BIVALIRUDIN FOR ENDOVASCULAR INTERVENTION IN
ACUTE ISCHEMIC STROKE: CASE REPORT
Mark R. Harrigan, M.D.
Department of Neurosurgery and
Toshiba Stroke Research Center,
School of Medicine and
Biomedical Sciences, University at
Buffalo, The State University of
New York, Buffalo, New York

Elad I. Levy, M.D.
Department of Neurosurgery and
Toshiba Stroke Research Center,
School of Medicine and
Biomedical Sciences, University at
Buffalo, The State University of
New York, Buffalo, New York

Bernard R. Bendok, M.D.
Department of Neurosurgery and
Toshiba Stroke Research Center,
School of Medicine and
Biomedical Sciences, University at
Buffalo, The State University of
New York, Buffalo, New York

L. Nelson Hopkins, M.D.
Department of Neurosurgery and
Toshiba Stroke Research Center,
School of Medicine and
Biomedical Sciences, University at
Buffalo, The State University of
New York, Buffalo, New York
Reprint requests:
L. Nelson Hopkins, M.D.,
Department of Neurosurgery,
University at Buffalo, Kaleida
Health, 3 Gates Circle, Buffalo, NY
14209-1194.
Email: mharrigan@buffns.com
Received, March 13, 2003.
Accepted, May 21, 2003.

OBJECTIVE AND IMPORTANCE: Intra-arterial thrombolysis has been demonstrated to
improve recanalization and outcomes among patients with acute ischemic stroke.
However, thrombolytic agents have limited effectiveness and are associated with a
significant risk of bleeding. Bivalirudin is a direct thrombin inhibitor that has been
demonstrated in the cardiology literature to have a more favorable efficacy and
bleeding profile than other antithrombotic medications. We report the use of bivalirudin during endovascular treatment of acute stroke, when hemorrhagic complications
are not uncommon.
CLINICAL PRESENTATION: A 71-year-old woman with atrial fibrillation presented
with right hemiparesis and aphasia and was found to have a National Institutes of
Health Stroke Scale score of 10. Computed tomographic scans revealed no evidence
of intracranial hemorrhage, aneurysm, or ischemic stroke. Cerebral angiography revealed thromboembolic occlusion of the superior division of the left middle cerebral
artery.
INTERVENTION: For anticoagulation, a loading dose of bivalirudin was intravenously
administered before the interventional procedure, followed by continuous infusion.
Attempts to remove the clot with an endovascular snare failed to induce recanalization
of the vessel. Bivalirudin was then administered intra-arterially. Immediate postprocedural angiography demonstrated restoration of flow in the left middle cerebral artery.
Repeat computed tomographic scans demonstrated no intracranial hemorrhage. The
patient’s hemiparesis and aphasia were nearly resolved and her National Institutes of
Health Stroke Scale score was 2 at the time of her discharge 5 days later.
CONCLUSION: To our knowledge, this is the first report of the use of bivalirudin for
treatment of acute ischemic stroke. Bivalirudin may be a useful agent for intravenous
anticoagulation and intra-arterial thrombolysis in this setting.
KEY WORDS: Acute stroke, Bivalirudin, Endovascular, Intra-arterial thrombolysis
Neurosurgery 54:218-223, 2004

I

DOI: 10.1227/01.NEU.0000097556.08044.1F

ntra-arterial thrombolytic therapy for
acute ischemic stroke has been demonstrated in randomized controlled studies
to be effective for selected patients (10, 13).
However, recanalization with intra-arterial
thrombolysis is unsuccessful for up to 25 to
40% of arterial occlusions (1, 5), and intraarterial thrombolytic therapy carries a significant risk of bleeding complications. Symptomatic intracerebral hemorrhage occurs for
approximately 10 to 15% of patients who undergo intra-arterial thrombolytic therapy for
stroke (10, 14), and mortality rates in this setting can reach 83% (14). Alternative approaches are needed.
Bivalirudin (Angiomax; The Medicines
Company, Cambridge, MA) is a synthetic di-

218 | VOLUME 54 | NUMBER 1 | JANUARY 2004

www.neurosurgery-online.com

rect thrombin inhibitor that has been extensively used as an alternative to heparin in
coronary interventions. Bivalirudin has several advantages over heparin, including a
higher specificity for thrombin inhibition and
a shorter half-life (3). In a clinical trial comparing bivalirudin with heparin for use in coronary angioplasty, bivalirudin was associated
with a lower risk of bleeding complications
than was heparin (4). Unlike heparin, bivalirudin inhibits both circulating and fibrin-bound
thrombin (29), suggesting that bivalirudin
might have thrombolytic activity. We report a
case in which bivalirudin was administered
intravenously, instead of heparin, during an
endovascular intervention for treatment of
acute stroke and was administered intra-

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BIVALIRUDIN FOR ACUTE STROKE

arterially for thrombolysis of a clot that was resistant to mechanical thrombolysis.

