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Circulation. 1996;93:1616-1617

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(Circulation. 1996;93:1616-1617.)
© 1996 American Heart Association, Inc.

Articles

Thrombolysis in Ischemic Stroke: Double or Quits?

J. van Gijn, MD, FRCPE

From the University Department of Neurology, Utrecht, Netherlands.

Correspondence to J. van Gijn, MD, FRCPE, University Department of Neurology, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail j.vangijn@neuro.azu.nl.


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
Thrombolytic therapy to open up blocked arteries has so far appealed less to physicians caring for patients with brain infarction than to those involved in the management of myocardial infarction. The skepticism has been sustained by some important differences in pathogenesis between the two conditions. First, whereas occlusion of coronary vessels is almost invariably superimposed on local atheroma and mural thrombosis, occlusion of large intracerebral arteries is most often caused (at least in whites) by embolism from proximal sites: the internal carotid artery,1 2 the heart,3 or the aorta.4 Spontaneous recanalization is common, to judge by the difficulty in demonstrating intracranial occlusions unless angiography or transcranial ultrasound is done within 6 hours (at which time 60% to 75% of patients have impaired flow).5 6 Second, neurons are highly vulnerable to ischemia; animal experiments may have demonstrated an "ischemic penumbra" of salvageable tissue around a dense core of irreversible necrosis, but it remains uncertain whether in human disease such rescue operations are feasible or at all rewarding in terms of preserved function. Last, sudden reperfusion of necrotic brain tissue may lead to brain swelling with herniation,7 to hemorrhagic infarction, or sometimes to hemorrhage far exceeding the borders of the original infarct. Fatal hemorrhages may even complicate cerebral infarction without thrombolysis8 or thrombolysis without cerebral infarction.9 10

Of course, the proof of the pudding is in the eating—ie, clinical trials. After all, plausible treatments have proved to be ineffective or even harmful (and vice versa). Until early 1995, the collective evidence was limited to 899 randomized patients (in eight trials that had used CT scanning before inclusion to exclude primary intracerebral hemorrhage); reduction of case fatality was not statistically significant, and a statistically significant difference (death or deterioration) was difficult to interpret.11

Toward the end of 1995, the picture became slightly clearer. To start with, the interim results of three trials with streptokinase (1.5 million units or placebo infused intravenously within 1 hour) became available. All three studies were terminated prematurely, at least in part because of a significant excess of intracerebral hemorrhages and early deaths in the streptokinase group. The first two trials, with the smallest numbers of subjects, were the European MAST study (270 patients included within 6 hours after stroke onset)12 and the Australian (ASK) study (228 patients included 3 to 4 hours after stroke onset; the results for 72 patients treated within 3 hours have not yet been published).13 Last December, the Italian MAST study appeared (622 patients treated within 6 hours), in which patients had additionally been randomized between aspirin (300 mg/d for 10 days) and placebo.14 Again, there was an increase of early (10-day) case fatality and symptomatic intracerebral hemorrhage in the streptokinase group. A statistically significant difference from the double placebo group emerged only for the subgroup treated with streptokinase plus aspirin, but of course this by itself does not acquit streptokinase as a single drug. An intriguing finding was the similarity between all four groups that emerged after 6 months, with death or disability as the primary outcome event (disability being defined as the patient's requiring at least some help every day). This implies that the excess of early deaths in the streptokinase groups of the trial was eventually offset by a reduction in disability. The question as to whether the results of MAST-I signified defeat or victory divided not only reviewers but even the authors themselves,15 an unprecedented event in the history of clinical trials.16 If these observations are generalizable (and unpublished data about long-term outcome in the other trials suggest that they are),17 future patients will be faced with a sinister trade-off between early death and avoidance of disability in case of survival.

Enter tissue-type plasminogen activator (TPA). Two trials were very recently completed, with alteplase (1.1 or 0.9 mg/kg body wt) being administered over 1 hour, with 10% as an initial bolus. One, conducted in Europe (ECASS), involved 620 patients treated within 6 hours. Again, intracranial hemorrhages were significantly more frequent in the treated group; fatal brain edema, distinguished only in this trial, also occurred more often, but a chance effect could not be excluded. Overall outcome in terms of death or disability at 90 days showed questionable benefit for the thrombolysis group in only some of multiple analyses.18 Most hope is offered by the NIH study, in which 624 patients were enrolled for treatment within the incredibly short period of 3 hours.19 The first half of the study had an explanatory design, depending on improvement in the first 24 hours after treatment; these early changes were measured by means of a "stroke scale," a controversial construct in which various elements of neurological function are assigned an arbitrary number of points (but patients are more than the sum of their signs).20 The degree of disability at 3 months proved to be not only a more sensible but also a more sensitive measure, with a definite advantage for TPA. The benefit was similar for the subgroup with occlusive disease of small intracranial vessels. Comparison with the streptokinase trials can be only incomplete, because the line of division in the analysis of the NIH study was not the ability to lead an independent life but the presence or absence of any neurological deficit. The rate of early hemorrhages was again increased, but at 3 months the death toll was not higher but rather slightly lower in the TPA group.

