CURRENT OPINION eNS Drugs 1996 Oct; 6 (4): 257-262 1172-7047/96/001 D-0257 /S0300/0

© Adis Internat ional Limited. All rights reseNed

Thrombolytic Therapy in Acute Ischaemic Stroke Do the Benefits Outweigh the Risks?

Geoffrey A. Donnanl and Stephen M. Davis2

1 Department of Neurology, Austin and Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria, Australia

2 Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia

Summary There is a body of experimental and anecdotal evidence to suggest that thrombo­lytic therapy may be useful in reducing morbidity and mortality after acute isch­aemic stroke. A series of clinical trials designed to test hypotheses concerning risk and benefit have now been published. Intravenous streptokinase when given within 6 hours of ischaemic stroke may be of marginal benefit when given alone, but of no benefit when given with aspirin (acetylsalicylic acid) because of an unacceptably high early mortality. There is a trend toward much better outcomes if streptokinase is given early (<3 hours post-stroke). Intravenous alteplase (tis­sue plasminogen activator; tPA) has a much better risk-benefit profile than streptokinase, particularly when given within 3 hours of a stroke at a dose of 0.9 mg/kg. Indeed, this dose was recently approved for use by the US Food and Drug Administration.

Any planned administration of thrombolytic therapy to patients with acute ischaemic stroke should be in centres with experienced staff and facilities to monitor clinical progress . Further trials are needed to identify which thrombo­lytic agents, time windows of administration and dosages provide the best risk­benefit ratios .

The recent publication of a series of trials of thrombolytic agents in acute ischaemic stroke,ll-5] and the positive results of some of these,[3,4] has

raised hopes that a form of medical therapy may at last be available to minimise the effects of cerebral ischaemia once it occurs. Stroke is the most com­mon form of focal neurological disease in adults and the third most common cause of death in most countries. The social and economic impact of stroke is considerable, since most strokes do not result in death but cause persistent disability. Up to this time there has been no medical therapy to minimise the

effects of acute stroke, but the introduction of new generation thrombolytic agents[6,7] that have been shown to be effective in reducing morbidity and mortality after myocardial infarction[8-10] has stim­

ulated interest in similar forms of therapy for acute cerebral ischaemia.

In this article, we will brielly ceview the back­ground to the issue of thrombolysis in ischaemic stroke and then review the recent major trials . There have been a number of earlier, smaller randomised controlled trials which will not be dis­cussed in detail.

258

1. Recovery from Stroke: Arterial Recanalisation and Tissue Reperfusion

Since arterial thrombosis and embolism are the fundamental mechanisms by which most strokes occur,[1l,12] thrombolytic therapy designed to re­canalise recently occluded vessels is a logical ther­apeutic approach. This is supported by earlier clin­ical studies of cerebral infarction with initial and then repeated angiographyJI3] These showed that occluded vessels may undergo spontaneous clot lysis, although in these cases there was no improvement in prognosis. However, single pho­ton emission computerised tomography (SPECT) has shown that reperfusion at the tissue level is associated with better outcomesJl4]

Much of the improvement may be in under­perfused areas where tissue remains viable, the so­called 'ischaemic penumbra' .lIS] Electrical and synaptic failure occurs in this zone due to a reduc­tion of blood flow to below a critical threshold. Further reduction of flow as a function of time leads to depletion of energy stores, membrane failure and subsequent infarction. However, the 'therapeutic window' of time available during which clot lysis with restoration of blood flow and recovery of neuronal function may occur is unclear.[II]

2. Thrombolytic Therapies

The introduction of fibrin-selective thrombo­lytic agents that have been shown to be well toler­ated and effective in a number of thrombolytic disorders rekindled interest in similar forms of therapy for acute ischaemic strokeJl6] Experimen­tal models of cerebral infarction have been used to show that thrombolytic agents such as alteplase [tissue plasminogen activator (tPA)], streptokinase and urokinase may cause clot lysis when given intra-arterially or intravenously and minimise the volume of infarction.[I?J Alteplase has strong the­oretical advantages because of its fibrin specificity and lack of other systemic thrombolytic effects[7] and, hence, has been the forerunner in trials of thrombolysis in cardiac disease. In these trials, alte-

© Adis International Limited. All rights reserved.

