Intra-arterial Pro-urokinase in Ischemic Stroke
To the Editor:
Dr del Zoppo et al are to be congratulated for successfully completing the first randomized, double-blind, controlled trial of intra-arterial pro-urokinase (pro-UK) in ischemic stroke (PROACT).1 A sophisticated route of administration of pro-UK by microcatheter into the thrombus was chosen in order to maximize lysis and minimize hemorrhagic side effects. Moreover, at the low infusion rate (6 mg over 2 hours) that was used, there is no systemic conversion of pro-UK to urokinase, and its effect is entirely fibrin specific. As a result, little or no bleeding should have occurred, because in stroke, bleeding is correlated with nonspecificity (ie, streptokinase induces more bleeding than tPA).
In view of this prudent protocol, it is curious that intravenous heparin was given concomitantly with pro-UK in the treatment group or given alone in the placebo group.
Early anticoagulation with heparin for ischemic stroke has long been considered hazardous, and it has been recommended that heparin be delayed for at least 48 hours after embolism.2 Even when heparin was administered by the subcutaneous route to patients with ischemic stroke, a 4-fold increase in hemorrhagic stroke was reported in the International Stroke Trial.3 Consequently, heparin has been scrupulously avoided in all of the clinical trials of tPA in stroke. Therefore, it is not surprising that in the PROACT study, a 15% incidence of intracranial bleeding occurred and more than a 3-fold increase in hemorrhagic stroke was observed when pro-UK was combined with a higher dose of heparin compared with a lower dose. Since no significant difference was seen in the two placebo groups given the two doses of heparin alone, it was the adjunctive heparin which was probably largely responsible for the hemorrhagic strokes in this study.
The rationale for using heparin in this study was based on previous observations that heparin augments the thrombolytic effect of pro-UK.4 5 Indeed a doubling of the recanalization rate at the higher dose of heparin was found (82% versus 40%) in the PROACT study, confirming the previous data that heparin significantly promotes thrombolysis by pro-UK. The question then is this: can this beneficial effect of heparin be preserved without incurring the risk of concomitant administration with pro-UK?
Heparin has no promoting effect on clot lysis in a plasma milieu by either pro-UK or tPA in vitro. Therefore, heparin is not integral to clot lysis by pro-UK and is related to certain in vivo effects. Several mechanisms have been proposed. First, thrombolysis with tPA can induce certain procoagulant effects that are reversible by heparin. However, in contrast to tPA, this was not the case when coronary thrombolysis was induced by pro-UK,6 so this problem can be excluded when pro-UK is used. Second, thrombin inactivates pro-UK.7 Therefore, neutralizing the thrombus-bound thrombin by heparin has been postulated to be responsible for its augmentation of pro-UK–induced thrombolysis.5 Third, heparin induces the release of tPA from endothelial cells, and a 2- to 3-fold increase in plasma tPA antigen levels has been reported after intravenous heparin.8 This heparin effect is relevant, because tPA and pro-UK are synergistic in fibrinolysis9 and an initial small bolus of tPA has been shown to strongly promote coronary thrombolysis by pro-UK.10 Finally, although some binding of heparin to plasminogen and pro-UK has also been reported, there is no evidence that this property of heparin promotes clot lysis.
Thrombin neutralization and/or tPA release are, therefore, the most likely effects of heparin responsible for its promotion of thrombolysis by pro-UK. These beneficial effects could probably be fully achieved by a single bolus of heparin given prior to the pro-UK infusion.
The authors stated that a new study involving 180 patients given 9 mg pro-UK intra-arterially is now in progress. It would be most unfortunate if the potential benefits of reperfusion by pro-UK are needlessly undermined by a concomitant infusion of heparin that causes bleeding into the infarct zone.
- Copyright © 1998 by American Heart Association
del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M, and the PROACT Investigators. PROACT: a phase II randomized trial of recombinant prourokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke. 1998;29:4–11.
Shields RW Jr, Laureno R, Lachman T, Victor M. Anticoagulant-related hemorrhage in acute cerebral embolism. Stroke. 1984;15:426–437.
Tebbe U, Windeler J, Boesl I, Hoffmann H, Wojcik J, Ashmawy M, Schwarz ER, von Loewis P, Rosemeyer P, Hopkins G, Barth H, on behalf of the LIMITS Study Group. 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.
Gurewich V, Pannell R. Inactivation of single chain urokinase (pro-urokinase) by thrombin and thrombin-like enzymes: relevance of the finding to the interpretation of fibrin binding experiments. Blood. 1987;69:769–772.
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.
Zarich SW, Kowalchuk GJ, Weaver WD, Loscalzo J, Sassower M, Manzo K, Byrnes C, Muller JE, Gurewich V, for the PATENT Study Group. Sequential combination thrombolytic therapy for acute myocardial infarction: results of the pro-urokinase and t-PA enhancement of thrombolysis (PATENT) trial. J Am Coll Cardiol. 1995;26:374–379.
We are grateful to Drs Gurewich and Liu for raising several interesting and important issues regarding our first report of a randomized, double-blind, controlled trial of intra-arterial pro-urokinase (rpro-UK) in ischemic stroke (PROACT).R1 The use of heparin anticoagulation in this study had a significant impact on both recanalization efficacy and hemorrhagic transformation. The interactions between pro-urokinase and heparin both in vitro and in vivo were indeed known to us during the trial design period. The heparin dosing was not adjusted for the purposes of augmenting pro-UK activity, however. A range of heparin dosages and infusion schedules are used for diagnostic angiography and microcatheter placement currently, but no consensus exists. The heparin dose rates are often chosen empirically. In discussion among the neurointerventional collaborators in this project, it was decided that a heparin dose of 100 IU/kg bolus (maximum, 10 000 IU) followed by 1000 IU/h intravenous infusion for 4 hours would be adequate to prevent catheter-dependent thrombosis. However, during the early stages of the trial, the frequency of hemorrhagic transformation suggested that the heparin dosing be examined more carefully. The subsequent decrease in heparin dose was accompanied by a decrease in hemorrhage and recanalization efficacy.R1 Albeit with low numbers of patients, the frequency of symptomatic brain hemorrhage in the low heparin dose cohort (6.7%) was not apparently different from that of intravenous rtPA in the National Institutes of Neurological Diseases and Stroke study,R2 despite a longer time to treatment and the inclusion of proximal middle cerebral artery strokes in PROACT. From that experience and the known in vivo effects of rpro-UK and heparin in other arenas indicated by Drs Gurewich and Liu, we would concur that dosing of heparin in the face of rpro-UK infusions in the central nervous system must be performed with caution.
The heparin dosing for PROACT II, the follow-on trial of intra-arterial infusion of 9 mg rpro-UK in 180 patients now in progress, also attempts to balance the risk of hemorrhage and efficacy benefit. Here, a higher dose of rpro-UK (9 mg) has been combined with the lower dose rate of heparin used in PROACT (2000 IU bolus followed by 500 IU/h for 4 hours). As of late February 1998, 146 patients have been recruited, for whom hemorrhagic transformation and serious adverse events, carefully monitored by the External Safety Committee, have thus far not exceeded prospectively established safety rules. We concur with Drs Gurewich and Liu that care must be taken to restrict the dosage of heparin to prevent untoward complicating ischemia-related hemorrhages with rpro-UK but not to allow catheter-related thrombosis.