Optimal Timing of ThrombolyticTherapy in Acute Ischaemic StrokeKen Madden

Marshfield Clinic, Marshfield, Wisconsin, USA

Abstract The clinical benefit of thrombolytic therapy for patients experiencing acutecerebral ischaemia has been demonstrated by both clinical trials and phase IVstudies. However, such treatments must be initiated in a rapid manner, with treat-ing physicians adhering to strict protocols designed to minimise delays and max-imise safety. The efficacy of intravenous drug administration has been establishedwith alteplase (recombinant tissue plasminogen activator; tPA) and ancrod, butonly if these drugs can be administered within 3 hours of symptom onset. Theuse of alteplase beyond this timeframe, or outside of established protocols, may behazardous. The use of alternative intravenous thrombolytic agents, such as strep-tokinase, also appears hazardous. Intra-arterial delivery of thrombolytic drugs suchas pro-urokinase may extend clinical benefit to the 6-hour time frame.

CURRENT OPINION CNS Drugs 2002; 16 (4): 213-2181172-7047/02/0004-0213/$25.00/0

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Therapy for ischaemic stroke has evolved in adramatic fashion over the last 6 years, due in largepart to clinical trials demonstrating the efficacy ofthrombolysis. Patients are now encouraged throughpublic education campaigns and direct medicalcontact to present to emergency rooms as quicklyas possible after symptom onset to be consideredfor interventions. Physicians, who formerly fo-cused on supportive care for their patients afflictedwith this disorder, must now prioritise this condi-tion as a neurological emergency. Both cranial im-aging and patient evaluations must be accomplishedin an urgent manner. If appropriate protocols arefollowed and therapy can be initiated, either intra-venous or intra-arterial thrombolysis can signifi-cantly reduce cerebral injury and clinical deficit.However, substantial limitations of these therapiescontinue to restrict their application to a small minor-ity of patients with stroke. Foremost among theselimitations is the element of time.

1. Establishing Efficacy of Alteplase

The development of thrombolytic drugs led toearly therapeutic attempts for patients with stroke,nearly coincident with the initial use of these drugsfor coronary disease. However, early studies forstroke were terminated rapidly over concern forhigher mortality rates in treated patients.[1] Theseearly studies suffered from two main flaws. Cranialimaging was not obtained to exclude patients withhaemorrhagic pathology, and patients were treatedup to 3 days following the onset of stroke symptoms.With the widespread availability of computed to-mography (CT) imaging, cautious re-exploration ofthe potential benefit of these treatments for strokebegan. Using both clinical and radiographic criteria,small case series started to emerge suggesting clini-cal efficacy, encouraging recanalisation rates, andacceptable safety outcomes.[2]

Several small, randomised clinical trials usingalteplase (recombinant tissue plasminogen activa-

tor; tPA) then followed. Mori et al.[3] demon-strated improved angiographic recanalisationand significant clinical improvement at 4 weeksin alteplase-treated patients compared with thosewho received placebo. Haley and colleagues[4] dem-onstrated greater clinical improvement at 24 hoursin patients treated with the drug. None of these earlytrials suggested greater rates of symptomatic intra-cranial haemorrhage in alteplase-treated patients.

Two pilot feasibility trials then ensued. A phar-maceutical company–sponsored trial[5] includedangiograms pre- and immediately post-alteplase in-fusion in patients who were treated within 8 hoursof their symptom onset. Major intracerebral arteryocclusion was a requirement for patient entry. In 94patients, 35% had some degree of recanalisationduring the 1-hour infusion. Significant haemor-rhage occurred in 11%. An American trial spon-sored by the National Institute of NeurologicDisorders and Stroke (NINDS) treated 74 patientswithin 90 minutes of stroke onset using varyingdoses of alteplase.[6] CT was required for entry butangiograms were not performed. This study docu-mented a 4% rate of significant haemorrhage and a39% rate of early improvement. These data werejudged to be encouraging enough to proceed withlarge-scale clinical trials of thrombolytic drugsfor stroke.

