Clinical

Neuroradiology Review Article

Acute Stroke Therapy 1981–2009*

Bernd Eckert1

Abstract
This article includes a review of major intravenous and endovascular stroke trials, treatment options, and future aspects
of acute stroke treatment in hemispheric and vertebrobasilar stroke. Since the invention of local intraarterial thrombolysis
by Hermann Zeumer in 1981, acute stroke diagnostics and treatment have undergone dramatic improvement. This article
addresses major topics in recent stroke treatment debates: optimization of patient selection, intravenous versus endovas-
cular therapy, time window limitations, combined treatment with intravenous/intraarterial bridging therapies (intrave-
nous/intraarterial recombinant tissue plasminogen activator [rtPA] bridging and intravenous glycoprotein IIb/IIIa in-
hibitor/intraarterial rtPA bridging) and modern endovascular treatment modes like percutaneous transluminal angioplasty
(PTA)/stenting and mechanical thrombectomy devices. Modern acute stroke therapy networks should optimize their non-
invasive diagnostic capacity to early identify candidates for endovascular therapy with rapid access to specialized neuro-
endovascular centers using standard protocols. The most promising approach in acute stroke treatment seems to be a
combination of intravenous and endovascular revascularization procedure, combining early treatment initiation with di-
rect clot manipulation and PTA/stenting in underlying stenosis with atherothrombotic occlusions. Further randomized
studies comparing intravenous and endovascular treatment, mainly in the anterior circulation, have to be expected and
need wide support of the neurologic and neuroradiologic stroke community.

Key Words: Endovascular stroke therapy · Cerebral thrombolysis · Acute stroke · GP inhibitor · rtPA

Clin Neuroradiol 2009;19:8–19

DOI 10.1007/s00062-009-8033-0

Therapie des akuten Schlaganfalls 1981–2009

Zusammenfassung
Seit Einführung der lokalen intraarteriellen Thrombolyse durch Hermann Zeumer 1981 haben sich die Diagnostik und die
Behandlung des akuten Schlaganfalls dramatisch gebessert. Der Artikel umfasst die Ergebnisse der wichtigsten intravenösen
und endovaskulären Schlaganfallstudien, Behandlungsoptionen und zukünftige Aspekte der akuten Schlaganfalltherapie in
der vorderen und hinteren Zirkulation. Folgende Themen werden in der aktuellen Diskussion angesprochen: Optimierung der
Patientenauswahl, intravenöse versus endovaskuläre Therapie, Betrachtungen zum Zeitfenster, die Kombination von intra-
venöser und intraarterieller „Bridging“-Therapie (intravenöses/intraarterielles rTPA-[rekombinanter Gewebe-Plasminogen-
aktivator-]Bridging und intravenöses-Glykoprotein IIb/IIIa mit intraarterielles rTPA-Bridging) und moderne endovaskuläre
Methoden wie PTA/Stenting und mechanische Thrombektomiesysteme. Moderne Netzwerke für die akute Schlaganfallsbe-
handlung sollten ihre nichtinvasive CT/MR-Diagnostik optimieren, um Kandidaten für die endovaskuläre Behandlung mög-
lichst früh zu erkennen und die Therapie mit assoziierten neurovaskulären Zentren schnellstmöglich einzuleiten. Zuneh-
mende Bedeutung erlangen Kombinationstherapien mit intravenöser und endovaskulärer Therapie, um einen möglichst
frühen Behandlungsbeginn mit direkter Thrombusmanipulation und ggf. PTA/Stenting bei zugrundeliegenden Stenosen zu
gewährleisten. Randomisierte Studien von intravenöser und endovaskulärer Therapie sind insbesondere in der vorderen
Zirkulation erforderlich und benötigen die breite Unterstützung der neurologischen und neuroradiologischen „stroke com-
munity“.

Schlüsselwörter: Endovaskuläre Schlaganfalltherapie · Zerebrale Thrombolyse · Akuter Schlaganfall · GP-Inhibitor · rtPA

*Dedicated to Professor Hermann Zeumer, MD, on the occasion of his 65th birthday
and his retirement.

1
Department of Neurology, Asklepios Hospital Altona, Hamburg, Germany.

Received: August 29, 2008; revision accepted: November 3, 2008

8 Clin Neuroradiol 2009 · No. 1 © Urban & Vogel

Eckert B. Acute Stroke Therapy 1981–2009

Introduction and became a milestone in acute stroke treatment,

It was in 1981, neurology still being a conservative,
“contemplative” discipline, and interventional neuro-
radiology at its very beginning, when a 22-year-old fe-
male table tennis player presented with the symptoms
of an acute basilar occlusion in the University Hospital
of Aachen, Germany. Hermann Zeumer had already
focused his clinical and research activity in acute stroke
treatment with regard to treatment results of throm-
bolysis in cardiology. After diagnostic angiography he
decided not only to watch and assume progressive
brain stem symptoms, but to perform the first local in-
traarterial thrombolysis (LIT) worldwide. The treat-
ment resulted in a dramatic neurologic improvement
published in 1982 in Deutsche Medizinische Wochen-
schrift [1]. This first endovascular stroke treatment in
conjunction with diagnostic CT imaging was the start-
ing signal for most modern aspects of acute stroke di-
agnostics and therapy. His ideas, created in Aachen
and Hamburg within the last 3 decades, have been a
major pacemaker in further international stroke re-
search and therapy. New concepts were always inte-
grated in a pathophysiologic concept respecting scien-
tific evidence. It remained his ambition to convince his
neurologic colleagues and create common studies and
further evidence in the neuroradiologic and neurologic
stroke community. As a person who combined funda-

