Lees, K.R.

Quinn, T.J.

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Advances in emerging therapies 2007

Terence J. Quinn

Kennedy R. Lees

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Advances in Emerging Therapies 2007

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       Quinn, T.J. and Lees, K.R. (2008) Advances in emerging therapies 2007. Stroke, 39 (2). pp. 255-257. ISSN 0039-2499  http://eprints.gla.ac.uk/18034/  Deposited on: 19 January 2012   Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Terence J. Quinn and Kennedy R. LeesAdvances in Emerging Therapies 2007ISSN: 1524-4628 Copyright © 2008 American Heart Association. All rights reserved. Print ISSN: 0039-2499. OnlineStroke is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514doi: 10.1161/STROKEAHA.107.5082912008, 39:255-257: originally published online January 10, 2008Stroke  http://stroke.ahajournals.org/content/39/2/255located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/reprintsReprints: Information about reprints can be found online at    journalpermissions@lww.com410-528-8550. E-mail: Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters   http://stroke.ahajournals.org//subscriptions/Subscriptions: Information about subscribing to Stroke is online at  at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from Advances in Emerging Therapies 2007Terence J. Quinn, MRCP; Kennedy R. Lees, MD, FRCPCynics may consider that review of emergent stroketherapies in 2007 is likely to make for quick reading—itis certainly true that many high profile trials reported unex-pected neutral outcomes. However, although these disap-pointments made for headline medical news, there were stilla number of encouraging results of novel acute therapies.The first “casualty” of the year was neuroprotection. Thefree radical trapping agent NXY-059 had been consistentlyshown to reduce infarct size and improve functional out-comes in published reports of animal models. The first phaseIII study in humans (SAINT) was positive, reporting astatistically significant improvement in global disability (Fig-ure).1 Unfortunately, the follow up SAINT II trial did notconfirm this result (Figure).2 This randomized placebo-controlled study of 3306 ischemic stroke patients up to 6hours from ictus demonstrated no significant improvement inthe primary end point of day 90 modified Rankin score(mRS). Subgroup analyses also failed to replicate the previ-ous finding of reduced hemorrhagic transformation rate inpatients treated with thrombolytic.Although the result was disappointing, the trial itself wasrigorous and it optimized statistical analyses to describefunctional outcomes across the treatment groups. A clearmessage from the SAINT trials is that even large-scalemeticulously planned trials are subject to the play of chance,and that initial positive results require verification with asecond adequately powered study. These themes have beenechoed in other acute stroke trials throughout the year.As the European Safe Implementation of Thrombolysis inStroke Monitoring Study (SITS-MOST) confirmed safety andefficacy of intravenous thrombolysis in routine practice, thestroke community were already advancing knowledge onnovel approaches to reperfusion. The second Desmoteplase inIschemic Acute Stroke (DIAS II) study sought to build on thesuccess of previous studies using the fibrin specific plasmin-ogen activator desmoteplase.3 The aim was to target therapyto those most likely to benefit by including only patients withperfusion-diffusion mismatch of at least 20% total infarctvolume or equivalent CT-perfusion findings. In a cohort ofpatients 3 to 9 hours after event, placebo was tested againstintravenous boluses of 90 g/kg and 125 g/kg desmote-plase. In contrast to previous results, no benefit was foundfrom desmoteplase; in fact patients treated at highest doseshowed a trend toward excess mortality.The reasons for this neutral result remain unclear and mayrelate to the active agent, to the imaging based protocol, or tostatistical underpowering—at 186 patients this was still asmall trial. It seems unlikely that patients selected for persis-tence of penumbra 3 to 9 hours after stroke will show agreater response to thrombolysis than we achieve with rapidalteplase use. Groups of 60 patients are too small to confirmtreatment effects comparable to those of alteplase when usedunder optimal conditions. The excess mortality in the higherdesmoteplase dosage group seems unlikely to relate directlyto desmoteplase as, of the 14 deaths, 9 were considerednonneurological and 9 occurred 1 week or later after treat-ment. Were the DIAS trialists simply victims of “significant”bad luck?At present the future of desmoteplase is unclear. However,the evidence base for using penumbral imaging to target acutetherapies continues to grow. The DEFUSE study successfullyused MRI imaging to predict patients likely to benefit fromtPA in the 3- to 6-hour time period,4 a result confirmed in arecent analysis of pooled data from 5 European centers.5Intraarterial delivery of thrombolytic has theoretical advan-tages over intravenous administration, including local deliv-ery of agent and reduced systemic effects. It is almost adecade since the PROACT-II study first suggested efficacy ofintraarterial thrombolysis.6 A confirmatory trial was nevercompleted, although many centers continued to use intraar-terial lytics for patients ineligible for standard intravenoustherapy. The MELT study (MCA Embolism Local fibrino-lytic intervention Trial) helps reassure us that the intraarterialapproach represents a viable treatment option.7 This prospec-tive trial randomized 114 patients, with confirmed occlusionof the M1 or M2 MCA segment and within 