CASE REPORT
History and Examination Findings
A 71-year-old woman with a history of chronic atrial fibrillation that required warfarin treatment underwent a colon
polypectomy. The warfarin therapy had been discontinued for
1 week before the surgical procedure, which was performed
without incident. Ten days after surgery, while the patient
was recovering at home and before she resumed taking warfarin, she developed dense right hemiplegia and expressive
aphasia. She was brought to the emergency room at our facility, and an examination revealed aphasia and right hemiparesis. The patient’s National Institutes of Health Stroke Scale
score was 10. Computed tomographic scans demonstrated no
evidence of intracranial hemorrhage, aneurysm, or ischemic
stroke (Fig. 1). Cerebral angiography demonstrated occlusion
of the superior division of the left middle cerebral artery
(MCA) (Fig. 2). Because of the patient’s significant neurological impairment and because her symptoms began approximately 4 hours before an arterial occlusion was identified in
the angiographic study, we elected to treat the lesion with
intra-arterial thrombolysis. The patient met all published criteria for the use of intra-arterial thrombolytic therapy (10, 13).

FIGURE 2. Initial angiogram. Anteroposterior (A) and lateral (B) digital
subtraction images demonstrate abrupt occlusion of the superior division
of the MCA (arrow). A large anterior temporal branch and the inferior
division of the MCA bifurcation can be observed. A paucity of distal MCA
branch filling can be observed in the lateral view (B).

Procedure
Angiographic assessment of the left common carotid artery,
with local anesthesia, demonstrated occlusion of the superior
division of the left MCA. Bivalirudin (a bolus loading dose of 0.5
mg/kg, followed by continuous infusion at 1.75 mg/kg/h for the
duration of the procedure) was intravenously administered for
systemic anticoagulation. The activated coagulation time was 368
seconds after administration of the loading dose. A Prowler-Plus
microcatheter (Cordis Neurovascular, Miami Lakes, FL) with a
0.014-inch microwire (PVS-35; Precision Vascular Systems, West
Valley City, UT) was advanced through a guide
catheter into the left MCA.
An Amplatz Goose Neck microsnare (Microvena, White
Bear Lake, MN) was then
guided through the microcatheter and into the MCA
thrombus. An attempt was
made to remove the thrombus with the snare, but the
follow-up microcatheter angiogram demonstrated a
persistent filling defect (Fig.
3). The microwire and micro- FIGURE 1. Initial computed tomocatheter were then advanced graphic scan, demonstrating no evidence
as a unit through the cathe- of acute infarction, intracerebral hemorter and into the thrombus. rhage, or aneurysm.

NEUROSURGERY

FIGURE 3. Angiogram obtained after an attempt at mechanical thrombolysis. Anteroposterior (A) and lateral (B) digital subtraction images demonstrate persistent occlusion of the superior division of the MCA (arrow),
with scant filling of the MCA distal branches.

The microwire was removed, and an intra-arterial infusion of
bivalirudin (15 mg in 10 ml of heparinized saline solution) was
administered through the microcatheter, as the tip of the microcatheter was slowly withdrawn to the proximal portion of the
thrombus. The microcatheter was then removed, and the microcatheter angiogram demonstrated recanalization of the superior
division of the left MCA (Fig. 4). The catheter was removed.

FIGURE 4. Final angiogram, demonstrating the patent MCA. Anteroposterior
(A) and lateral (B) images demonstrate restoration of flow in the MCA. There is
overlap of the proximal portion of the superior division of the MCA (arrowheads) with distal filling of the MCA branches (arrows).

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HARRIGAN ET AL.

Postprocedural Course
After completion of the procedure, the patient underwent
computed tomographic scanning, which excluded the presence of intracerebral hemorrhage, and was then admitted to
the neurosurgical intensive care unit for observation. Because
of the patient’s atrial fibrillation, heparin was intravenously
administered to maintain the activated partial thromboplastin
time between 50 and 70 seconds until the prothrombin time
was within the therapeutic range with warfarin treatment. The
patient’s neurological status gradually improved in the subsequent several days, and she was discharged 5 days after
admission, with warfarin therapy. Her hemiparesis had resolved except for the presence of partial facial palsy, and her
aphasia had improved significantly. Her National Institutes of
Health Stroke Scale score at the time of discharge was 2.