Donnan & Davis

plase has been shown to reduce mortality after myocardial infarction.[8-IOJ Streptokinase has also been shown to be equally effective in this role,[9] while agents such as prourokinase and recombi­nant staphylokinase remain to be testedJI8J

3. When Should Therapy Begin?

Although data from experimental models of ce­rebral ischaemia do suggest that neuronal recovery may still occur after 6 hours post-ischaemia,[19-2IJ this information is difficult to translate into the clinical sphere. While there are arguments to sug­gest that longer therapeutic time windows may ex­ist in humans,l22J it seems logical that the earlier thrombolytic therapy is given, the greater the like­lihood of success. This has been borne out in sub­sequent clinical trials and will be discussed in sec­tion 5.

4. Haemorrhagic Transformation

One of the main concerns regarding the use of thrombolytic agents in ischaemic stroke has been the potential to transform a 'bland' infarct into a cerebral haemorrhage with subsequent clinical deterioration. Such transformation may occur at multifocal sites via diapedesis through damaged capillary and venular walls, and results in pete­chiae of various sizes. Occasionally, confluence of petechiae results in confluent purpura or a haema­toma. Cardiac embolic strokes have a higher pro­pensity for haemorrhagic infarction (51 to 71 % prevalence)[23,24J than non-cardiac embolic strokes (2 to 21 % prevalence).[24,2SJ Haemorrhagic infarc­tion may be detected on computed tomography (CT) scan, and is seen in up to 5% of scans per­formed within 24 hours of the stroke and up to 69% of cases when CT scan is performed within weeks post-stroke. [26-29J Although anticoagulant therapy does not appear to increase the likelihood of haemo­rrhagic transformation, it may accentuate the degree of frank haemorrhage on CT, with an estimated in­cidence of clinical deterioration of 5 to 20%.[30J

One major problem in determining the inci­dence of haematoma in clinical series of ischaemic stroke lies in defining haematoma in the presence of

eNS Drugs 1996 Oct; 6 (4)

Thrombolytics in Acute Ischaemic Stroke

infarction using CT criteria. It is often extremely difficult to distinguish between confluent haemo­rrhagic transformation with associated mass effect due to underlying infarction and pure haematoma per se. In an overview of earlier, small controlled and uncontrolled trials, Wardlaw and Warlow[30] found a 5% cerebral haematoma rate from over 50 studies performed since 1958 (excluding the recent major trials discussed in section 5). It was of inter­est that alteplase was found to be associated with a modest increased risk of cerebral haemorrhage compared with streptokinase in the large GUSTO (Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) trial of the use of these agents in myo­cardial infarction. IIO] However, this is a very dif­ferent setting to that of acute stroke therapy and the pattern is not followed in the stroke trials discussed in section 5.

There is reasonable evidence, therefore, that the use of thrombolytic agents is associated with in­creased risk of symptomatic haematoma formation with associated clinical deterioration. Like many forms of therapy, both medical and surgical, this needs to be balanced with the likelihood of im­proved outcomes. A more realistic approach to this balance between risks and benefits was not possi­ble until a series of major trials was conducted during the early 1990s.

5. Recent Trials of Thrombolytic Therapy

Based on the available experimental evidence and the encouraging nature of some small prelim-