6 hours of event,to intraarterial urokinase or medical therapy. The trial wasterminated early when intravenous tPA was licensed forclinical use in Japan. Although no difference was seen onprimary end point (mRS 0 to 2; P0.345; Figure), onprespecified secondary end point analysis an increase inpatients showing excellent recovery was demonstrated (mRS0 to 1; P0.045; Figure) with no significant difference inmortality or hemorrhage.Primary intracerebral hemorrhage (ICH) is a frustratingentity, with higher levels of mortality and disability thanischemic stroke and few proven therapies. Pilot results usingthe hemostatic agent recombinant factor VII (rFVII) hadReceived October 24, 2007; accepted October 29, 2007.From the Department Cardiovascular and Medical Sciences, University of Glasgow, UK.Correspondence to Dr Terence J. Quinn, Gardiner Institute of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow G11 6NT UK. E-mailTjq1t@clinmed.gla.ac.uk(Stroke. 2008;39:255-257.)© 2008 American Heart Association, Inc.Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.107.508291255Advances in Stroke 2007 at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from suggested efficacy, therefore results of the phase III FASTtrial were eagerly awaited.8 In FAST, 821 patients diagnosedwithin 3 hours of onset were randomized to rFVII 20 g/kg;80 g/kg or placebo. Despite a significant dose-dependentreduction in hematoma growth, no significant difference wasseen in the main end point of the trial of death or severedisability at 90 days. These data seem counterintuitive: hema-toma growth is known to be independently associated with pooroutcome. Although this could represent further play ofchance, analysis of trial subpopulations may offer explana-tion. According to baseline characteristics presented at theEuropean Stroke Conference in 2007 (http://www.eurostroke.org/esc_gla_highlights.htm#oral%20presentation, accessed 24/10/07), more patients in the treatment arms had low consciouslevel, had evidence of left ventricular hypertrophy, and hadintraventricular extension of hemorrhage–all powerful pre-dictors of outcome. It should also be noted that unlike mostacute stroke trials, FAST did not specify an upper age limit.It seems plausible that rFVII may only impact on outcomes ina younger, fitter cohort. We await publication of the fullresults so that we can consider all likely confoundinginfluences.The disappointing result of FAST must be balanced bypromising work in other areas of ICH intervention. TheINTERACT pilot study of blood pressure reduction hascompleted initial work demonstrating that rapid reduction ofblood pressure to a target of 140/90 mm Hg is feasible andwell tolerated. In recognition of the grave prognosis associ-ated with intraventricular hemorrhage the CLEAR trials aretesting local thrombolysis to aid clot resolution. Results todate are promising with a suggestion of markedly improvedoutcomes,9 and a definitive trial is being planned.Physiological monitoring is an important component ofacute stroke unit care. However, there is little evidence toguide treatment when parameters become deranged. TheGlucose in Stroke Trial (GIST) was the first multicenter studyof acute glycaemic intervention.10 Patients were randomizedto treatment with a glucose-potassium-insulin infusion (GKI)to maintain euglycaemia (capillary blood glucose 4 to7 mmol/L) or placebo. Treatment conferred no benefit eitherin terms of 90-day mortality or functional outcome measures(Figure). This neutral result does not necessarily signal theend of glycaemic control in acute stroke; at 933 patients thestudy population fell well short of the planned 2355 andalthough statistically significant, the mean difference inglucose between GKI and control (0.57 mmol/L) was clini-cally modest, probably less than can be achieved with insulininfusion.11 Further trials targeting insulin therapy to patientswith higher baseline sugars are ongoing.Last year may have been disappointing for acute pharma-cotherapy but was less so for nondrug intervention. TheWingspan stenting device was approved by the US Food andDrug administration in 2005 for use in intracranial stenosis.An NIH funded registry of 131 stenting outcomes reported ahigh degree of technical success (97%) and a low rate of earlycomplications (4.6%).12 Observational data have also beenreported for the mechanical embolectomy device—theMERCI retriever. The Multi-MERCI study of 164 patientoutcomes again reported high rates of successful recanalisa-tion (57.8%) with few periprocedural complications (6.9%).13Although new tools for use in acute stroke are welcome, theseresults should be treated with some caution. Voluntaryregistries and single arm studies are likely to overestimatebenefits from treatment. There is now an ethical and scientificneed to build on these observational data with prospectiverandomized controlled trials comparing intervention with bestmedical therapy.Malignant MCA infarction is a feared complication ofischemic stroke, with mortality approaching 80%. Decom-pressive hemicraniectomy has been practiced for many yearswith case-series suggesting potential for good outcomes butno adequately powered randomized controlled trials. Threerecent European trials have compared hemicraniectomy toconservative management. Individually the trials provided astrong suggestion of benefit; however, it took this year’spooled analysis to finally prove efficacy. Compared with bestmedical treatment, numbers needed to treat to prevent death,severe disability, or moderate disability are 2, 2, and 4,respectively.14 It is remarkable that in a complication ofstroke previously considered fatal, intervention can leave asubstantial proportion with slight disability