Table 1. Anterior circulation: randomized thrombolysis trials in hemispheric stroke. ATLANTIS: Alteplase Thrombolysis for Acute Noninterventional
Therapy in Ischemic Stroke; DIAS: Dynamic Image Analysis System; ECASS: European Cooperative Acute Stroke Study; ITT: intention-to-treat ana-
lysis; IVT: intravenous thrombolysis; LIT: local intraarterial thrombolysis; NINDS: National Institute of Neurological Disorders and Stroke; PROACT:
Prolyse in Acute Cerebral Thromboembolism; rtPA: recombinant tissue plasminogen activator; TP: target population analysis after exclusion of CT
protocol violations (17.4%); UK: urokinase.

Trial Median NIHSS on admission Good neurologic Symptomatic

outcome 90 days bleeding rate
n Treatment/agent Placebo/verum Time to treatment Stroke imaging Placebo/verum Placebo/verum

NINDSa [7] 624 IVT/rtPA 15/14 <3h Native CCT 26.0%/39.0% 0.6%/6.4%
ECASS I: ITT [8] 620 IVT/rtPA 12/13 <6h Native CCT 29.3%/35.7% 6.5%/19.8%b
ECASS Ia: TP [8] 511 IVT/rtPA 12/13 <6h Native CCT 29.2%/40.9% 5.9%/15.3%b
ECASS II [9] 800 IVT/rtPA 11/11 <6h Native CCT 36.6%/40.3% 3.4%/8.8%
ECASS IIIa [10] 821 IVT/rtPA 9/10 3–4.5 h Native CCT 52.4%/45.2% 0.2%/2.4%
ATLANTIS [11] 613 IVT/rtPA 10/10 3–5 h Native CCT 32.0%/34.0% 1.1%/7.0%
DIAS 2 [13] 186 IVT/desmoteplase 9/9 3–9 h Multimodal MR or CT 46%/90 µg/kg: 47.4% 0% 90 µg/kg: 3.5%
46%/125 µg/kg: 36.4% 0%/125 µg/kg: 4.5%
PROACTa [12] 180 LIT/r-proUK 17/17 <6h CT and angiography 25.0%/40.0% 2.0%/10.0%

a
significant treatment benefit
b
parenchymal hematoma rate

Table 2. Major treatment studies in acute vertebrobasilar occlusion. GPI: glycoprotein IIb/IIIa inhibitor; ICH: intracranial hemorrhage; IVT: intra-
venous thrombolysis; LIT: local intraarterial thrombolysis; NA: not available; PTA: percutaneous transluminal angioplasty; TIMI: thrombolysis in
myocardial infarction.

Study Hacke et al. Brandt et al. Eckert et al. Arnold et al. Lindsberg et al. Eckert et al.a Schulte-Altedorne-
1988 [2] 1996 [14] 2002 [15] 2004 [16] 2004 [17] 2005 [6] burg et al.a 2006
[18]

n 43 51 83 40 50 47 180
Treatment LIT LIT LIT LIT IVT GPI i.v., LIT, LIT
PTA/stent
TIMI 2/3 recanalization rate 44% 51% 66% 80% 52% 72% 74%
Mortality all 67% 68% 60% 42% 40% 38% 43%
Good outcome rate 23% 20% 23% 35% 24% 34% NA
Parenchymal hematoma symptomatic ICH 9% 6% 8% 5% 14% 13% 14%