DISCUSSION
Thrombin occupies a central role in the regulation of blood
coagulation, and its inhibition is a primary means of achieving
an antithrombotic and anticoagulant state. Thrombin converts
fibrinogen to fibrin by cleaving off fibrinopeptides A and B
and binds to fibrin via interaction with its fibrinogen recognition site (11). Thrombin promotes its own production by activating Factors V and VIII (9). Thrombin also activates Factor
XIII, which promotes clot stability (9). In addition, thrombin
promotes platelet activation and aggregation via thrombinmediated signaling through protease-activated receptors (12,
18, 27).
Heparin, the standard anticoagulant for neurointerventional procedures, is a glycosaminoglycan that indirectly inhibits thrombin via activation of antithrombin III, a native
anticoagulant. The effects of heparin are heterogeneous and
nonspecific. Heparin binds to endothelium, acute-phase
plasma proteins, and platelet Factor IV. Heparin is unable to
inhibit clot-bound thrombin (29) and is susceptible to neutralization by activated platelets (29). Recent studies demonstrated that heparin also binds to and activates glycoprotein
IIb-IIIa receptors on platelets, leading to platelet activation (28,
31).
Bivalirudin (previously called Hirulog) is a synthetic, 20amino acid, polypeptide analog of hirudin, a naturally occurring anticoagulant produced by the salivary glands of the
European leech (Hirudo medicinalis). Bivalirudin is a bivalent
molecule consisting of three domains, i.e., a carboxyl-terminal
domain that binds to the fibrinogen recognition site, an aminoterminal domain capable of blocking the catalytic activity of
thrombin, and a linker domain of four glycine residues (20).
Experimental studies have demonstrated that inhibition of
both sites on thrombin, the fibrinogen recognition site and the
catalytic site, markedly increases the antithrombotic potency
of bivalirudin, compared with inhibition of either site alone
(15). Bivalirudin binds to thrombin in a 1:1 stoichiometric
complex (20). After binding to thrombin, bivalirudin is slowly
cleaved by thrombin (24), which frees the active site of throm-

220 | VOLUME 54 | NUMBER 1 | JANUARY 2004

bin and leaves the remaining fragment of bivalirudin binding
competitively to the fibrinogen recognition site of thrombin
(12). This reversible interaction is thought to be the basis for
the lesser tendency of bivalirudin to cause bleeding complications, compared with heparin.
Bivalirudin reversibly inhibits all of the major actions of
thrombin, including cleavage of fibrinogen to fibrin, activation
of platelets, and activation of Factors V and VIII (21, 23).
Bivalirudin produces dose-dependent increases in activated
partial thromboplastin time, prothrombin time, and thrombin
time (6). Bivalirudin is rapidly cleared from the plasma by a
combination of renal mechanisms and proteolytic cleavage
(19) and has a relatively short half-life of 25 minutes (package
insert; The Medicines Company). Unlike the effects of heparin,
which can be reversed with protamine, there is no known
agent to reverse the therapeutic effects of bivalirudin, although there have been no reports of overdoses in clinical
trials (6).
Bivalirudin has several properties that distinguish it from
heparin. In contrast to heparin, bivalirudin does not bind to
plasma proteins, platelet Factor IV, or red blood cells (26), and
it is capable of inhibiting both circulating and fibrin-bound
thrombin (29). The property of fibrin-bound thrombin inhibition suggests that bivalirudin might have thrombolytic activity in the setting of acute thrombosis. Moreover, unlike heparin, bivalirudin does not seem to activate platelets.
In this case, we used intravenously administered bivalirudin to obtain systemic anticoagulation during the intervention. The intravenous use of bivalirudin has been widely reported in the cardiology literature. Most clinical trials of
bivalirudin compared the agent with unfractionated heparin,
administered intravenously, for the treatment of acute coronary syndromes and percutaneous coronary interventions,
and evidence has accumulated to indicate that bivalirudin has
superior antithrombotic efficacy and is associated with fewer
bleeding complications. A meta-analysis of six trials that compared bivalirudin with heparin among 5674 patients with
acute coronary syndromes demonstrated a 27% reduction in
the rate of death or myocardial infarction and a 59% reduction
in the rate of major bleeding episodes among patients treated
with bivalirudin (16). In a randomized trial of 17,073 patients
who underwent intravenous thrombolytic therapy for acute
myocardial infarctions, patients who received bivalirudin
demonstrated a 30% lower rate of reinfarction, compared with
patients who received heparin (30). In a double-blind, randomized trial of 4312 patients who underwent coronary artery
angioplasty for treatment of unstable or postinfarction angina,
patients who received bivalirudin demonstrated a 22% reduction in myocardial ischemic complications and a 62% reduction in the relative risk of clinically significant bleeding, compared with patients who received heparin (4). A randomized
trial of 1056 patients who underwent percutaneous coronary
interventions in combination with the provisional use of glycoprotein IIb-IIIa inhibitors compared bivalirudin and heparin
(17). There was a 20% reduction in the rate of the composite
clinical end point of death, myocardial infarction, repeat re-