In the early 1990s, the European CooperativeAcute Stroke Study (ECASS)[7] and the AmericanNINDS rt-PA Stroke Study Group[8] began enroll-ing patients into clinical trials nearly synchro-nously, using slightly differing doses of alteplaseand, more importantly, significantly different timewindows between symptom onset and initiation ofthe drug. The ECASS group used 1.1 mg/kg of al-teplase and entered patients within 6 hours of onsetof their stroke symptoms. The NINDS group used0.9 mg/kg of the drug and stratified enrolment ofpatients into time windows of 0 to 90 minutes or90 to 180 minutes after symptom onset. Bothstudies utilised functional outcome measures anda variety of safety criteria.

The ECASS study reported mixed results. Someoutcome measures suggested a trend toward a ben-

efit of alteplase,[9] but overall there was a signifi-cant risk of the drug with regard to intracerebralbleeding and death. The authors of this study attrib-uted some of the adverse outcomes to substantialrates of protocol deviation by investigators. The mostsignificant deviation was the presence of early is-chaemic change on CT imaging in 52 of the 620patients. Such patients had a high rate of deathwhen treated with alteplase.

In contrast to the European study,[7] the NINDStrial[8] demonstrated substantial efficacy of throm-bolysis and provided the pivotal data leading to theapproval of alteplase for stroke in the US. This wasa randomised, double-blind, controlled, US multi-centre two-part study assessing the benefit of al-teplase for patients with stroke. A major differencefrom the European trial was the requirement thatpatients receive alteplase within 3 hours of the on-set of ischaemic symptoms. Abaseline CT showingno evidence of intracranial haemorrhage was re-quired. Factors used to exclude patients from studywere largely based on past medical history, base-line laboratory values and blood pressure (systolicabove 185mm Hg, diastolic above 110mm Hg).291 patients were enrolled in the first part of thestudy and 333 were enrolled in the second part.Alteplase was given at a dose of 0.9 mg/kg (maxi-mum of 90mg). The initial 10% was given as abolus with the remaining 90% infused over 1 hour.No anticoagulants or antiplatelet drugs were givenwithin the first 24 hours and blood pressure wasmaintained within specified values.

Four 3-month outcome measures were utilisedthat were largely based on functional capabilities.All four outcome measure instruments showed bet-ter improvement at 3 months in alteplase-treatedpatients, compared with patients treated with pla-cebo. Specifically, these patients had at least a 30%increased likelihood to recover with minimal or nodisability. These data represent absolute increasesof 11 to 12% for alteplase-treated patients havingminimal or no disability at 3 months. The major riskof the drug was symptomatic intracranial haemor-rhage, occurring in 6.4% of drug-treated patientscompared with 0.6% of placebo-treated patients.

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Death rates, however, trended lower in the alteplase-treated cohort. Patients treated within both the 0 to90– and 90 to 180–minute windows benefited fromthe therapy.

A secondary analysis of the ECASS trial fol-lowed this report, examining outcomes for the patientcohort treated within 3 hours.[10] The results essen-tially mirrored those reported for the NINDS trial.[8]

Despite the encouraging outcomes of clinicaltrial cohorts treated within 3 hours of stroke symp-tom onset, concerns about the benefit and safety ofalteplase lingered. These doubts fuelled a numberof postmarket phase IV studies of thrombolyticstroke therapy. The largest such study was the Stan-dard Treatment with Alteplase to Reverse Stroke(STARS) trial,[11] which collected data from med-ical centres experienced in thrombolysis that treatedpatients using the NINDS protocol. The most strik-ing results from this study were the safety data –only 3.3% of 389 patients experienced symptom-atic intracranial haemorrhage. Efficacy data werealso impressive (although there was no comparisonpopulation in this study), with 35% of patients ex-periencing a complete or near-complete recoveryby 30 days.

Smaller studies documented symptomatic haem-orrhage rates between 3 and 9%, with similar fav-ourable recovery rates.[12-15] One phase IV study[16]

reported a symptomatic haemorrhage rate of 15.7%,but this community hospital–based study was alsonotable for a protocol deviation rate of 50%.

