Can the Time Window for Administration of Thrombolytics in Stroke be Increased?

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  • CNS Drugs 2003; 17 (14): 995-1011CURRENT OPINION 1172-7047/03/0014-0995/$30.00/0 Adis Data Information BV 2003. All rights reserved.

    Can the Time Window forAdministration of Thrombolytics inStroke be Increased?Geoffrey A. Donnan,1 David W. Howells,1,2 Romesh Markus,1 Danilo Toni3 andStephen M. Davis4

    1 National Stroke Research Institute, Austin & Repatriation Medical Centre, West Heidelberg,Victoria, Australia

    2 Department of Medicine, University of Melbourne, Austin & Repatriation Medical Centre,Heidelberg, Victoria, Australia

    3 Stroke Unit, Department of Neurological Sciences, University La Sapienza, Rome, Italy4 Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria, Australia

    Level 1 evidence now shows that thrombolysis in cases of acute ischaemicAbstractstroke is effective if administered within 3 hours of stroke onset. This benefit hasbeen shown to be time dependent and potentially extends beyond 3 hours, withevidence that potentially viable penumbral tissue may be present in a significantproportion of cases well beyond 36 hours and, in isolated cases, perhaps up to 48hours. This exposes a stroke recovery gap, the difference observed between theclinical response to thrombolytic therapy in a given population of patientspresenting with ischaemic stroke and the potential clinical recovery if all of thepenumbra were salvaged under ideal circumstances.

    The means of bridging this stroke recovery gap using thrombolysis mustinvolve extending the therapeutic time window (i.e. the time between stroke onsetand administration of thrombolytics). Approaches to do this include the use of: (i)improved patient selection with modern neuroimaging techniques, particularlymagnetic resonance imaging using perfusion-weighted image/diffusion-weightedimage mismatch; (ii) newer thrombolytic agents; (iii) lower doses of these agents;(iv) varied methods of administration of thrombolytic therapy including combinedintravenous and intra-arterial approaches; and (v) adjunctive therapies such asneuroprotectants. Should these means of extending the time window for throm-bolysis prove successful, a more widespread use of this form of acute stroketherapy will be possible.

    Stroke is the second most common cause of death now changed. Morbidity and/or mortality of patientsglobally and a major cause of disability.[1] Until who present with acute ischaemic stroke is reducedquite recently, there were no management or thera- by the administration of oral aspirin (acetylsalicylicpeutic approaches that had been shown to be effec- acid) within 48 hours[2] and use of the thrombolytictive in improving outcomes. Fortunately, this has agent alteplase (recombinant tissue plasminogen ac-

  • 996 Donnan et al.

    tivator; rtPA) within 3 hours[3] of stroke onset. For its efficacy and reduce complication rates. Fortu-nately, these three issues are inter-related, and theyall forms of stroke, management in a stroke unit alsoare the focus of this article. Rather than undertakingimproves outcomes.[4] Of these strategies, throm-a systematic review of the literature, we have pre-bolysis is the most biologically effective. The num-sented our own views and supported these withber of patients needed to treat to benefit one personappropriate preventing disability or death associated with

    stroke is about 83 for aspirin, 18 for management in1. What is the Time Window fora stroke unit and only 16 for alteplase.[5]Tissue Salvage?

    In spite of their biological efficacy, thrombolyticagents have two major shortcomings. First, the dura-

    1.1 Tissue Salvage Generallytion of time between stroke onset and administrationof the drug (or the therapeutic time window) is Tissue salvage relates to the life span of theonly 3 hours; second, haemorrhagic complications ischaemic penumbra. The penumbra may be definedmay occur. For the latter, symptomatic intracranial as functionally compromised but structurally intacthaemorrhage rates are about 7%; overall, intracer- tissue usually adjacent to or surrounding a core ofebral haemorrhage rates about double this fig- infarcted tissue.[12] Theoretically, all penumbral tis-ure.[6-11] Currently, because of these limitations, al- sue has the potential to be salvaged at any giventeplase is only administered in about 12% of pa- time. In natural history studies, about 50% of pen-tients with ischaemic stroke in the US, although in umbral tissue imaged during the acute phases ofsome specialised centres the rate may be as high as stroke survives and about 50% dies.[13-17] The dura-10%. Clearly, there is a need to extend the time tion of the existence of the penumbra seems to varywindow for thrombolytic therapy, further maximise from case to case in clinical studies.[13] Evidence

    from experimental models suggests that the life spanof the penumbra (and time to ischaemic cell death) isdependent upon the degree and duration of the re-duction of cerebral blood flow (CBF).[18]

    There are a large number of data available frominvestigators working with animal models of cere-bral ischaemia, where the time window until tissuedeath occurs is reasonably well documented. Theduration is dependent upon the two factors men-tioned above as well as presumed variations in tissuevulnerability in different animal species. The lifespan of the ischaemic penumbra in various animalmodels is less well understood but again is depen-dent upon both the extent and duration of the reduc-tion of CBF.