Clearly, there is more work for meta-analysts to do. It is too early in the day to conclude that thrombolysis is cost-effective, if only because factors other than time that increase the risk of hemorrhage need to be identified. For progress to be rapid, the medical community needs to abandon its gallant nihilism toward ischemic stroke. Even patients who present after the first few hours can expect at least some advantage from treatment with antithrombotic drugs: low-molecular-weight heparin, another landmark trial of recent months,21 and perhaps also heparinoid (TOAST trial, in progress) or aspirin with or without standard heparin (International Stroke Trial, in progress). It seems we have reached the end of the beginning.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Fisher CM. Occlusion of the internal carotid artery. Arch Neurol Psychiatr. 1951;65:346-377.
  2. Lhermitte F, Gautier JC, Derouesné C. Nature of occlusions of the middle cerebral artery. Neurology. 1970;20:82-88. [Free Full Text]
  3. Hart RG. Cardiogenic embolism to the brain. Lancet. 1992;339:589-594. [Medline] [Order article via Infotrieve]
  4. Amarenco P, Duyckaerts C, Tzourio C, Henin D, Bousser MG, Hauw JJ. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med. 1992;326:221-225. [Abstract]
  5. Fieschi C, Argentino C, Lenzi GL, Sacchetti ML, Toni D, Bozzao L. Clinical and instrumental evaluation of patients with ischemic stroke within the first six hours. J Neurol Sci. 1989;91:311-321. [Medline] [Order article via Infotrieve]
  6. Zanette EM, Roberti C, Mancini G, Pozzilli C, Bragoni M, Toni D. Spontaneous middle cerebral artery reperfusion in ischemic stroke: a follow-up study with transcranial Doppler. Stroke. 1995;26:430-433. [Abstract/Free Full Text]
  7. Koudstaal PJ, Stibbe J, Vermeulen M. Fatal ischaemic brain oedema after early thrombolysis with tissue plasminogen activator in acute stroke. BMJ. 1988;297:1571-1574.
  8. Bogousslavsky J, Regli F, Uske A, Maeder P. Early spontaneous hematoma in cerebral infarct: is primary cerebral hemorrhage overdiagnosed? Neurology. 1991;41:837-840. [Abstract/Free Full Text]
  9. Wijdicks EFM, Jack CR Jr. Intracerebral hemorrhage after fibrinolytic therapy for acute myocardial infarction. Stroke. 1993;24:554-557. [Abstract/Free Full Text]
  10. Sloan MA, Price TR, Petito CK, Randall AMY, Solomon RE, Terrin ML, Gore J, Collen D, Kleiman N, Feit F, Babb J, Herman M, Roberts WC, Sopko G, Bovill E, Forman S, Knatterud GL. Clinical features and pathogenesis of intracerebral hemorrhage after rt-PA and heparin therapy for acute myocardial infarction: the Thrombolysis in Myocardial Infarction (TIMI) II pilot and randomized clinical trial combined experience. Neurology. 1995;45:649-658. [Abstract/Free Full Text]
  11. Wardlaw JM, Yamaguchi T, del Zoppo G, Hacke W. Thrombolysis in acute ischaemic stroke. In: Warlow C, van Gijn J, Sandercock P, eds. Stroke Module, Cochrane Database of Systematic Reviews. London, UK: BMJ Publishing; 1995.
  12. Hommel M, Boissel JP, Cornu C, Boutitie F, Lees KR, Besson G, Leys D, Amarenco P, Bogaert M, MAST Study Group. Termination of trial of streptokinase in severe acute ischaemic stroke. Lancet. 1995;345:57. Letter.
  13. Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ, Rosen D, Stewart Wynne EG, Tuck RR. Trials of streptokinase in severe acute ischaemic stroke. Lancet. 1995;345:578-579. Letter. [Medline] [Order article via Infotrieve]
  14. Candelise L, Aritzu E, Ciccone A, Ricci S, Wardlaw J, Tognoni G, Roncaglioni MC, Negri E, Colombo F, Boccardi E, De Grandi C, Scialfa G, Argentino C, Bertele V, Maggioni AP, Perrone P, Barnett HJM, Bogousslavsky J, Del Favero A, Loi U, Peto R, Warlow C, Canzi S, Comparetti S. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet. 1995;346:1509-1514. [Medline] [Order article via Infotrieve]
  15. Tognoni G, Roncaglioni MC. An alternative interpretation of MAST-I. Lancet. 1995;346:1515. Dissent. [Medline] [Order article via Infotrieve]
  16. Horton R. MAST-I: agreeing to disagree. Lancet. 1995;346:1504. Editorial.
  17. Sandercock P. Thrombolytic therapy for acute ischaemic stroke: promising, perilous, or unproven. Lancet. 1995;346:1504-1505.
  18. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, Von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, Hennerici M. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017-1025. [Abstract]
  19. Marler JR, Brott T, Broderick J, Kothari R, O'Donoghue M, Barsan W, Tomsick T, Spilker J, Miller R, Sauerbeck L, Jarrell J, Kelly J, Perkins T, McDonald T, Rorick M, Hickey C, Armitage J, Perry C, Thalinger K, Rhude R, Schill J, Becker PS, Heath RS, Adams D. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587. [Abstract/Free Full Text]
  20. Van Gijn J, Warlow CP. Down with stroke scales! Cerebrovasc Dis. 1992;2:244-246.
  21. Kay R, Wong KS, Yu YL, Chan YW, Tsoi TH, Ahuja AT, Chan FL, Fong KY, Law CB, Wong A, Woo J. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med. 1995;333:1588-1593.[Abstract/Free Full Text]



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