2. Thrombolysis Beyond 3 Hours or withOther Drugs

Based on the evident benefit of alteplase whenadministered within 3 hours of symptom onset,a number of further trials were designed to deter-mine if benefit could be extended beyond thishyperacute phase of stroke.

The major American effort was the AlteplaseThrombolysis for Acute Noninterventional Ther-apy in Ischaemic Stroke (ATLANTIS) trial,[17]

which used nearly identical trial criteria to that ofthe NINDS,[8] except patients were treated be-tween 3 and 5 hours after symptom onset. All out-

come measures for this trial were nearly identicalfor alteplase- and placebo-treated patients. An ear-lier phase of this trial (prior to the demonstratedbenefit of alteplase when administered 0 to 3 hoursafter symptom onset) had utilised a treatment win-dow of 0 to 6 hours.[18] This phase also failed todemonstrate efficacy for the drug on outcomemeasures. As with the ECASS trial,[7] however,secondary analysis of the patient cohort treatedwithin 3 hours suggested similar efficacy as estab-lished by the NINDS trial.[19]

The European Cooperative Group organised a sec-ond major trial (ECASS II)[20] using the alteplasedose from the NINDS trial,[8] stricter baseline CTinterpretation guidelines and a 0 to 6 hour window.Once again, this group was not able to report sign-ificant benefit of alteplase. Intracerebral haemorrhagewas more prevalent in the alteplase-treated patients.

Thus, three major trials[7,17,20] using alteplaseadministered 0 to 6 hours after symptom onset, andone trial that specifically targeted a timeframe after3 hours,[17] universally failed to establish efficacyof intravenously administered drug.

Coincident with the European and NINDS al-teplase trials were three major trials in Europe andAustralia investigating the benefit of intravenousstreptokinase for acute stroke.[21-23] These trialsutilised time to treatment windows of 4 or 6 hours,with pretreatment CT scans documenting the ab-sence of intracranial haemorrhage. All three trialswere terminated early because of safety concerns.Patients treated with streptokinase had higher ratesof both intracranial haemorrhage and death thanplacebo-treated patients. At this point, it is not clearwhether the dismal results of these trials were relatedto the longer delay before initiation of therapy, dos-ing issues or the type of thrombolytic utilised.

Intravenous thrombolytic therapy administeredmore than 3 hours after the onset of cerebral isch-aemic symptoms, therefore, appears to be eithernon-efficacious or frankly hazardous. However,thrombolytics given via the intra-arterial routemay theoretically offer a safer, more effective ad-ministration. Because, using this route, a drug canbe delivered in close proximity to occlusive throm-

Timing of Thrombolysis for Stroke 215

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bus, the local concentrations of the drug can behigh while systemic exposure remains substan-tially lower. Thus, the desired effect of clot lysismay be achieved with less potential for systemicadverse effects. Of course, the most worrisome ad-verse effect of thrombolytics is local cerebralhaemorrhage, and the high local concentrations ofa lytic drug may certainly pose more risk for thiscomplication.

The Prolyse in Acute Cerebral Thromboembo-lism (PROACT) II trial[24] treated patients withangiographically-proven intracranial occlusion ofthe middle cerebral artery (M1 or M2 branches)within 6 hours of stroke symptom onset, compar-ing intra-arterial pro-urokinase followed by intra-venous heparin to heparin alone. The 121 patientsreceiving the thrombolytic achieved greater recanal-isation rates (66%) and better functional outcomeat 90 days (40%) than the 59 patients who receivedheparin alone (18 and 25%, respectively). Symp-tomatic intracranial haemorrhage was more fre-quent after pro-urokinase therapy (10 versus 2%),but death rates were slightly lower (25 versus 27%).These data have encouraged a number of stroke treat-ment centres to offer delayed thrombolytic therapywith alteplase or other agents intra-arterially, ifpatients cannot be treated intravenously within 3hours. This practice is not widely accepted, how-ever, based on the limited clinical trial evidence.