only (Figure).Having now proven benefit, we must better define optimaltiming and patient characteristics. In these studies the popu-lation were relatively young (mean age 43 years, maximal age60 years) and intervention was rapid (less than 48 hours fromstroke).So perhaps there were fewer successful emergent therapiesin 2007 than we dared to hope. Regardless, we have stillstrengthened the evidence base for acute stroke care. Trialswould not be performed if we were already certain of theoutcome, and the major trials of last year, both positive andneutral, have greatly added to our knowledge of stroke careand reconfirmed that large scale well conducted clinical trialsare possible in acute stroke. Medicine advances incremen-tally; we should celebrate the opportunities that await asmuch as the successes we have achieved.DisclosuresK.R.L was international principal investigator for the SAINT I trialand chaired the steering committee for the CHANT and SAINT I &II trials (AstraZeneca). He chaired the data monitoring committee for0% 20% 40% 60% 80% 100%Trial interventionFigure. Functional outcomes in major stroke trials of 2007; forcomparison results of both SAINT trials are presented.256 Stroke February 2008 at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from DIAS, DEDAS, and DIAS-II trials (Forest, Paion). Both authorshave participated in locally funded projects examining acute glycae-mic control in stroke. Neither author has any specific conflict ofinterest in relation to the content of this article.References1. Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener HC,Grotta J, Lyden P, Shuaib A, Hardemark HG, Wasiewski WW.Stroke-Acute Ischemic NXY Treatment (SAINT I) Trial Investigators.NXY-059 for acute ischemic stroke. N Engl J Med. 2006;354:588–600.2. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Diener HC,Ashwood T, Wasiewski WW, Emeribe U. SAINT II Trial Investigators.NXY-059 for the treatment of acute ischemic stroke. N Engl J Med.2007;357:562–571.3. Hacke W, Furlan A; for the DIAS-2 Investigators Results from the phaseIII study of desmoteplase in acute ischaemic stroke trial (DIAS 2) Pre-sented at European Stroke Conference, Glasgow 2007.4. Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E,Bammer R, Kakuda W, Lansberg MG, Shuaib A, Coplin W, Hamilton S,Moseley M, Marks MP. DEFUSE Investigators. Magnetic resonanceimaging profiles predict clinical response to early reperfusion: the dif-fusion and perfusion imaging evaluation for understanding stroke evo-lution (DEFUSE) study. Annals Neurol. 2006;60:508–517.5. Schellinger PD, Thomalla G, Fiehler J, Ko¨hrmann M, Molina CA,Neumann-Haefelin T, Ribo M, Singer OC, Zaro-Weber O, Sobesky J.MRI-based and CT-based thrombolytic therapy in acute stroke within andbeyond established time windows: an analysis of 1210 patients. Stroke.2007;38:2640–2645.6. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, PessinM, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterialprourokinase for acute ischemic stroke. The PROACT II study: a ran-domized controlled trial. Prolyse in acute cerebral thromboembolism.JAMA. 1999;282:2003–2011.7. Ogawa A, Mori E, Minematsu E, Taki W, Takahashi A, Nemoto S,Miyamoto S, Sasaki M, Inoue T; for The MELT Japan Study Group.Randomized trial of intraarterial infusion of urokinase within 6 hours ofmiddle cerebral artery stroke: the Middle Cerebral Artery EmbolismLocal Fibrinolytic Intervention Trial (MELT) Japan. Stroke. 2007;38:2633–2639.8. Mayer SA, Begtrup BK, Broderick JP, Davis SM, Diringer MN, SkolnickBE, Steiner T; on behalf of the FAST investigators. Randomized placebo-controlled, double-blind phase III study to assess rFVIIa efficacy in acuteintracerebral hemorrhage: the FAST trial. Presented at European StrokeConference, Glasgow 2007.9. D Hanley; for the CLEAR IVH Investigative Team. Results of CLEARIVH B; Dose-response for 3rd and 4th ventricular blood clearance. Pre-sented at European Stroke Conference, Glasgow 2007.10. Gray CS, Hildreth AJ, Sandercock PA, O’Connell JE, Johnston DE,Cartlidge NE, Bamford JM, James OF, Alberti KG. GIST Trialists Col-laboration. Glucose-potassium-insulin infusions in the management ofpost-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial(GIST-UK). Lancet Neurol. 2007;6:397–406.11. Walters MR, Weir CJ, Lees KR. A randomised, controlled pilot study toinvestigate the potential benefit of intervention with insulin in hypergly-caemic acute ischaemic stroke patients. Cerebrovasc Dis. 2006;22:116–122.12. Fiorella D, Levy EI, Turk AS, Albuquerque FC, Niemann DB, Aagaard-Kienitz B, Hanel RA, Woo H, Rasmussen PA, Hopkins LN, Masaryk TJ,McDougall CG. US multicenter experience with the wingspan stentsystem for the treatment of intracranial atheromatous disease: peripro-cedural results. Stroke. 2007;38:881–887.13. Flint AC, Duckwiler GR, Budzik RF, Liebeskind DS, Smith WS. MERCIand Multi MERCI Writing Committee. Mechanical thrombectomy ofintracranial internal carotid occlusion: pooled results of the MERCI andMulti MERCI Part I trials. Stroke. 2007;38:1274–1280.14. K Vahedi, J Hofmeijer and E Juettler, Vicaut E, George B, Algra A,Amelink GJ, Schmiedeck P, Schwab S, Rothwell PM, Bousser MG, vander Worp HB, Hacke W; and for the DECIMAL, DESTINY, andHAMLET investigators. Early decompressive surgery in malignantinfarction of the middle cerebral artery: a pooled analysis of three ran-domised controlled trials. Lancet Neurol. 2007;6:215–222.KEY WORDS: acute care  acute stroke  clinical trials  hyperglycaemia interventional neuroradiology  intracranial hemorrhage  neuroprotectant thrombolysisQuinn and Lees Advances in Emerging Therapies 2007 257 at GLASGOW UNIV LIB on January 19, 2012http://stroke.ahajournals.org/Downloaded from 