a
multicenter assessment

Clin Neuroradiol 2009 · No. 1 © Urban & Vogel 9

Eckert B. Acute Stroke Therapy 1981–2009
mental knowledge of neurology and neuroradiology
he teached his pupils to integrate clinical and neurora-
diologic findings in order to create a treatment ratio-
nale in every individual case to indicate or withdraw
further endovascular approach. His treatment maxim
consisted in clear and consequent concepts (“as easy
and as fast as possible”) based on standard protocols
rather than “interventional artistics” at any price. Dur-
ing a common endovascular stroke treatment, he
pushed and inspired everybody in the angio suite with
his strength to fight the thrombus and his enthusiasm
in case of success. Acute stroke interventions with
Hermann Zeumer was the translation of “time is brain”
in daily neuroradiologic practice.
His main research activity included type and dosage
of plasminogen activator therapy [2, 3], combining dif-
ferent pharmacological approaches to speed up recana-
lization like the adjunction of lys-plasminogen [4] and
glycoprotein (GP) IIb/IIIa inhibitor (GPI) agents [5],
optimization of patient selection with noninvasive acute
stroke imaging, continuous improvement of endovascu-
lar techniques like percutaneous transluminal angio-
plasty (PTA)/stenting [6], and mechanical thrombecto-
my systems.
This article will address main actual topics and de-
bates in endovascular stroke treatment. The results of
major thrombolysis trials in the anterior circulation are
summarized in Table 1 [7–13]. Table 2 presents major
single-arm studies in acute vertebrobasilar occlusion
(VBO) [2, 6, 14–18].
Patient Selection
Modern noninvasive stroke imaging with multimodal
MRI and CT imaging providing high-quality informa-
tion about occlusion type, irreversible infarct core, and
penumbral tissue (see article in this issue by Kucinski
[19]) has replaced catheter angiography as diagnostic
tool in acute stroke.
In intravenous thrombolysis (IVT) trials, with pa-
tient selection by native CT scan to exclude hemorrhage
and major infarct signs, the number needed to treat
(NNT) to prevent one disabling stroke was found to be
10.7 < 3 h, 13 < 6 h and increased to 26 with treatment
3–6 h and even to 100 with treatment 4.5–6 h after symp-
tom onset [20, 21]. The recently published European
Cooperative Acute Stroke Study III (ECASS III) re-
vealed an NNT of 14 in the 3- to 4.5-h treatment window
[10]. With MRI-based patient selection for IVT, an
NNT of approximately 5 may be achieved [22, 23]. In a
10
multicenter data analysis MRI-based thrombolysis
within 6 h was found to be safer and potentially more
efficacious than standard CT-based thrombolysis within
3 h despite significantly longer time windows and sig-
nificantly higher baseline NIHSS scores [24].
The Prolyse in Acute Cerebral Thromboembolism
II (PROACT II) Trial with LIT within 6 h after symp-
tom onset revealed an NNT of 7. The results might be
due to optimized patient selection with angiographic
evidence of middle cerebral artery (MCA) occlusion.
294/474 patients were excluded although they fulfilled
the National Institute of Neurological Disorders and
Stroke (NINDS) criteria (acute neurologic deficit, no
hemorrhage on CT) [12].
These results strongly indicate the importance of
patient selection criteria based on modern acute stroke
imaging for individual therapeutic decisions and further
stroke therapy trials.
Intravenous versus Endovascular Therapy
Anterior Circulation
A randomized trial, comparing intravenous and endo-
vascular therapy has not been performed so far. The
IMS III (Interventional Management of Stroke III) Tri-
al randomizing IVT versus IVT/LIT bridging therapy
has started enrollment of projected 900 patients in June
2006 [25]. Individual-based therapeutic decision about
the treatment mode depends on clinical state, time to
treatment, size of the irreversible infarct core, evidence
of penumbral tissue, occlusion type, and, last but not
least, the availability of endovascular treatment. The
therapy recommendations by the „Hamburger Arbeits-
gemeinschaft Schlaganfall“ (HAGS) are summarized in
Figure 1. Despite ECASS III results HAGS consensus
recommendations still differ in < 3 h and > 3 h treatment
window.
Within 3 h of symptom onset the exclusion of hem-
orrhage in a native CT scan is sufficient to initiate IVT.
However, multimodal MRI or CT imaging even within
3 h provide additional information and may switch the
therapeutic decision to primary endovascular access in
case of carotid T occlusion (CTO) or unexpected VBO.
After 3 h of symptom onset, stroke imaging requires
multimodal performance. Exclusion of major infarct signs
(less than one third of MCA territory) and the evidence of
penumbral tissue are prerequisites to perform any revas-
cularization therapy. Treatment decision mainly depends
on the type of vessel occlusion and local logistics with or
without the access of neuroendovascular therapy.
Clin Neuroradiol 2009 · No. 1 © Urban & Vogel
Eckert B. Acute Stroke Therapy 1981–2009
Figure 1. Treatment consensus “Hamburger Arbeitsgemeinschaft Schlaganfall” (HAGS, http://
www.hamburg-gegen-den-Schlaganfall.de). BAO: basilar artery occlusion; CTO: carotid T occlu-
sion; MCA: middle cerebral artery.
Occlusion Type
Intracranial CTO (Figure 2) with mortality rates of >
50% [26] to 63% [27] after LIT remain a therapeutic
problem. Mechanical thrombectomy was shown to be a
