Jian-ning Liu, PhD,
Beth Israel Deaconess Medical Center,
Harvard Medical School,
Boston, Massachusetts
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.
References
1.
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.
2.
Shields RW Jr, Laureno R, Lachman T, Victor M.
Anticoagulant-related hemorrhage in acute cerebral
embolism. Stroke. 1984;15:426–437.
3.
International Stroke Trial Collaborative Group.
The International Stroke Trial (IST): a randomised trial of
aspirin, subcutaneous heparin, both, or neither among 19,435 patients
with acute ischaemic stroke. Lancet. 1997;349:1569–1581.[Medline]
[Order article via Infotrieve]
4.
Burke SE, Lubbers NL, Nelson RA, Henkin J.
Recombinant pro-urokinase requires heparin for optimal clot
lysis and restoration of blood flow in a canine femoral artery
thrombosis model. Thromb Haemost. 1993;69:375–380.[Medline]
[Order article via Infotrieve]
5.
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.[Abstract]
6.
Weaver WD, Hartmann JR, Anderson JL, Reddy PS,
Sobolski JC, Sasahara AA. New recombinant glycosylated
prourokinase for treatment of patients with acute myocardial
infarction. J Am Coll Cardiol. 1994;24:1242–1248.[Abstract]
7.
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.
8.
Huber K, Resch I, Rosc D, Probst P, Kaindl F, Binder
BR. Heparin-induced increase of t-PA antigen plasma levels in
patients with unstable angina: no evidence for clinical benefit of
heparinization during the initial phase of treatment.
Thromb Res. 1989;55:779–784.[Medline]
[Order article via Infotrieve]
9.
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.
10.
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.[Abstract]
The Scripps Research Institute
University of California, San Francisco
The Cleveland Clinic Foundation
University of California, San Francisco
Hamilton Civic Hospitals Research Centre,
and the PROACT Investigators
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).1 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.1 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,2 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.
References
1.
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 pro-urokinase by direct
arterial delivery in acute middle cerebral artery
stroke. Stroke. 1998;29:4–11.
2.
The NINDS rt-PA Stroke Study Group. Tissue
plasminogen activator for acute
ischemic stroke. N Engl J Med. 1995;333:1581–1587.
© 1998 American Heart Association, Inc.
Letters to the Editor
Intra-arterial Pro-urokinase in Ischemic Stroke
Response
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  A. Furlan, R. Higashida, L. Wechsler, M. Gent, H. Rowley, C. Kase, M. Pessin, A. Ahuja, F. Callahan, W. M. Clark, et al. Intra-arterial Prourokinase for Acute Ischemic Stroke: The PROACT II Study: A Randomized Controlled Trial JAMA, December 1, 1999; 282(21): 2003 - 2011. [Abstract] [Full Text] [PDF]
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