Intra-arterial Prourokinase for Acute Ischemic Stroke: The PROACT II Study: A Randomized Controlled Trial | Cerebrovascular Disease | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.  Tissue plasminogen activator for acute ischaemic stroke.  N Engl J Med.1995;333:1581-1587.Google Scholar
Hacke W, Kaste M, Fieschi C.  et al.  Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS).  JAMA.1995;274:1017-1025.Google Scholar
Donnan GA, Davis SM, Chambers BR.  et al.  Streptokinase for acute ischemic stroke with relationship to time of administration.  JAMA.1996;276:961-966.Google Scholar
The Multicenter Acute Stroke Trial—Europe Study Group.  Thrombolytic therapy with streptokinase in acute ischemic stroke.  N Engl J Med.1996;335:145-150.Google Scholar
The Multicenter Acute Stroke Trial–Italy (MAST–I) Group.  Randomised controlled trial of streptokinase, aspirin and combination of both in treatment of acute ischaemic stroke.  Lancet.1995;346:1509-1514.Google Scholar
Hacke W, Kaste M, Fieschi C.  et al.  Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II).  Lancet.1998;352:1245-1251.Google Scholar
Clark WM, Albers GW.for the ATLANTIS Stroke Investigators.  The Atlantis rt-PA (Alteplase) Acute Stroke Trial: final results [abstract].  Stroke.1999;30:234.Google Scholar
Muir KW, Grosset DG. Neuroprotection for acute stroke: making clinical trials work.  Stroke.1999;30:180-182.Google Scholar
Sandercock P, Hennerici MG, Orgogozo JM, Davis SM, Gorelick PB. Mega trials versus small trials in stroke. In: Fisher M, Bogousslavsky J, eds. Current Review of Cerebrovascular Disease. Boston, Mass: Butterworth-Heinemann; 1999:217-222.
Gonner F, Remonda L, Mattle H.  et al.  Local intra-arterial thrombolysis in acute ischemic stroke.  Stroke.1998;29:1894-1900.Google Scholar
del Zoppo GJ, Ferbert A, Otis S.  et al.  Local intra-arterial fibrinolytic therapy in acute carotid territory stroke: a pilot study.  Stroke.1988;19:307-313.Google Scholar
Theron J, Courtheoux P, Casasco A.  et al.  Local intraarterial fibrinolysis in the carotid territory.  AJNR Am J Neuroradiol.1989;10:753-765.Google Scholar
Mori E, Tabuchi M, Yoshida T.  et al.  Intracarotid urokinase with thromboembolic occlusion of the middle cerebral artery.  Stroke.1988;19:802-812.Google Scholar
Zeumer H, Freitag HJ, Zanella F.  et al.  Local intra-arterial fibrinolytic therapy in patients with stroke: urokinase versus recombinant tissue plasminogen activator (r-TPA).  Neuroradiology.1993;35:159-162.Google Scholar
Hacke W, Zeumer H, Ferbert A.  et al.  Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease.  Stroke.1988;19:1216-1222.Google Scholar
Pessin M, del Zoppo GJ, Furlan AJ. Thrombolytic treatment in acute stroke: review and update of selective topics. In: Moskowitz MA, Caplan LR, eds. Cerebrovascular Diseases: Nineteenth Princeton Stroke Conference. Boston, Mass: Butterworth-Heinemann; 1995:409-418.
del Zoppo GJ, Higashida RT, Furlan AJ.  et al.  PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke.  Stroke.1998;29:4-11.Google Scholar
Kasai S, Arimura H, Nishida M, Suyama T. Primary structure of single-chain pro-urokinase.  J Biol Chem.1985;260:12382-12389.Google Scholar
Pannell R, Gurewich V. Pro-urokinase: a study of its stability in plasma and of a mechanism for its selective fibrinolytic effect.  Blood.1986;44:217-228.Google Scholar
Tebbe U, Windeler J, Boesl I.  et al.  Thrombolysis with recombinant unglycosylated single-chain urokinase-type plasminogen activator (saruplase) in acute myocardial infarction: influence of heparin on early patency rate (LIMITS Study).  J Am Coll Cardiol.1995;26:365-373.Google Scholar
Gurewich V, Liu J. Intra-arterial pro-urokinase in ischemic stroke [letter].  Stroke.1998;29:1255.Google Scholar
Brott T, Adams Jr HP, Olinger CP.  et al.  Measurements of acute cerebral infarction: a clinical examination scale.  Stroke.1989;20:864-870.Google Scholar
TIMI Study group.  Special report: the Thrombolysis in Myocardial Infarction (TIMI) trial.  N Engl J Med.1985;312:932-936.Google Scholar