therapeutic option with recanalization rates up to 63%
and good clinical outcome in 39% in recanalized patients
in the MERCI 1 Trial [28]. 90 day mortality rate was 30%
in recanalized versus 73% in nonrecanalized patients. In
case of recanalization failure, early craniectomy has to be
considered in order to avoid fatal infarct swelling.
Treatment in tandem ICA/MCA occlusions due to
proximal internal carotid artery (ICA) stenosis with
periocclusional MCA embolism remain controversial.
Small series with LIT in the MCA via the occluded ICA
(n = 8) [27] or even IVT (n = 12) [22] revealed favorable
outcome rates of 40–50%. A recent MRI-based study
comparing IVT in isolated MCA (n = 24) versus tandem
ICA/MCA (n = 14) occlusions within 6 h with compa-
rable initial perfusion (246 vs. 246 ml) and diffusion le-
sion volume (22 ml vs. 21 ml) revealed similar infarct
volumes (30 vs. 39 ml) and favorable outcome rates
(50% vs. 46%). The authors concluded, that there ap-
pears to be no evidence to exclude patients with tandem
ICA/MCA occlusion from IVT [29]. In case of sponta-
neous proximal ICA recanalization at the site of steno-
Clin Neuroradiol 2009 · No. 1 © Urban & Vogel
sis, PTA/stenting can be performed
in a second treatment session. Acute
ICA stenting with MCA revascular-
ization bears the risk of hemispheric
reperfusion hemorrhages. Howev-
er, in a combined therapy study with
acute proximal ICA stenting and
endovascular MCA treatment, suc-
cessful ICA stenting was performed
in 21/25 patients and good MCA re-
canalization was achieved in 11/25
patients. At 3 months 56% of pa-
tients had a favorable outcome.
Mortality was 20% [30].
In proximal MCA occlusion
(M1- up to proximal M2 occlusions)
thrombolysis in myocardial infarc-
tion II/III (TIMI II/III) recanaliza-
tion rates with LIT have shown to
be 70–80% [27, 31] with good out-
come rates of 50%. With MRI-based
IVT within 6 h of treatment onset,
TIMI I–III recanalization within 24
h could be attempted in 23/30 pa-
tients [22]. A recent study compared LIT within 6 h and
IVT within 3 h in two different stroke centers in patients
with hyperdense middle cerebral artery sign (HMCAS)
on the native CT scan. Stroke severity at baseline and
patient age were similar in both groups. LIT was associ-
ated with a significantly higher rate of good outcome
(53% vs. 23%) and a lower mortality rate (7% vs. 23%),
despite a significant delay in treatment onset (mean
time to treatment: LIT: 244 ± 63 min; IVT: 156 ± 21 min)
[32]. A randomized study comparing IVT and endovas-
cular treatment is warranted in this frequent occlusion
type.
In distal MCA occlusion (distal M2 to M4 segments)
LIT, TIMI II/III recanalization rates were found to be
lower (64–73%) [27, 31] but the favorable outcome rate
was even better than in proximal MCA occlusions. Also
with MRI-based IVT [21] peripheral MCA occlusion
type was associated with a favorable outcome. Thus
MCA occlusions are probably better candidates for in-
travenous therapy.
Posterior Circulation
Numerous studies have shown clinical improvement
with LIT treatment in acute VBO compared to medical
therapy (Table 2). Angiography-based IVT studies re-
11
Eckert B. Acute Stroke Therapy 1981–2009
a b
d e
vealed a poor clinical outcome with mortality rates of
70% [33, 34]. However, a recently published Finnish
IVT study with diagnosis and recanalization success
based on MR angiography (MRA) only, disclosed a
mortality rate of only 40%, a favorable outcome rate of
22%, and a recanalization rate of 52% [17]. The patient
cohort in the Finnish MR study might differ from the
cohort in LIT studies with angiographically document-
ed basilar occlusion.
Lindsberg & Mattle analyzed therapy of VBO com-
paring IVT (n = 76) and LIT (n = 344) results [34]. Re-
canalization was achieved more frequently with LIT
(65%) than with IVT (53%), but survival rates after
IVT (50%) and LIT (45%) were equal. A total of 24%
of patients treated with LIT and 22% treated with IVT
12
c
Figures 2a to 2e. Carotid T occlusion: combined therapy with i.v. tirofi-
ban, i.a. rtPA and mechanical thrombus aspiration. Treatment proce-
dure: 10:00 symptom onset (NIHSS 20); 12:45 multimodal CT revealed
carotid T occlusion, minor early hypodensities and large perfusion de-
lay in the left hemisphere (“mismatch” constellation); 13:00 i.v. tirofi-
ban application, intubation; 14:00 beginning of angiography, local rtPA
lysis and mechanical aspiration with the “Catch” system, complete re-
canalization: 17:00; clinical course: MCA infarct with moderate clinical
improvement, mRS 4 after 90 days. a–c) Superselective angiography
(AP views) via left distal ICA. a) Evidence of embolism occluding the
entire carotid T segment before endovascular therapy. b) Recanaliza-
tion of the ACA and the ICA, persistent MCA occlusion after first at-
tempt of mechanical thrombus retraction (“Catch” device) and local
40 mg rtPA application. c) Complete recanalization after second at-
tempt of thrombus retraction. d, e) Angiography via left CCA. d) Lat-
eral view, before endovascular therapy. Occlusion of the ICA, due to
carotid T embolism with collapse of the remaining ICA lumen. e) AP
view, after therapy. After carotid T recanalization, reperfusion of the
collapsed ICA lumen.
reached good outcomes (p = 0.82). Without recanaliza-
tion the likelihood of good outcome was close to nil
(2%). However, 50 of the analyzed 76 IVT cases were