259

inary trials,[31 ,32] a series of major trials of thrombo­lytic therapy in acute ischaemic stroke was initiated in Europe,lI-3J the US[4] and Australia,rs] While there were many common features to these trials, important differences existed (table I). Two of the European trials [the Multicentre Acute Stroke Trial-Europe (MAST-E) and -Italy (MAST-I)]I1 -21 and the Australian Streptokinase (ASK) trial 13] used streptokinase as the thrombolytic agent at a dose usually used post-myocardial infarction (1.5MU). Alteplase was used in both the National Institute of Neurological Disorders and Stroke (NINDS) trial[4] and the European Cooperative Acute Stroke Study (ECASS).13] The NINDS group did an ear­lier dose-escalation study and determined that a dose of alteplase of 0.9 mg/kg was likely to have the best risk-benefit ratio,133,34] while 1.1 mg/kg was used in the ECASS trial. In all trials, the thrombolytic agent was administered intrave­nously. For ASK, MAST-I and NINDS, all acute ischaemic stroke patients were considered for trial entry, while for MAST-E and ECASS only pa­tients with supratentorial hemispheric ischaemic strokes were considered.

While all trials used relatively short time windows from stroke onset to therapy (the longest time window being 6 hours) both the ASK and NINDS groups pushed the entry time to even shorter limits. The ASK time window was 4 hours, with an a priori hypotheses that there would be a difference in outcomes between patients entered 0 to 3 hours and those entered more than 3 hours post-stroke. The NINDS trial allowed stratification

Table I. Recent trials of thrombolytic therapy in acute ischaemic stroke: main features

Trial Therapy Intravenous dose Ischaemic stroke type No. of patients Time window to therapy (h)

MAST-EI11 Streptokinase 1.5MU Hemispheric 270 6 MAST-112] Streptokinase 1.5MU All 622 6 ECASS[3] Alteplase 1.1 mg/kg Hemispheric 620 6 NINDS[4] Alteplase 0.9 mg/kg All 624 3a

ASK[5] Streptokinase 1.5MU All 340 4b

a Part 1 of this study involved patients treated 0 to 90 minutes post-stroke; part 2 involved patients treated 90 to 180 minutes post-stroke.

b The a priori hypothesis was that there would be a difference in effect between patients treated 0 to 3 hours post-stroke and those treated >3 hours post-stroke.

Abbreviations: ASK = Australian Streptokinase trial; ECASS = European Cooperative Acute Stroke Study; MAST-E = Multicentre Acute Stroke Trial-Europe; MAST-I = Multicentre Acute Stroke Trial-Italy; NINDS = National Institute of Neurological Disorders and Stroke trial.

© Adis International Limited. All rights reserved. eNS Drugs 1996 Oct; 6 (4)

260

of patients into 0 to 90 minutes or 91 to 180 minutes post-stroke at entry, thus having a large number of patients with very early onset of treatment, a fea­ture not present in any of the other studies.

5.1 Trial Outcomes

In November 1994, MAST-E was stopped by the Steering Committee because of unacceptably poor outcomes in the streptokinase-treated group.[11 There was approximately a 2-fold increase in the odds of early mortality in the treatment compared with placebo groups, and this was considered to be due to haematoma formation. This information had a cascade effect on the other streptokinase tri­als: the ASK data were re-examined and similarly poor outcomes (excess deaths) were found for those patients receiving streptokinase more than 3 hours post-stroke, but no such problem existed for the 0 to 3-hour group)S1

The Steering Committee of the ASK trial felt that it was impractical to continue recruitment for the 0 to 3-hour group under the circumstances created. A full analysis revealed that although there was early hazard of death associated with therapy [odds ratio (OR) 2.6, 95 % confidence intervals (CI) 1.5 to 4.6])51 this was restricted to the greater than 3-hour time window group. Further, for the 0 to 3-hour group there was a strong trend toward better outcomes, using a combination of death and disability as the primary end-point (poor outcome = dead or Barthel Index score <60, good outcome = Barthel Index score >60) [OR 0.5, 95% CI 0.2 to 1.3]. During this time MAST-I was halted to enable a full interim analysis to be performed, the results of which have now been published.[21

For MAST-I there was a nonsignificant reduc­tion in the primary end-point of death and disability in the treatment compared with placebo groups (OR 0.9, 95% CI 0.7 to 1.3), but this was balanced by an early hazard of excess deaths in the strepto­kinase group (OR 2.7, 95% CI 1.7 to 4.3). The fac­torial design enabled a subgroup analysis of those who received both streptokinase and aspirin (acetylsalicylic acid) to be made - this combination appeared to increase the likelihood of 10-day case

© Adis International Limited. All rights reserved.