Wolfe CD, Taub NA, Woodrow BA, Burney PG. Assessment of scales of disability and handicap for stroke patients.  Stroke.1991;22:1242-1244.Google Scholar
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJA, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients.  Stroke.1988;19:604-607.Google Scholar
Furlan AJ. Natural history of atherothromboembolic occlusion of cerebral arteries: carotid versus vertebrobasilar territories. In: Hacke W, del Zoppo GJ, Hirschberg M, eds. Thrombolytic Therapy in Acute Ischemic Stroke. New York, NY: Springer-Verlag; 1991:71-76.
del Zoppo GJ, Poeck K, Pessin MS.  et al.  Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke.  Ann Neurol.1992;32:78-86.Google Scholar
Ferguson RD, Ferguson JG. Cerebral intraarterial thrombolysis at the crossroads: is a phase III trial advisable at this time?  AJNR Am J Neuroradiol.1994;15:1201-1216.Google Scholar
del Zoppo GJ, Higashida RT, Furlan AJ. The case for a phase III trial of cerebral intraarterial fibrinolysis.  AJNR Am J Neuroradiol.1994;15:1217-1222.Google Scholar
Moulin T, Cattin F, Crepin-Leblond T.  et al.  Early CT signs in acute middle cerebral artery infarction: predictive value for subsequent infarct locations and outcome.  Neurology.1996;47:366-375.Google Scholar
von Kummer R, Allen KL, Holle R.  et al.  Acute stroke: usefulness of early CT findings before thrombolytic therapy.  Radiology.1997;205:327-333.Google Scholar
Toni D, De Michele M, Fiorelli M.  et al.  Influence of hyperglycemia on infarct size and clinical outcome of acute ischemic stroke patients with intracranial arterial occlusion.  J Neurol Sci.1994;123:129-133.Google Scholar
Lodder J, Krijne-Kubat B, Broekman J. Cerebral hemorrhagic infarction at autopsy: cardiac embolic causes and the relationship to cause of death.  Stroke.1986;17:626-629.Google Scholar
Hornig CR, Dorndorf W, Agnoli AL. Hemorrhagic cerebral infarction—a prospective study.  Stroke.1986;17:179-185.Google Scholar
Okada Y, Yamaguchi T, Minematsu K.  et al.  Hemorrhagic transformation in cerebral embolism.  Stroke.1989;20:598-603.Google Scholar
The NINDS t-PA Stroke Study Group.  Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke.  Stroke.1997;28:2109-2118.Google Scholar
Wolpert SM, Bruckmann H, Greenlee R.  et al.  Neuroradiology evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator.  AJNR Am J Neuroradiol.1993;14:3-13.Google Scholar
Genentech, applicant.  Summary basis for approval: activaseTM for acute ischemic stroke. New Drug Application. PLA96-0350.
Tomsick T, Brott T, Barsan W.  et al.  Prognostic value of the hyperdense middle cerebral artery sign and stroke scale score before ultraearly thrombolytic therapy.  AJNR Am J Neuroradiol.1996;17:79-85.Google Scholar
Marler JR, Jones PW, Emr M. Rapid Identification and Treatment of Acute Stroke: Proceedings of a National SymposiumBethesda, Md: National Institutes of Health; 1997. NIH Publication 97-439.
Ueda T, Sakaki S, Nochide I.  et al.  Angioplasty after intra-arterial thrombolysis for acute occlusion of intracranial arteries.  Stroke.1998;29:2568-2574.Google Scholar
Emergency Management of Stroke (EMS) Investigators.  Combined intra-arterial and intravenous tPA for stroke [abstract].  Stroke.1997;28:273.Google Scholar
Pannell R, Black J, Gurewich V. The complementary modes of action of tissue plasminogen activator (t-PA) and pro-urokinase (pro-UK) by which their synergistic effect on clot lysis may be explained.  J Clin Invest.1988;81:853-859.Google Scholar
Fisher M, Garcia JH. Evolving stroke and the ischemic penumbra.  Neurology.1996;47:884-888.Google Scholar
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;26:2219-2221.Google Scholar
Fisher M, Prichard JW, Warach S. New magnetic resonance techniques for acute ischemic stroke.  JAMA.1995;274:908-911.Google Scholar
Staroselskaya IA, Baird AE, Linfante I.  et al.  Correlations between MR diffusion-perfusion studies and MRA in acute stroke.  Neurology.1999;52(suppl 2):455.Google Scholar
Original Contribution
December 1, 1999