included from their own MRI-based study, reducing the
significance of their review analysis.
However, if endovascular treatment is not available
or would cause a severe treatment delay, IVT seems to be
a reasonable alternative, especially in case of embolic oc-
clusion if detected by CT angiography (CTA) or MRA.
In contrast to predominant embolic occlusion in the
anterior circulation, about 40% in acute VBO is caused
by atherothrombotic occlusion due to a preexisting ste-
nosis [15, 35]. Embolic basilar occlusion may also origin
from a proximal stenosis/occlusion of the vertebral ar-
tery with arterioarterial embolism (Figure 2). In both
Clin Neuroradiol 2009 · No. 1 © Urban & Vogel
Eckert B. Acute Stroke Therapy 1981–2009
cases, endovascular therapy and PTA/stenting of the
underlying stenosis appears to be an convincing concept
rather than IVT alone. In embolic occlusions mechani-
cal thrombectomy devices (see below) offer additional
treatment options. A subanalysis of the MERCI Trial
investigated the clinical results of 27 patients with VBO
[36]. Recanalization occurred in 78% patients. Mortali-
ty was 44% and good outcomes were seen in 41%.
Thus, if available with a passable time delay, endo-
vascular therapy including GPI/recombinant tissue
plasminogen activator (rtPA) bridging, PTA/stent and
thrombectomy devices (Figure 2) is still widely consid-
ered the treatment of choice in acute VBO.
Time Window Limitations
Anterior Circulation
The NINDS Study has proven clinical benefit of IVT
within 3 h of symptom onset [7]. ECASS I, ECASS II [8,
9], and the Alteplase Thrombolysis for Acute Noninter-
ventional Therapy in Ischemic Stroke (ATLANTIS)
Study [11] failed to prove benefit in later treatment on-
set. However, in the recently published ECASS III, IVT
between 3 and 4.5 h after the onset of symptoms was as-
sociated with a modest but significant improvement in
the clinical outcomes without a higher rate of symptom-
atic intracranial hemorrhage (ICH) than reported in the
IVT Trials within 3 h [10]. The PROACT II Trial [12] in
MCA occlusion type demonstrated a significant benefit
of LIT with treatment onset up to 6 h after symptom
onset. LIT was accomplished within up to 8 h after
symptom onset.
The dose-finding phase II trial with i.v. desmoteplase
(Desmoteplase In Acute ischemic Stroke [DIAS]) based
on multimodal MR/CT imaging in the 3- to 9-h treat-
ment window demonstrated significantly higher reper-
fusion rates (up to 71.4% vs. 19.2% with placebo) and a
favorable 90-day clinical outcome in IVT patients
(13.3% with 62.5 µg/kg and 60% with 125 µg/kg vs.
22.2% of placebo-treated patients) [37]. However, the
following phase III DIAS 2 Trial failed (Table 1) [13].
The reasons have not been analyzed yet. The median
NIHSS on admission was only 9 compared to 12 in the
phase II trial (Table 1; median NIHSS on admission:
NINDS trial: 14; PROACT II Trial: 17) and suggests a
high inclusion rate of peripheral occlusions or lacunar
infarcts with a favorable spontaneous prognosis, thus
declaring the good clinical results in the placebo group.
Interventional stroke therapies with treatment on-
set in the 6- to 9-h time windows have been described
Clin Neuroradiol 2009 · No. 1 © Urban & Vogel
and should be based on individual brain vessel patholo-
gy with favorable penumbral tissue evaluation [38].
New trial results with IVT and LIT in the extended
time window using multimodal stroke imaging have to
be expected in the future.
Posterior Circulation
Stroke due to angiographically documented VBO is a
dramatic clinical event with a mortality rate approach-
ing 90% if patients are treated by standard medical ther-
apy including anticoagulation agents [2, 39, 40]. Time
window considerations carry a lower impact in the ther-
apeutic decision than in anterior circulation stroke.
The clinical success on LIT in VBO depends on
multiple factors including the clinical state, the etiology
of occlusion (atherothrombotic vs. embolic), treatment
time, and recanalization success [35]. Most LIF studies
approved recanalization as a significant treatment fac-
tor [16, 18, 35] with a positive trend in early treatment
onset.
In our own results [15] early treatment onset, how-
ever, proved to be the most important factor for suc-
cessful endovascular therapy in acute VBO. If LIT was
initiated within up to 6 h after the onset of symptoms,
the mortality rate was 52% and the favorable outcome
rate was 36%. In LIF onset after 6 h the mortality rate
increased to 70% and the favorable outcome rate de-
creased to only 7%. Furthermore, the rate of symptom-
atic bleeding seems to be increased in late treatment
onset. In five of the seven fatal PHs, LIT was initiated
6–10 h after symptom onset [15]. Cross et al. reported on
two patients treated after 72 and 79 h with a good neu-
rologic outcome [41]. These cases might reflect chronic
stages with adequate collateralization to maintain suffi-
cient flow [42]. The critical period for severe morbidity
and mortality is presumably around the time of occlu-
sion [42, 43]. Only if patients have survived this critical
period with only minimal deficits or none, and remain
stable, collateralization itself may have led to the stable
state and the effect of further endovascular treatment
might thus be predetermined.
Bridging Therapies
Stroke neurologists always worry about the treatment
delay in case of endovascular therapy. Treatment strate-