Donnan & Davis

fatality (34%) and symptomatic intracranial haem­orrhage (10%) compared with those who received no therapy (13 and 6%, respectively). As pointed out by dissenting members of the MAST-E Steer­ing Committee,DS.361 caution needs to be exercised when interpreting such data. However, it is of in­terest that the 6-month mortality for patients in the ASK trial, all of whom received aspirin as well as streptokinase, was 36% compared with 200/0 in the placebo group (aspirin alone).

Both alteplase studies were successfully com­pleted. The ECASS group found that there was a significant improvement on primary end-point outcomes of death and disability for a 'targeted' group of patients after protocol violators had been excludedP1 Most of these were patients who had early changes of infarction on CT, a stipulated exclusion criterion in the original protocol. How­ever, this approach can be criticised since 109 pa­tients were excluded and when all patients were considered (i.e . intention-to-treat analysis) there was no beneficial effect seen for the active com­pared with placebo treatment. This result led to cautious optimism among many investigators in the area that a modified approach to thrombolytic therapy with future trials might provide a better result.

Indeed, this optimism was rewarded with a pos­itive result from the NINDS alteplase trial, which was published in December 1995)41 There was a 30% relative increase in favourable outcomes (minimal or no disability on the clinical assessment scales) for those patients who received alteplase. While there was some increased risk of symptom­atic haematoma formulation (6.4% in the treatment group compared with 0.6% in the placebo group; a significant difference), there was no difference in mortality between those receiving alteplase and those receiving placebo. While not statistically sig­nificant, there was a strong trend toward greater improvement in neurological scores within 24 hours among those who received alteplase, partic­ularly for those who were entered into the study within 90 minutes of stroke onset.

eNS Drugs 1996 Oct; 6 (4)

Thrombolytics in Acute lschaemic Stroke 261

Table II. Haematoma rates in major clinical trials of thrombolytic therapy in acute ischaemic stroke

Trial Symptomatic Asymptomatic Total

therapy (%) placebo (%) therapy (%) placebo (%) therapy (%) placebo (%) MAST-Ell] 33/156 (21.2) 4/154 (2.6) NP NP NP NP MAST-112] 25/313 (8) 1/156 (0.6) NP NP NP NP ECAss13]a NP NP NP NP 48/247 (19.4) 18/264 (6.8) NINDSI4] 20/312 (6.4) 2/312 (0 .6) 14/312 (4 .5) 9/312 (2 .9) 34/312 (10.9) 11/312 (3.5) ASKIS] NP NP NP NP 23/174 (13.2) 5/166 (3)

a Target population only.

Abbreviations: ASK = Australian Streptokinase trial; ECASS = European Cooperative Acute Stroke Study; MAST-E = Multicentre Acute :troke Trial-Europe; MAST-I = Multicentre Acute Stroke Trial-Italy; NINDS = National Institute of Neurological Disorders and Stroke tnal. NP - data not yet published.

5.2 Risks and Benefits

A summary of the available data covering the risks of therapy in terms of haematoma formation (symptomatic and asymptomatic) is shown in table II.

While there are difficulties with differing defi­nitions of haematoma between studies, it can be seen that there is early hazard associated with thrombolytic therapy (symptomatic haematoma formation) of anywhere between about 6 to 18%, depending on the therapeutic agent used, dose and time windows of administration.

Alteplase has the most clinical benefit with the lowest hazard, particularly when given at a dose of 0.9 mg/kg and within 3 hours of stroke onset. The risk-benefit ratio for streptokinase when given at a dose of I.SMU intravenously within 6 hours of stroke onset is marginal, and probably of no benefit when given with aspirin. There is a suggestion that streptokinase may be well tolerated and effective if given within 3 hours of stroke onset (see section 5.1), but this hypothesis would need to be tested by further randomised trials before it could be stated with certainty.