Intra-arterial Prourokinase for Acute Ischemic Stroke: The PROACT II Study: A Randomized Controlled Trial

Author Affiliations

Author Affiliations: Cerebrovascular Center, Department of Neurology, Cleveland Clinic Foundation, Cleveland, Ohio (Dr Furlan). Department of Neuroradiology, University of California, San Francisco (Drs Higashida and Rowley); Stroke Institute, University of Pittsburgh, Pittsburgh, Pa (Dr Wechsler); Department of Clinical Epidemiology and Biostatistics, McMaster University and Clinical Trials Methodology Group, Hamilton Civic Hospital Research Center, Hamilton, Ontario (Dr Gent); Department of Neurology, Boston University School of Medicine (Dr Kase), Department of Neurology, New England Medical Center (Dr Pessin), Boston, Mass; Department of Neurosurgery, St Lukes' Medical Center, Milwaukee, Wis (Dr Ahuja); Neurologic Consultants PC, Centennial Medical Center, Nashville, Tenn (Dr Callahan); Department of Neurology, Oregon Health Sciences University, Portland (Dr Clark); Department of Neurology, The Toronto Hospital–Western Division, Toronto, Ontario (Dr Silver); and Department of Vascular and Interventional Radiology, Baylor University Medical Center, Dallas, Tex (Dr Rivera). Dr Pessin is deceased.

JAMA. 1999;282(21):2003-2011. doi:10.1001/jama.282.21.2003

Context Intravenous tissue-type plasminogen activator can be beneficial to some patients when given within 3 hours of stroke onset, but many patients present later after stroke onset and alternative treatments are needed.

Objective To determine the clinical efficacy and safety of intra-arterial (IA) recombinant prourokinase (r-proUK) in patients with acute stroke of less than 6 hours' duration caused by middle cerebral artery (MCA) occlusion.

Design PROACT II (Prolyse in Acute Cerebral Thromboembolism II), a randomized, controlled, multicenter, open-label clinical trial with blinded follow-up conducted between February 1996 and August 1998.

Setting Fifty-four centers in the United States and Canada.

Patients A total of 180 patients with acute ischemic stroke of less than 6 hours' duration caused by angiographically proven occlusion of the MCA and without hemorrhage or major early infarction signs on computed tomographic scan.

Intervention Patients were randomized to receive 9 mg of IA r-proUK plus heparin (n = 121) or heparin only (n = 59).

Main Outcome Measures The primary outcome, analyzed by intention-to-treat, was based on the proportion of patients with slight or no neurological disability at 90 days as defined by a modified Rankin score of 2 or less. Secondary outcomes included MCA recanalization, the frequency of intracranial hemorrhage with neurological deterioration, and mortality.

Results For the primary analysis, 40% of r-proUK patients and 25% of control patients had a modified Rankin score of 2 or less (P = .04). Mortality was 25% for the r-proUK group and 27% for the control group. The recanalization rate was 66% for the r-proUK group and 18% for the control group (P<.001). Intracranial hemorrhage with neurological deterioration within 24 hours occurred in 10% of r-proUK patients and 2% of control patients (P = .06).

Conclusion Despite an increased frequency of early symptomatic intracranial hemorrhage, treatment with IA r-proUK within 6 hours of the onset of acute ischemic stroke caused by MCA occlusion significantly improved clinical outcome at 90 days.