gies combining early i.v. treatment onset with subse-
quent endovascular access in a continuous emergency
protocol have become important treatment options.
One option consists in initial IVT with rtPA, early as-
13
Eckert B. Acute Stroke Therapy 1981–2009
sessment of recanalization success and following LIT
with rtPA using reduced dosages in nonrecanalized pa-
tients (IVT/LIT rtPA bridging). The second option is
early i.v. application of a platelet glycoprotein (GP) IIb/
IIIa receptor inhibitor (GPI) and subsequent LIT with
reduced dosage of rtPA (GPI/rtPA bridging, total max-
imum rtPA dosage: 40 mg). Both bridging concepts may
be combined with additional mechanical endovascular
treatment options. However, after i.v. application of
> 40 mg rtPA, additional GPI therapy is contraindicated
because severe extra- and intracranial bleeding compli-
cations have to be expected. Any case of bridging thera-
pies combining intravenous and endovascular treatment
need a very close monitoring with early transcranial
Doppler (TCD) or control CTA/MRA (within 30–60
min), tissue at risk imaging, and rapid transferal to a
neurovasular center, considering this treatment as a
continuous process to achieve recanalization within the
first treatment hours.
IVT/LIT Bridging with rtPA
In the Emergency Management of Stroke (EMS) Bridg-
ing Trial in 1999 [44], the patients were first treated in-
travenously with a dosage of 0.6 mg (per kg), followed
by an immediate angiography and subsequent further
LIT in case of permanent vessel occlusions. The patients
were randomized in an i.v./i.a. arm (n = 17) versus the
placebo/i.a. group (n = 18, i.a. therapy: 10 mg/h). The
pilot study demonstrated that i.v./i.a. bridging treatment
is feasible and provides better recanalization rate with-
out increase of bleeding complications, but was not as-
sociated with improved clinical outcomes. In another
i.v./i.a. study, patients underwent primary IVT (rtPA
dosage: 0.9 mg/kg). Transcranial color-coded duplex so-
nography (TCCD) was performed 30 min after IVT. In
non-recanalized patients IVT was stopped and subse-
quent LIT with additional application of 8–34 mg rtPA
was accomplished. In the IVT group (n = 17) 59% of
patients had a favorable outcome and in the i.v./i.a. co-
hort (n = 16) 56% had a favorable outcome. One symp-
tomatic ICH occurred in each group [45]. In a recent
study (n = 69), LIT was shown to be effective and safe
even after initial application of a full-dose i.v. rtPA ther-
apy (0.9 mg/kg). LIT consisted of reteplase (n = 56;
mean dosage 2.8 U), rtPA (n = 7; mean dosage 8.6 mg),
and urokinase (n = 6; mean dosage 700,000 U). Symp-
tomatic ICH occurred in 5.8% of patients and a favor-
able outcome was seen in 55% of patients [46]. For fur-
ther evidence the above-mentioned IMS III Study
14
randomizing IVT versus IVT/LIT bridging therapy has
started enrollment in June 2006 [25].
GPI/rtPA Bridging
Platelet GPIs induce a rapid and effective inhibition of
platelet aggregation. GPIs have been reported to pre-
serve microvascular patency in animal stroke studies
and may have neuroprotective properties [47–50]. Ad-
junctive GPI application might improve the rate and
extent of intraarterial fibrinolysis in acute stroke by
thrombolysis of the platelet thrombus (“white clot”)
and by preventing rethrombosis. Subsequent TCD dur-
ing i.v. thrombolysis has demonstrated that arterial re-
occlusion is a major contributor to secondary clinical
deterioration [50, 51]. In a recent report on LIF, a reoc-
clusion rate of 17% was documented during the inter-
vention [52]. The desired increase of plasmin induced
by plasminogen activators such as rtPA also effects an
increase of thrombin [53] with subsequent platelet acti-
vation [54]. PTA/stenting with disruption of atheroscle-
rotic plaque and endothelial erosion is another mecha-
nism that triggers platelet activation [53]. GPI impedes
platelet aggregation and inhibits platelet-induced
thrombin generation [55] with subsequent reduction of
platelet counterregulatory granule secretion of native
tPA inhibitor 1 (PAI-1) and α2-antiplasmin [56]. Finally,
GPI may increase clot porosity and decrease the elast-
icty of the platelet fibrin mesh [57] thus allowing im-
proved penetration of fibrinolytic agents.
In cerebral circulation, successful adjunctive abcix-
imab therapy after failed intraarterial fibrinolysis has
initially been described as rescue treatment in rare cases
of basilar artery rethrombosis [58, 59] and acute MCA
stroke [60]. Three main GPI agents exist: abciximab is a
specific complete receptor antibody. Tirofiban and ep-
tifibatide only bind to one specfic side of the GP IIb/IIIa
receptor and have a lower molecular weight (“small
molecules”). A major pharmacokinetic difference is the
short half-life (2–3 h) of tirofiban and eptifibatide in
comparison to abciximab (48 h). During this period the
pharmacodynamic effect cannot be antagonized. In ab-
ciximab treatment the application of platelet concentra-
tions can reverse the platelet inhibition. Successful GPI/
rt-PA bridging with i.v. tirofiban and i.v. rtPA based on
MRA has been reported in basilar artery occlusion [61]
and in MCA occlusion [62].
The multicenter FAST Study (combined local Fi-
brinolysis and intravenous Abciximab in acute verte-
brobasilar Stroke Treatment) demonstrated an im-
Clin Neuroradiol 2009 · No. 1 © Urban & Vogel
Eckert B. Acute Stroke Therapy 1981–2009