    Memezawa et al.[19] used a rat model of arterialmiddle cerebral artery occlusion to show that fol-lowing 15 minutes of vessel occlusion, selectiveneuronal necrosis in the medial caudoputamen oc-curred, after 30 minutes infarcts extended to thelateral caudoputamen with some involvement of theneocortex, and by 60 minutes cortical infarction wasuniversally present. The infarct size increased pro-







    6InfarctPenumbra (18FMISO)


    a (m

    m2 )








    8765321 4

    Coronal section through infarct



    Fig. 1. Loss of ischaemic penumbra (18F-misonidazole [18FMISO]autoradiography) and growth of infarction over 22 hours after 2hours of transient middle cerebral artery occlusion in rats (n 6).Areas from coronal sections at eight defined anatomic planes en-compassing the infarct are shown at (a) 1 hour and (b) 22 hourspost-occlusion (courtesy of the National Stroke Research Institute,Heidelberg West, VIC, Australia).

    Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (14)

  • Increasing the Time Window for Thrombolytics in Stroke 997

    Heiss et al.[20] were able to furnish evidence ofviable tissue on the border zone of infarcts up to 48hours after stroke in a positron emission tomography(PET) study of 16 patients using CBF, cerebralmetabolic rate of oxygen, cerebral metabolic rate ofglucose and oxygen extraction fraction as markersof tissue viability. Using 18FMISO as a PET markerof hypoxic tissue to identify the penumbra, Read etal.[17] were able to document the presence of signif-icant areas of potentially viable tissue up to 42 hourspost-ischaemic stroke, although this technique as a

    Table I. Maximum duration of the ischaemic penumbra in humansafter acute ischaemic stroke as determined using different tech-niques

    Reference Technique Penumbral Maximummeasure duration (h)

    Heiss et al.[20] PET OEF 48

    Read et al.[17] PET 18FMISO 42

    Darby et al.[21] MRI PWI/DWI 24mismatch

    18FMISO = 18F-misonidazole; DWI = diffusion-weighted imaging;MRI = magnetic resonance imaging; OEF = oxygen extractionfraction; PET = positron emission tomography; PWI = perfusion-weighted imaging.

    penumbral marker is still being validated. Longergressively with increasing occlusion time up to duration studies, using magnetic resonance imaging

    (MRI) parameters, have been less frequently carriedabout 120180 minutes, after which the infarct sizeout. Darby et al.[21] showed that perfusion-weighteddid not grow further. This suggests that penumbralimage (PWI)/diffusion-weighted image (DWI) mis-tissue exists in this animal model for only 120180match as an index of the penumbra exists for at leastminutes. In our hands, using a transient thread oc-24 hours poststroke. The proportion of patients withclusion model in rats and 18F-misonidazoleat least some penumbral tissue were shown in MRI(18FMISO), a hypoxic ligand, as a penumbral mark-and/or 18FMISO PET studies to decline from nearlyer, significant 18FMISO uptake was seen for up to 6100% of patients within the first hours of acutehours, and at least some uptake was still present atischaemic stroke to

  • 998 Donnan et al.

    Table II. Animal studies of intravenous (IV) or intra-arterial (IA) administration of thrombolytic agents[23]

    Reference Drug Route of Time to first treatment Mean infarct size with treatment,administration after occlusion (min) relative to control size

    Andersen et al.[27] Alteplase IV 45 0.65

    Carter et al.[28] Alteplase IV 60 0.21

    Alteplase IV 120 0.51

    Del Zoppo et al.[29] Urokinase IA 180 0.22

    Lekieffre et al.[30] Alteplase IV 60 0.45

    Overgaard et al.[31] Alteplase IV 120 0.24

    Sakurama et al.[32] Alteplase IV 5 0.18

    Alteplase IV 180 0.40

    Alteplase IV 360 0.60

    Urokinase IV 5 0.25

    Sereghy et al.[33] Alteplase IV 120 0.20

    Zhang et al.[34] Tenecteplase-alteplase IA 120 0.60

    Tenecteplase-alteplase IA 240 0.82

    Alteplase IV 120 0.67

    Alteplase IV 240 1.10

    animals treated with thrombolytics up to 6 hours by functional recovery of the patient). This de-creases steadily as the time since the onset of strokepost-onset of ischaemia compared with controlincreases, to about 48 hours (figure 4). Superim-groups (table II).[23] For humans, as mentioned earli-posed upon this is the actual tissue salvaged usinger, the time window established for efficacy of intra-thrombolysis. As can be seen from the comparison,venous alteplase for acute ischaemic stroke is 3there is considerable room for improvement in: (i)hours, based on the National Institute of Neuro-the amount of tissue that can be salvaged usinglogical Disorders and Stroke (NINDS) trial.[6] Inter-therapeutic agents; and (ii) the time window duringestingly, in the Australian Streptokinase Trialwhich salvage can occur. Narrowing the recovery(ASK), a trend towards efficacy was seen for ther-gap or tissue salvage gap is the implicit goal of allapy given within 3 hours, although the drug was notresearchers involved in acute stroke therapy trials.effective overall.[24,25] Marler and colleagues[26]