6. Where to Now?

The evidence that alteplase given within 6 hours, and, particularly, if given within 3 hours, of stroke onset may improve clinical outcomes is now very strong. After nearly 40 years of a gradu­ation from anecdotal reports through to formal randomised controlled trials of thrombolytic ther­apy, some success has been attained. Indeed, alte-

© Adis International Limited. All rights reserved.

plase has now been approved for use as a form of acute stroke therapy by the US Food and Drug Ad­ministration. For all forms of acute stroke therapy, ranging from haemodilation or anticoagulants through to neuroprotective forms of therapy, this is the first clear indication that there can be a success­ful translation of a therapy that has been shown to be effective in laboratory models of stroke into the clinical sphere.

Steps must now be put into place to carefully allow the introduction of thrombolytic therapy into routine clinical practice. It is clear that this must be, in the first instance, in centres where there is a high level of expertise in stroke management so that appropriate patient selection and monitoring can be undertaken. Patients for whom this therapy is appropriate are those: (i) with acute onset of stroke within the proceeding 3 hours; (ii) no contraindications to thrombolytic therapy; and (iii) no early change of ischaemia as seen on CT scan.

Trials of newer thrombolytic agents using dif­fering doses and time windows in combination with a variety of neuroprotective agents now ap­pear likely. Hopefully, this will lead to an even greater reduction in morbidity and mortality from stroke.

References I. Hommel M , Boissel JP, Cornu C, et al. for the MAST Study

Group. Termination of trial of streptokinase in severe acute ischaemic stroke. Lancet 1995; 345: 57

2 Multicenter Acute Stroke Trial-Italy (MAST-I) Group. Ran-. domised controlled trial of streptokinase, aspirin. and combi­

nation of both in treatment of acute ischaemic stroke. Lancet 1995; 346: 1509-14

eNS Drugs ]996 Oct; 6 (4)

262

3. The European Cooperative Acute Stroke Study (ECASS). Intra­venous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995; 274: 1017-25

4. The 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: 1581-7

5. Donnan GA, Davis SM, Chambers BR, et al. Trials of strepto­kinase in severe acute ischaemic stroke. Lancet 1995; 345: 578-9

6. Rijken DC, Collen D. Purification and characterization of the plasminogen activator secreted by human melanoma cells in culture. J BioI Chem 1981; 256: 7035-41

7. Verstraete M, Collen D. Thrombolytic therapy in the eighties. Blood 1986; 67: 1529-41

8. ISIS-2 (Second International Study of Infarct Survival) Collab­orative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; II: 349-60

9. Gruppo Italiano per 10 Studio della Sopravvivenza nell'lnfarto Miocardico. GISSI-2: a factorial randomized trial of alteplase versus streptokinase and heparin versus no heparin among 12 490 patients with acute myocardial infarction. Lancet 1990; 336: 65-71

10. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673-82

II. Fieschi C, Argentino C, Lenzi GL, et al. Therapeutic window for pharmacologic treatment in acute focal cerebral isch­aemia. Ann NY Acad Sci 1988; 522: 662-6

12. Fieschi C, Corrado A, Lenzi GL, et al. Clinical and instrumental evaluation of patients with ischaemic stroke within the first six hours. J Neurol Sci 1989; 91 : 311-22

13. Dalal PM, Sheth SC, Deshpande CK. Cerebral embolism: an­giographic observations on spontaneous clot lysis. Lancet 1965; I: 61-4

14. Baird AE, Austin MC, McKay WJ, et al. Changes in cerebral tissue perfusion during the first 48 hours of ischaemic stroke: relationship to clinical outcome. J Neurol Neurosurg Psychi­atry 1996; 61: 26-9

15. Lassen NA, Astrup J. Ischemic penumbra. In: Wood JH, editor. Cerebral blood flow: physiologic and clinical aspects. New York: McGraw-Hill, 1987: 458-66