a b c
f

d e g

Figures 3a to 3g. External patient: combined therapy with i.v. tirofiban, i.a. rtPA and mechanical thrombus aspiration. Basilar embolism due to a
filiform stenosis of the right vertebral artery (VA) with arterioarterial embolism. Treatment procedure: 09:00 symptom onset (NIHSS 24); 11:15 CT
diagnosis of basilar embolism in external hospital and contact with neurovascular center; 11:30 i.v. tirofiban application, intubation and patient
transport; 13:30 (neurovascular center) beginning of angiography, local rtPA lysis and mechanical aspiration; 15:00 complete recanalization. Clini-
cal improvement, mRS 1 after 5 days. a) Subtotal right VA stenosis; occlusion of left proximal VA (not shown). b) PTA/stenting of VA stenosis; access
to intracranial vessels. c) Extended basilar embolism. d, e) Partial and complete recanalization with “PENUMBRA” thrombus aspiration system.
f, g) Control MRI (4 days) showing small pontine and cerebellar infarction.

provement of neurologic outcome and significantly
reduced mortality in combined abciximab/rtPA therapy
(FAST cohort: n = 47, median rt-PA dosage: 20 mg,
range 10–40 mg) in comparison to LIT (RtPA cohort, n
= 41, median rtPA dosage: 40 mg) [6, 63]. In case of se-
vere residual stenosis in atherothrombotic occlusions,
additional PTA/stenting was performed in the FAST
cohort. The TIMI 2/3 recanalization rate was similar
(FAST: 72%, RtPA: 68%), but TIMI 3 rate was mark-
edly higher in combined therapy (FAST: 45%, RtPA:
22%). Neurologic outcome appeared better (FAST vs.
rtPA: favorable outcome rate: 34% vs. 17%) with a sig-
nificantly lower mortality rate (FAST vs. rtPA: 38% vs.
68%; p = 0.006). Clinical results were consistent accord-
ing to embolic occlusions (FAST vs. rtPA: favorable
outcome: 36% vs. 13%, mortality: 46% vs. 69%) or ath-
erothrombotic occlusions (FAST vs. rtPA: favorable
outcome: 32% vs. 20%, mortality: 26% vs. 68%). Over-
all bleeding rate was higher in combined therapy, but
the rate of symptomatic intracerebral bleeding did not
differ (FAST vs. rtPA: extracerebral hemorrhage: 3%
vs. 0%, asymptomatic intracerebral hemorrhage: 32%