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BIVALIRUDIN FOR ACUTE STROKE

vascularization, or major bleeding in the bivalirudin group,
compared with the heparin group.
The activated coagulation time of approximately 350 seconds during the procedure in the case reported here corresponds to the optimal activated coagulation time range (350–
375 s) that has been determined for percutaneous coronary
interventions (7). The primary disadvantage of bivalirudin is
the lack of an agent to reverse its anticoagulant effects. Bivalirudin should therefore be used with caution among patients
with intracranial vascular lesions and only in situations in
which the perceived risk of vessel thrombosis exceeds that of
lesion rupture during the procedure.
In this case, we also used intra-arterially administered bivalirudin for thrombolysis. To our knowledge, this is the first
report of the intra-arterial use of bivalirudin. Fibrinolytic
agents were demonstrated in randomized trials to yield significantly higher rates of recanalization (10) and improvements in neurological outcomes (13) in acute ischemic stroke.
Mechanical clot disruption (2, 22, 25) and snare removal (8) are
adjunctive maneuvers to reopen occluded vessels in stroke.
Mechanical techniques offer the potential advantage of decreasing the dose of, or even the need for, fibrinolytic agents.
In this case, it is possible that the attempt at snare removal
macerated the thrombus and effectively increased the surface
area available for thrombolysis with intra-arterial infusion of
bivalirudin.

CONCLUSION
Intravenously administered bivalirudin is an established
anticoagulant for cardiological interventions with numerous
advantages, compared with intravenously administered heparin, in terms of efficacy and reduction of hemorrhagic complications. It is a potential alternative to intravenously administered heparin for neuroendovascular procedures. Intraarterially administered bivalirudin may be an effective
thrombolytic agent in acute ischemic stroke.

DISCLOSURE
LNH receives research support from and is a consultant for
Cordis. He also is a consultant for and has a financial interest
in Precision Vascular Systems.

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30. White H: Thrombin-specific anticoagulation with bivalirudin versus heparin
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Acknowledgments
We thank Paul H. Dressel for preparation of the illustrations.

COMMENTS

H

arrigan et al. have submitted an exciting report detailing
the use of a new thrombin-inhibiting agent for the intraarterial treatment of an acute thromboembolic event. The article is very well written, and the discussion is appropriately
detailed. The authors have made an important contribution.
The only point left unclear by the article revolves around
why the authors selected this particular patient for treatment
with bivalirudin. I suspect that this experienced group sees
many patients with acute stroke who are candidates for intraarterial thrombolysis. Were there any unique issues in this
case that led to the authors’ choice of this novel agent? Future
selection criteria for the use of this agent would have been a
welcome and important addition to the Discussion section.
Are the authors recommending bivalirudin as a first-line option for intra-arterial thrombolysis in all patients with acute
intracranial arterial occlusion, or will they continue to use
more traditionally accepted agents, such as tissue plasminogen activator? Similarly, it would have been worthwhile for
the authors to have commented on whether this patient was
treated as part of an institutional review board-approved
protocol.
Despite these issues, the authors have provided us with an
important new option in the management of patients with
acute intracranial arterial occlusion. We look forward to future
contributions from this group that further elucidate the role of
this agent in the management of acute stroke.
Eric S. Nussbaum
Minneapolis, Minnesota