16. Verstraete M, Collen D. Thrombolytic therapy in the eighties. Blood 1986; 67: 1529-41

17. del Zoppo GJ, Copeland BR, Waltz TA, et al. The beneficial effect of intracarotid urokinase on acute stroke in a baboon model. Stroke 1986; 17: 638-43

18. Vanderschueren S, Stoch L, Wilms G, et al. Thrombolytic ther­apy of peripheral arterial occlusion with recombinant staphylokinase. Circulation 1995; 92: 2050-7

19. Kamijyo Y, Garcia JH, Cooper J. Temporary regional cerebral ischemia in the cat: a model of hemorrhagic and subcortical infarction. J Neuropathol Exp Neurol 1977; 36: 338-50

© Adis International Limited. All rights reserved.

Donnan & Davis

20. Petito CK. Early and late mechanisms of increased vascular permeability following experimental cerebral infarction. J Neuropathol Exp Neurol 1979; 38: 222-34

21. Garcia JH, Mitchem HL, Briggs L, et al. Transient focal isch­emia in subhuman primates: neuronal injury as a function of local cerebral blood flow. J Neuropathol Exp Neurol 1983; 42: 44-60

22. Baron JC, von Kummer R, del Zoppo GJ. Treatment of acute ischemic stroke: challenging the concept of a rigid and uni­versal time window. Stroke 1995; 26: 2219-21

23. Lodder J, Krijne-Kubat B, Broekman J. Cerebral hemorrhagic infarction at autopsy: cardiac embolic cause and the relation­ship to the cause of death. Stroke 1986; 17: 626-9

24. Fisher CM, Adams RD. Observations on brain embolism with special reference to hemorrhagic infarction. In: Furlan AJ, editor. The heart and stroke. Berlin: Springer-Verlag, 1987: 17-36

25. Hakim AM, Ryder-Cooke A, Melanson D. Sequential compu­terized tomographic appearance of strokes. Stroke 1983; 14: 893-7

26. Cerebral Embolism Study Group. Immediate anticoagulation of embolic stroke: a randomized trial. Stroke 1983; 14: 68-76

27. Hornig CR, DorndorfW, Agnoli AL. Hemorrhagic cerebral in­farction: a prospective study. Stroke 1986; 17: 179-85

28. Minematsu K, Yamaguchi T, Omae T. Spectacular shrinking deficit: rapid recovery from a major hemispheric syndrome by migration of an embolus. Neurology 1992; 42: 157-62

29. Okada Y, Yamaguchi T, Minematsu K, et al. Hemorrhagic trans­formation in cerebral embolism. Stroke 1989; 20: 598-603

30. Wardlaw J, Warlow CPo Thrombolysis in ischaemic stroke: does it work? Stroke 1992; 23: 1826-39

31. Mori E. Safety and efficacy of fibrinolytic agents in acute isch­aemic stroke. Cerebrovasc Dis 1993; 3: 264-8

32. Yamaguchi T, Hayakawa T, Kiuchi H. Intravenous tissue plas­minogen activator ameliorates the outcome of hyperacute em­bol ic stroke. Cerebrovasc Dis 1993; 3: 269-72

33. Brott TG, Haley EC, Levy DE, et al. Urgent therapy for stroke: part I. Pilot study of tissue plasminogen activator adminis­tered within 90 minutes. Stroke 1992; 23: 632-40

34. Haley EC, Levy DE, Brott TG, et al. Urgent therapy for stroke: part II. Pilot study of tissue plasminogen activator adminis­tered 91-180 minutes from onset. Stroke 1992; 23: 641-5

35. Tognoni G, Roncaglioni Me. Dissent: an alternative interpreta­tion of MAST-I. Lancet 1995; 346: 1515

36. Horton R. MAST-I: agreeing to disagree [commentary]. Lancet 1995; 346: 1504

Correspondence and reprints: Prof. Geoffrey A. Donnan, Director of Neurosciences, Austin and Repatriation Medical Centre, Studley Rd, Heidelberg, Vic 3084, Australia. E-mail: map@austin.unimelb.edu.au.

eNS Drugs 1996 Oct: 6 (4)