    One means of narrowing the stroke recovery gap ishave shown that the benefit of alteplase diminishesto extend the time window for thrombolysis.with time up to 3 hours, with significantly reduced

    benefit after this. Based on data from the European2. How Does Thrombolysis Work?Cooperative Acute Stroke Study I (ECASS I)[7] and

    the European-Australasian Cooperative Acute Fibrinolysis is triggered by circulating endoge-Stroke Study II (ECASS II),[8] there is no definite nous plasminogen activators (figure 5).[35] Thesebenefit for intravenous alteplase given between 3 are present in very low concentrations (aboutand 6 hours after stroke onset, although a trend 100 000-fold lower than that of plasminogen) andexists. We have conducted a recent meta-analysis of include endogenous plasminogen activators such asall available published data on the use of alteplase in tissue plasminogen activator (tPA) and urokinase-acute ischaemic stroke; the asymptotic effect of time type plasminogen activator (uPA). Recombinanton a steadily reducing benefit can be seen in figure forms of these activators such as alteplase and mu-3. tant forms of the human enzyme tenecteplase[36] can

    Based on our understanding of the duration of the be used to trigger the fibrinolytic process. Alterna-ischaemic penumbra in humans, a theoretical model tively, bacterial proteins such as streptokinase orcan be constructed of a maximum amount of tissue staphylokinase may be used.[37] These triggers thenthat can salvaged by an ideal therapy (as represented stimulate the fibrinolytic system by converting plas-

    Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (14)

  • Increasing the Time Window for Thrombolytics in Stroke 999

    minogen to plasmin. Plasmin then cleaves fibrin into These inhibitors, particularly PAI-1[38] andTAFI,[39] represent important potential targets forits degradation products. When thrombolytic ther-therapy, since their inhibition will enhance the fibri-apy is administered, large amounts of plasminogennolytic effects of exogenously administered plasmi-activators (e.g. tPA, uPA, streptokinase) are used,nogen activators.which result in plasma concentrations that are about

    At least one of the plasminogen activators, tPA,1000-fold higher than concentrations of endogenousmay also be potentially neurotoxic.[40] tPA is presentplasminogen activators but still 100-fold lower thanin neurons and microglia and may have other func-concentrations of plasminogen.[35]tions apart from those in the fibrinolytic pathway.There are two phases in the fibrinolytic process.These include roles in cell migration, astrocyte dif-

    In the first phase, plasminogen binds to intact fibrinferentiation and neuron-cell interactions.[41] Tsirka

    and initial fibrinolysis occurs. Then, partly degradedet al.[40,42] provided in vitro evidence that alteplase

    fibrin exposes new binding sites (carboxy terminal exacerbates excitotoxic neuronal degeneration.residues) for plasminogen. In the second phase, fi- Some support for this was shown in vivo in a mousebrinolysis is enhanced because the local plasmi- stroke model where those animals given alteplasenogen concentration is increased and has higher were shown to have larger areas of focal infarc-reactivity. tion,[43] while tPA-deficient transgenic mice had

    The fibrinolytic system is inhibited at at least smaller infarcts than their wild-type litter mates.[43]

    However, these findings have not been confirmed inthree important levels (figure 5):[35]

    rat models of focal ischaemia where alteplase has1. Plasminogen activator inhibitor 1 (PAI-1) regu-not altered focal infarct size.[44,45] Although thelates plasminogen activators.mechanism of neurotoxicity remains unclear, there

    2. Plasmin is inhibited by 2-antiplasmin (2-AP) is some evidence that tPA may amplify haemo-and to a lesser extent by 2-macroglobulin. globin-induced neurotoxicity in rat neuronal cul-3. Thrombin-activatable fibrinolysis inhibitor tures[46] as well as NMDA- and kainic acid-mediated

    neurodegeneration or neuronal death.[40,42,47](TAFI) eliminates carboxy terminal lysine residuesfrom the partially degraded fibrin and hence inhibits Although the findings are of importance concern-the second phase of fibrinolysis. ing possible neurotoxicity of tPA, there is a great

    3 hours

    >36 hours



    OR(95% CI fixed)

    OR(95% CI fixed)

    Alteplase better Placebo better

    0.1 0.2 1 5 10

    ECASS I 28 / 47 28 / 37 0.47 (0.18, 1.23)ECASS II 47 / 81 48 / 77 0.84 (0.44, 1.58)NINDS 179 / 312 229 / 312 0.49 (0.35, 0.68)

    ECASS I 173 / 266 189 / 270 0.80 (0.55, 1.1...