A randomised, controlled pilot study to investigate the potential benefit of intervention with insulin in hyperglycaemic acute ischaemic stroke patients. Cerebrovasc Dis.

A; for the DIAS-2 Investigators Results from the phase III study of desmoteplase in acute ischaemic stroke trial (DIAS 2) Presented at European Stroke Conference,

and for the DECIMAL, DESTINY, and HAMLET investigators. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials.

for the CLEAR IVH Investigative Team. Results of CLEAR IVH B; Dose-response for 3rd and 4th ventricular blood clearance. Presented at European Stroke Conference,

GIST Trialists Collaboration. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol.

Inoue T; for The MELT Japan Study Group. 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)

Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in acute cerebral thromboembolism.

Investigators. NXY-059 for acute ischemic stroke.

Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Annals Neurol.

MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an analysis of 1210 patients.

SAINT II Trial Investigators. NXY-059 for the treatment of acute ischemic stroke.

T; on behalf of the FAST investigators. Randomized placebocontrolled, double-blind phase III study to assess rFVIIa efficacy in acute intracerebral hemorrhage: the FAST trial. Presented at European Stroke Conference,

US multicenter experience with the wingspan stent system for the treatment of intracranial atheromatous disease: periprocedural results.

Writing Committee. Mechanical thrombectomy of intracranial internal carotid occlusion: pooled results of the MERCI and Multi MERCI Part I trials.

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