222 | VOLUME 54 | NUMBER 1 | JANUARY 2004

H

arrigan et al. describe their experience in using bivalirudin administered both intra-arterially and intravenously
in a patient who presented with an acute ischemic event
caused by a soft clot. As the authors discuss, this is a synthetic
amino acid polypeptide that has been used extensively in the
realm of interventional cardiology and has been found to be
markedly beneficial in reducing reocclusion and also reducing
the incidence of hemorrhagic complications.
Quite interestingly, with no heparin administered, the activated clotting time was dramatically elevated to well over 300
seconds. Despite that effect, recanalization seems to be excellent in hemorrhagic idiopathies and, particularly in the cardiology patient population, has been really quite minimal. This
is certainly one of the problems with intra-arterial and intravenous thrombolysis in hemorrhagic conversion of an ischemic lesion, and obviously, the intracranial catastrophe that
often results is worse than the problem being treated and
makes a bad situation worse.
If recanalization can be achieved and hemorrhagic complications reduced, this drug certainly will have a role in the
treatment of acute ischemic stroke. As many investigators
know, the hemorrhagic conversion is often a problem of delayed intervention or not knowing the time of the original
ictus, and patients are then treated beyond the “6-hour window” for safe intervention. This drug in particular is something that should become very familiar to all endovascular
therapists who are treating acute ischemic stroke, and we look
forward to hearing more from this group regarding their
continued experience.
Robert H. Rosenwasser
Philadelphia, Pennsylvania

S

ince first being developed in 1994, bivalirudin has saved
many lives. Originally developed for the treatment of coronary angioplasty, the early data suggested only marginal
advantages and unfavorable economics compared with heparin. The second life of the drug began in 1997, when the agent
was licensed to a new sponsor and a less expensive manufacturing process was developed. These events, combined with a
high-profile reanalysis of the early data on angioplasty for
unstable or postinfarction angina, resulted in renewed interest
in this direct thrombin inhibitor as an alternative to heparin.
As Harrigan et al. point out, the interest grows from the fact
that, unlike heparin, bivalirudin inhibits both fluid-phase and
clot-bound thrombin, is not bound by plasma proteins, and is
not neutralized by platelet factors. Moreover, bivalirudin inhibits platelet activation by noncompetitively and reversibly
interfering with active-site binding of the thrombin receptor
by thrombin, which in turn blocks glycoprotein IIb/IIIa receptor activation and fibrinogen-dependent platelet aggregation.
Heparin, by comparison, has been shown to induce glycoprotein IIb/IIIa receptor activation despite its antithrombin IIIdependent anticoagulant effect. The overall result of these
differences is that bivalirudin is not only an anticoagulant but
also an antiplatelet agent that has markedly more predictable

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BIVALIRUDIN FOR ACUTE STROKE

pharmacokinetics and is associated with lower rates of bleeding. In fact, a 6000-patient Phase III trial of bivalirudin versus
heparin plus glycoprotein IIb/IIIa receptor antagonists was
recently published (1), showing equivalence in the setting of
coronary stenting completely driven by a reduction in major
bleeding events for the novel therapy. These data certainly
support the experimental use of bivalirudin in neurointerventional procedures, especially when heparin is contraindicated
or bleeding complications are expected.
Although our results are unpublished, we have performed
procedures in patients with anti-heparin antibodies using
bivalirudin with good results. Whether bivalirudin turns out
to be better than heparin for patients undergoing intracranial
thrombolysis remains to be seen, but the authors have suggested this possibility. They should also be encouraged to
further explore their hypothesis that the drug is capable of
actually lysing clot when injected directly into the thrombus.
Although disaggregation of existing thrombi would not be
expected on the basis of the known activities of the drug, it is
possible that the catheter mechanically disrupted the clot to

some degree and the bivalirudin facilitated reflow by binding
the thrombin on the clot surface. This debate could certainly
be addressed in ex vivo models. If verified, it could turn out
that even if intravenous bivalirudin is no better than heparin,
new-generation heparinoids, or drugs in development such as
inhibitors of tissue factor or Factor Xa, it may have an important intra-arterial role in cerebral clot extraction when immediate and early rethrombosis remains an important problem.
E. Sander Connolly, Jr.
Sean D. Lavine
New York, New York

1. Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD,
Sarenbock IJ, Cohen DJ, Spriggs D, Ebrahimi R, Keren G, Carr J, Cohen EA,
Betriu A, Desmet W, Kereiakes DJ, Rutsch W, Wilcox RG, de Feyter PJ,
Vahanian A, Topel EJ: Bivalirudin and provisional glycoprotein IIb/IIIa
blockade compared with heparin and planned glycoprotein IIb/IIIa blockade
during percutaneous coronary intervention: REPLACE-2 randomized trial.
JAMA 289:853–863, 2003.

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not only information about the many activities of the WFNS, but also opportunities for
young neurosurgeons all around the world to communicate with each other and to
participate in web-based educational activities. These include interesting cases, clinicopathological conferences, and the web-based journal Critical Reviews, the official electronic journal of the WFNS. We hope you will participate. Those of you who would like
to become more involved in the WFNS web site activities are very welcome to volunteer
your efforts, which will be much appreciated.
Edward R. Laws, Jr.
President

NEUROSURGERY

VOLUME 54 | NUMBER 1 | JANUARY 2004 | 223