. - PubMed
VASTT {published data only}
    1. Hill M, Demaerschalk B, Teal P, Pawsey S, Kwiatkowski K, Stratton G. VASTT ‐ the V10153 acute stroke thrombolysis trial. International Journal of Stroke 2008;3 Suppl 1:133.
Wang 1999a {published data only}
    1. Wang Y. Observations of effect of defibrase in treatment of 30 cases with acute cerebral thrombosis. Chinese Journal of Critical Care Medicine ‐ Zhongguo Ji Jiu Yi Xue 1999;19(8):485.
Wang 2007h {published data only}
    1. Wang F, Yang H, Chu L‐Z, Hu Y‐C, Sui J‐M, Liu J. Combined intravenous and intra‐arterial infusion of recombinant tissue plasminogen activator for treatment of acute ischemic stroke. Chinese Journal of Cerebrovascular Diseases 2007;4(4):160‐3.
Won 2010 {published data only}
    1. Won YD, Yoo DS, Park JW, Shin HE, Huh PW, Kim KT. Clinical significance of perfusion/diffusion mismatching in additional intraarterial thrombolytic therapy after full dose i.v.‐tPA administration. International Journal of Stroke 2010;5 Suppl 2:110.
Wu 1995 {published data only}
    1. Wu X. Urokinase therapy in acute ischaemic stroke. Proceedings of the 4th Chinese Stroke Conference, Chengdu, China. 1995:149‐50.
Xiao 2002 {published data only}
    1. Xiao KT, Xu KE. Observation of efficacy of intra‐arterial thrombolysis and intravenous thrombolysis in 54 cases with acute cerebral infarction. Chinese Journal of Critical Care Medicine ‐ Zhongguo Ji Jiu Yi Xue 2002;22(10):607.
Xu 2000 {published data only}
    1. Xu H‐Q, Shao B, Zhou C‐Y. Comparison of the curative effects between ahylsantinfarctase and defibrinogenase on cerebral infarction. Journal of Wenzhou Medical College 2000;30(2):124‐6.
Yan 1997 {published data only}
    1. Yan LJ, Ma R, Li P. Clinical study of thrombolysis with gene‐recombinant streptokinase on treatment of acute cerebral infarction. Chinese Journal of Practical Internal Medicine (Zhongguo shi yong nei ke za zhi) 1997;17(11):667‐8.
Yoneda 1998 {published data only}
    1. Yoneda Y, Mori E, Uehara T, Tabuchi M. Intracarotid regional infusion of recombinant tissue plasminogen activator for acute hemispheric stroke. Cerebrovascular Diseases 1998;8:357‐9. - PubMed
Zhang 2001e {published data only}
    1. Zhang HX, Gu JQ, Han B. A study on alternative thrombolysis intra‐arterially in the treatment of cerebral infarction. Chinese Journal of Practical Internal Medicine (Zhongguo shi yong nei ke za zhi) 2001;21(11):656‐7.
Zhang 2006c {published data only}
    1. Zhang XY, Li XG, Fan DS, Wang LP, Zhang Y, Sun AP, et al. Combined intravenous recombinant tissue plasminogen activator (rt‐PA) and free radical scavenger (edaravone) for acute ischemic stroke. International Journal of Stroke 2006;1 Suppl 1:146.
Zhou 1996b {published data only}
    1. Zhou Y, Gao H, Ma R. Functions changes of VEC and therapeutic effect on VEC in patients with acute cerebral infarct. Stroke and Nervous Diseases 1996;3(4):191‐3.

References to studies awaiting assessment

Wadia 2009 {unpublished data only}
    1. Wadia RS. Clinical trial to assess the efficacy and safety of TNK‐TPA in acute ischemic stroke. Clinical Trials Registry ‐ India (CTRI) http://www.ctri.in 2009.

References to ongoing studies

BASICS {unpublished data only}
    1. BASICS. Ongoing study To be confirmed.
DIAS‐J {published data only}
    1. Lundbeck Japan KK. Clinical study of desmoteplase in Japanese patients with acute ischemic stroke (DIAS‐J). ClinicalTrials.gov 2010.
    1. Mori E. Desmoteplase in Japanese patients with acute ischaemic stroke (DIAS‐J): study objectives of a randomised, double‐blind, placebo‐controlled, dose escalation trial. International Journal of Stroke 2010;5 Suppl 2:192.
    1. Penner R. Paion's partner Lundbeck initiates Japanese clinical phase II trial with desmoteplase in ischaemic stroke. http://www.paion.de/images/stories/investoren/finanznachrichten/2010/en/... 2010.
    1. Kummer R, Albers GW, on behalf of the DIAS Steering Committee. Desmoteplase in Acute Ischaemic Stroke: status updated on the DIAS clinical trial programme. Poster presented at the 2011 European Stroke Conference; May 24‐27, 2011; Hamburg, Germany 2011.
ENCHANTED {unpublished data only}
    1. Lindley R. ENCHANTED. Powerpoint presentation.
FRALYSE {published and unpublished data}
    1. Trouillas P, Nighoghossian N, Derex L, Adeleine P. FRALYSE, a randomised blind multicenter study comparing 0.9mg/kg for 60 minutes and 0.8mg/kg for 90 minutes in a 7 hour window. Proceedings of the 7th International Symposium on Thrombolysis and Acute Stroke Therapy; 27‐28 May 2002; Lyon, France. 2002:74.
ITAIS {published data only}
    1. Wang Y. ITAIS. Imaging‐based thrombolysis trial in acute ischemic stroke. Internet Stroke Center. - PubMed
    1. Wang Y, Jiang W, Liao X, Du B, Zhao X, Dong K, et al. Comparison of intravenous and intra‐arterial with tPA within 3‐6 hours guided by multi‐MRI: randomised study of 36 patients. Stroke 2008;39:602.
    1. Wang Y, Jiang W, Zhao X, Du B, Dong K, Liao X, et al. Imaging‐based thrombolysis trial in acute ischemic stroke. http://www.abstractsonline.com/arch/RecordPrintView.aspx?LookupKey=12345.... 2007. - PubMed

Additional references

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