Despite the unfavourable results of the strepto-kinase stroke trials,[21-23] another trial was per-formed with an alternative thrombolytic in an at-tempt to achieve more effective and safer therapyfor stroke. The Stroke Treatment with Ancrod Trial(STAT)[25] treated 500 patients, using either intra-venous placebo or ancrod, a drug with both throm-bolytic and antithrombotic properties. This trialalso targeted patients treatable within 3 hours ofsymptom onset. A greater percentage of patientstreated with ancrod had a favourable recovery thanthose treated with placebo (43 versus 34%), at theexpense of a mild increase in symptomatic in-tracranial haemorrhage (5.2 versus 2.0%). Deathrates were identical (10%).

3. What Have We Learned?

The clinical trial data outlined in sections 1 and2 have demonstrated significant benefit of throm-bolytic therapy for patients with stroke, althoughat the risk of symptomatic worsening from intra-cranial haemorrhage. Both intravenous alteplaseand intravenous ancrod are effective drugs. The ef-ficacy of alternative intravenous thrombolytics hasnot been established, and streptokinase (as utilisedin completed clinical trials) appears hazardous foracute cerebral ischaemia.

The most critical aspect of thrombolysis hasbeen time to treatment from stroke symptom onset.As outlined in section 2, multiple attempts to es-tablish the efficacy of intravenous alteplase beyondthe 3-hour timepoint have been unsuccessful. Sec-ondary analyses of trials have in fact suggested alinear relationship between time to treatment andexpectation of benefit (figure 1), with efficacy lostshortly after 3 hours. These data compel treatingphysicians to not only observe the 3-hour limit, butalso to initiate therapy as soon as possible withinthe treatable timeframe.

It is notable that the PROACT II trial[24] sug-gested continued benefit of intra-arterial thrombo-lytics up to 6 hours following stroke symptom on-set. Further investigation of this delivery method isneeded before active treatment can be offered to thesubstantial number of patients who have had a

Rel

ativ

e be

nefit

1

2

Time from onset of symptoms (h)

1 2 3 4 5

Fig. 1. The relative benefit of alteplase (recombinant tissue plas-minogen activator; tPA) as a treatment for stroke, expressed asa function of time to treatment following onset of ischaemicsymptoms (Copyright 2001, Marshfield Clinic. All rights reserved.Reprinted with permission from the Marshfield Clinic Journal).[26]

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stroke and who present for medical care too late forintravenous therapy.

A number of other interventional techniquesutilising mechanical clot disruption without lyticdrugs are under investigation, which may also offerthe potential for delayed therapy. Such methods maynot carry the risk of systemic or distal arterialbleeding that pharmacological disturbance of hae-mostasis entails; however, most would require ar-terial catheterisation.

Imaging characteristics may also provide futurebasis for individual risk-benefit assessments ofthrombolysis in acute stroke, both within and outsideof the 3-hour time window. This is an active area ofbasic and clinical research, primarily utilising mag-netic resonance technology.

Although not specifically addressed in this arti-cle, other non-temporal factors must be weighed inthe consideration of thrombolytic therapy for stroke.Favourable risk-benefit has been established onlyfor a specific subpopulation of patients presentingwith stroke – that which mimics the inclusion/ex-clusion criteria of the NINDS alteplase trial.[8] Sub-sequent phase IVstudies have nearly uniformly dem-onstrated higher haemorrhage rates and pooreroutcomes for those patients treated outside of para-meters mimicking the NINDS protocol.[12,16,19] Thedecision to utilise thrombolytic therapy for patientswith stroke should therefore be well considered(see table I for outline). It requires an institution-wide commitment to evaluate patients who havehad a stroke with a thoroughness that allows con-

fident determination of the risk-benefit for eachindividual, yet still allows therapy to be initiatedas quickly as possible.

Acknowledgements

No sources of funding were used in the preparation ofthis manuscript and the author has no financial relationshipsthat are directly relevant to the contents of this article.