Clin Neuroradiol 2009 · No. 1 © Urban & Vogel 15

Eckert B. Acute Stroke Therapy 1981–2009
vs. 22%, symptomatic intracerebral hemorrhage: 13%
vs. 12%).
GPI/rtPA bridging also offers a treatment option
with patient transfer from the primary hospital to a
neurovascular center (Figure 3). GPI treatment can
immediately start in the peripheral hospital, may re-
duce the thrombus, but can prevent further thrombo-
sis, and may keep the patient with a sufficient collat-
eral supply in a stable state during transportation until
complete revascularization can be achieved in a neuro-
vascular center.
Mechanical Endovascular Treatment Mode
In the first years endovascular treatment was restricted
to LIT only. The attempts to speed up recanalization
using different pharmacological approaches have been
disappointing. In our own treatment group recanaliza-
tion did not differ between type and dosage of different
plasminogen activators [27]. Different mechanical de-
vices have been developed and improved endovascular
treatment in recent years. Especially in case of athero-
thrombotic occlusion with preexistent high-grade ste-
nosis in vertebrobasilar circulation, additional PTA/
stenting in the same endovascular session has shown to
be effective [6, 15, 64]. PTA has also been described as
one treatment option in case of embolic MCA occlusion
[65]. Several new endovascular devices have been suc-
cessfully tested for safety and are now being tested for
efficacy in larger clinical trials: the photoacoustic EKOS
system [66], the rheolytic ANGIOJET system [67], me-
chanical basket and snare systems like the CATCH and
inTime [68], the microfilament aspiration with the
PHENOX system [69], the MERCI retriever [70], and
the PENUMBRA aspiration system [71]. Balloon-
armed introducer catheters inducing blood flow rever-
sal in the ICA or the vertebral artery can be combined
with coaxial catheter thrombus aspiration or mechani-
cal retriever systems to prevent antegrade thrombus re-
embolization [72]. Recently, multicenter studies with
exclusive recruitment of major vessel occlusions have
been published using MERCI retriever and the PEN-
UMBRA system. In the single-arm multi MERCI Trial
164 patients with major vessel occlusions (ICA, MCA,
basilar artery; mean NIHSSS score: 19) were treated
within 8 h of symptom onset [70]. Successful recanaliza-
tion was achieved in 57.3% after MERCI retriever and
in 69.5% after adjunctive rtPA application. Favorable
outcome was significantly related to recanalization suc-
cess and was achieved in 36% of patients. The mortality
16
rate was 34%. Symptomatic ICH occurred in 9.8%, and
clinically significant procedural complications in 5.5%
of patients.
The PENUMBRA system was used in a phase II
single-arm trial with inclusion of 125 patients within 8 h
of symptom onset (mean NIHSS score: 17.6) [73]. In
82% of the patients a TIMI II/III revascularization
could be achieved with 41.6% of patients having a fa-
vorable outcome at 30 days. Four procedural 2/3 h were
reported (3.2%), none were attributed to device mal-
function or breakage. The rate of symptomatic ICH was
11.2% and the mortality rate was 26.4%.
These promising results underline the impact of me-
chanical devices in future endovascular therapy and trial
design. Most neurovascular centers have created a spe-
cific treatment strategy to combine pharmacological
and mechanical endovascular therapies to achieve rapid
revascularization. LIT therapy alone with microcathe-
ter placement and rtPA application have nowadays
been replaced by multipurpose treatment regimens. In
our institution (Neurocenter Asklepios Klinik Altona)
the treatment regimen is as follows: treatment decision
according to clinical and multimodal CT/MR imaging,
start of i.v. GPI treatment (bolus application with subse-
quent infusion), transportation to the angio suite, intu-
bation, diagnostic angiography, catheterization of the
occlusion site, and bolus rtPA application (5–10 mg)
with subsequent rtPA infusion (up to a total of 40 mg)
via the introducer catheter during mechanical thrombus
aspiration and or PTA/stenting.
Who Performs Endovascular Therapy?
Noninvasive CTA and MRA have mainly replaced
catheter angiography for diagnostic purposes. As a con-
sequence, diagnostic cerebral angiography being a stan-
dard procedure for radiologists in former times, has be-
come a tool for highly qualified experts to answer
specific questions, sometimes requiring superselective
catheterization. LIF with the pure microcatheter navi-
gation into the proximal intracranial vessel segments
has been replaced by complex endovascular procedures
including pharmacological bridging therapies, different
PTA/stent technologies, and thrombectomy devices us-
ing specific micro-guide wires. Thus, modern endovas-
cular stroke therapy has turned into a challenging inter-
ventional procedure, carrying increasing risks of
procedural vessel perforation and dissection with in-
creased bleeding complications, especially during GPI/
rtPA bridging treatment.
Clin Neuroradiol 2009 · No. 1 © Urban & Vogel
Eckert B. Acute Stroke Therapy 1981–2009
Conclusion
The most promising approach in acute stroke treatment
appears to be a combination of IVT with an endovascu-
lar revascularization procedure, combining early treat-
ment initiation with direct clot manipulation, utilizing
PTA/stenting in case of atherothrombotic occlusions
and modern thrombectomy devices in embolic occlu-
sion type.
Modern acute stroke therapy networks should com-
bine the noninvasive diagnostic capacity with rapid
transfer to specialized neuroendovascular centers. Re-
gional stroke units may optimize their MR- or CT-based
multimodal diagnostic acute stroke imaging with a rap-
id, preferably teleradiologic connection to a neurovas-
cular unit. Treatment decisions and initiation of trans-
port or bridging therapy should be started as early as
possible in order to minimize treatment delay, keeping
in mind, that the treatment success is restricted to the
first hours after symptom onset.
In Hamburg the HAGS network covering the whole
metropolitan area is organized with seven regional
stroke units and two supraregional stroke units, con-
taining neurovascular units on a 24/7-basis.
Conflict of Interest Statement
The author declares that there is no actual or potential conflict of in-
terest in relation to this article.
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Address for Correspondence
Bernd Eckert, MD
Department of Neuroradiology
Asklepios Hospital Altona
Paul-Ehrlich-Straße 1
22763 Hamburg
Germany
Phone (+49/40) 181881-1813, Fax -4917
e-mail: b.eckert@asklepios.com
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