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11. Albers GW, Bates VE, Clark WM, et al. Intravenous tissue-typeplasminogen activator for treatment of acute stroke: theStandard Treatment with Alteplase to Reverse Stroke(STARS) study. JAMA 2000; 283 (9): 1145-50

12. Buchan AM, Barber PA, Newcommon N, et al. Effectivenessof t-PA in acute ischemic stroke: outcome relates to appropri-ateness. Neurology 2000; 54 (3): 679-84

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14. Grond M, Stenzel C, Schmulling S, et al. Early intravenousthrombolysis for acute ischemic stroke in a community-basedapproach. Stroke 1998; 29 (8): 1544-9

15. Wang DZ, Rose JA, Honings DS, et al. Treating acute strokepatients with intravenous tPA. The OSF Stroke Network ex-perience. Stroke 2000; 31 (1): 77-81

Table I. General recommendations for the use of thrombolytictherapy for patients with acute stroke

Alteplase (recombinant tissue plasminogen activator; tPA) iseffective in improving clinical outcomes of patients presentingwith acute cerebral ischaemia, but only if therapy can be initiatedwithin 3 hours of symptom onset

Ancrod may be an alternative drug with thrombolytic potential foruse within 3 hours of symptom onset

Streptokinase is not a viable alternative intravenous thrombolytic

Intra-arterial delivery of thrombolytics may extend the treatmentwindow to 6 hours

Careful adherence to treatment protocol is necessary tomaximise the benefit and minimise the hazards of thrombolytictherapy for stroke

Timing of Thrombolysis for Stroke 217

© Adis International Limited. All rights reserved. CNS Drugs 2002; 16 (4)

16. Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plas-minogen activator for acute ischemic stroke: the Clevelandarea experience. JAMA 2000; 283 (9): 1151-8

17. Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3to 5 hours after symptom onset. The ATLANTIS Study: arandomized controlled trial. Alteplase Thrombolysis forAcute Noninterventional Therapy in Ischemic Stroke. JAMA1999 Dec 1; 282 (21): 2019-26

18. Clark WM, Albers GW, Madden KP, et al. The rtPA (alteplase)0- to 6-hour acute stroke trial, part A (A0276g): results of adouble-blind, placebo-controlled, multicenter study. Throm-bolytic therapy in acute ischemic stroke study investigators.Stroke 2000; 31 (4): 811-6

19. Albers GW, Clark WM, Madden KP, et al. The ATLANTIS t-PAacute stroke trial: results for patients treated within three hoursof stroke onset. Stroke 2000; 33 (2): 493-6

20. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blindplacebo-controlled trial of thrombolytic therapy with intrave-nous alteplase in acute ischaemic stroke (ECASS II). SecondEuropean-Australasian Acute Stroke Study Investigators.Lancet 1998; 352 (9136): 1245-51

21. Thrombolytic therapy with streptokinase in acute ischemicstroke. The Multicenter Acute Stroke Trial – Europe StudyGroup. N Engl J Med 1996 Jul 18; 335 (3): 145-50

22. Randomised controlled trial of streptokinase, aspirin, andcombination of both in treatment of acute ischaemic stroke.Multicentre Acute Stroke Trial – Italy (MAST-I) Group. Lan-cet 1995 Dec 9; 346 (8989): 1509-14

23. Donnan GA, Davis SM, Chambers BR, et al. Streptokinase foracute ischemic stroke with relationship to time of admin-istration: Australian Streptokinase (ASK) Trial Study Group.JAMA 1996; 276 (12): 961-6

24. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial pro-urokinase for acute ischemic stroke. The PROACT II study:a randomized controlled trial. Prolyse in Acute CerebralThromboembolism. JAMA 1999 Dec 1; 282 (21): 2003-11

25. Sherman DG, Atkinson RP, Chippendale T, et al. Intravenousancrod for treatment of acute ischemic stroke: the STATstudy: a randomized controlled trial. Stroke Treatment withAncrod Trial. JAMA 2000 May 10; 283 (18): 2395-403

26. Madden KP. Thrombolytic therapy for stroke. Marshfield ClinJ 2001; 2: 39-52

Correspondence and offprints: Dr Ken Madden, 1000 NorthOak Avenue (4F2), Marshfield, WI 54449, USA.E-mail: maddenk@mfldclin.edu

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