Perspectives in Medicine (2012) 1, 2124

Bartels E, Bartels S, Poppert H (Editors):

New Trends in Neurosonology and Cerebral Hemodynamics an Update.
Perspectives in Medicine (2012) 1, 2124

journal homepage: www.elsevier.com/locate/permed

Current trends in sonothrombolysis for acute

ischemic stroke
Andrei V. Alexandrov

Comprehensive Stroke Center, University of Alabama Hospital, Birmingham, USA

KEYWORDS Summary Intravenous tissue plasminogen activator (tPA) remains the only approved, fastest
and widely feasible treatment of acute ischemic stroke. Systemic tPA induces recanalization
Thrombolysis;
of an occluded vessel, the process thought to lead to neurological recovery. Augmentation
Recanalization;
of this brinolytic activity can be safely achieved with diagnostic ultrasound frequencies and
Stroke;
intensities. Ultrasound delivers mechanical pressure waves to thrombi exposing more thrombus
Outcome
surface to circulating drug. International multi-center CLOTBUST trial showed that patients
with acute stroke treated with sonothrombolysis (tPA+2 MHz TCD) had more dramatic clinical
recovery coupled with arterial recanalization (25% vs 8%) at no increase in the risk of symp-
tomatic intracerebral hemorrhage (sICH). Based on this trial and subsequent phase III studies
of a novel operator-independent device for delivery of the CLOBUST levels of ultrasound energy,
a phase III efcacy trial of sonothrombolysis (named CLOTBUSTER) is being launched in Europe
and North America.
2012 Elsevier GmbH. Open access under CC BY-NC-ND license.

Introduction (MCA) or internal carotid artery (ICA) thrombi [2,3]. Even

Intravenous tissue plasminogen activator (tPA) remains the
only approved therapy for acute ischemic stroke [1] that
can be administered fast and at any level emergency room
equipped with a non-contrast CT scanner. Even though
patients with severe strokes and proximal arterial occlu-
sions are less likely to respond to tPA, they still do
better than placebo-treated patients [1]. The presence
of a proximal arterial occlusion should not be viewed as
an insurmountable predictor of tPA failure since nutritious
recanalization can occur even with large middle cerebral
Corresponding author at: Department of Neurology, Comprehen-
if intra-arterial interventions are approved in the future
for stroke treatment, it is unrealistic to expect that all
patients with MCA occlusions either will reach comprehen-
sive stroke centers in time or their risk factor prole would
always make catheter intervention feasible. With bridging
intravenousintra-arterial protocols being tested, there is
even further need to amplify the systemic part of reperfu-
sion therapy so that more patients could benet from early
treatment initiation [4].
Arterial recanalization and reversibility of
stroke

sive Stroke Center, The University of Alabama at Birmingham, RWUH Early clinical improvement after stroke usually occurs after
M226, 619 19th Street South, Birmingham, AL 35249-3280, USA. arterial recanalization [58]. The so-called recanalization
Tel.: +1 205 975 8508; fax: +1 205 975 6785. hypothesis links the occurrence of recanalization with
E-mail address: avalexandrov@att.net increase of good functional outcome and reduction of death

2211-968X 2012 Elsevier GmbH. Open access under CC BY-NC-ND license.

doi:10.1016/j.permed.2012.02.035
22 A.V. Alexandrov

[9], however this hypothesis has not been conrmed in a
prospective clinical trial, subject of an ongoing CLOTBUST-
PRO multi-center study [10]. In the CLOTBUST trial [11],
early recanalization coupled with early dramatic recov-
ery was more common among tPA treated patients who
were exposed to continuous vs intermittent monitoring with
pulsed wave 2 MHz TCD (25% vs 8%). This, in turn, produced
a trend towards more patients recovering at 3 months to
modied Ranking score 01 (42% vs 29%) [11].
Diagnosis of an acute intracranial occlusion, re-
canalization and re-occlusion in the CLOTBUST trial was
based on the thrombolysis in brain ischemia (TIBI) residual
ow grading system [12]. It describes typical waveforms that
identify residual ow around an arterial occlusion, and their
detailed denitions were published elsewhere [13].
Delivery of tPA to and through the thrombus is depen-
dent on minuscule residual blood cell ow around the
thrombus and plasma ow through the thrombus and the
need for ultrasound exposure to facilitate drug delivery,
enzymatic and mechanical thrombus dissolution has been
emphasized by many research groups [1422]. Acute stroke
provided the clinical setting to test the effect of continu-
ous exposure to ultrasound energy in human subjects, goal
less attainable in acute coronary syndromes. The CLOT-
BUST trial demonstrated the positive biological effect of
low intensity 2 MHz pulsed wave transcranial Doppler on
enhancement of tPA-induced early recanalization. It paved
the road for subsequent studies that included combination
of ultrasound with gaseous microspheres [2329] (Table 1).
Detailed analysis of microspheres data is beyond the scope
of this update since at the moment the clinical develop-
ments in the eld of sonothrombolysis are focused on the
ultrasound device, i.e. drugdevice combination. Testing
tPA combination with such a device alone is necessary in
the rst place before more complex combination products
(drugdrugdevice or drugdevicedevice) can be tested
in clinical trials of microspheres activated with ultrasound
in the presence of tPA.
CLOTBUST levels of ultrasound energy and an
operator independent device
The main limitation of TCD technology used in the CLOT-
BUST trial is its extreme operator dependency and the need
for a qualied sonographer to be present at bedside to nd,
aim and deliver ultrasound beam to the thrombus residual
ow interface. Our collaborative group rst measured out-
puts of all devices used in the CLOTBUST trial [30], then
designed multi-transducer assembly to cover conventional
windows used for TCD examinations [31], and prospectively
evaluated its safety in human volunteers [35] and ischemic
stroke patients treated with intravenous tPA [36]. In these
phase III clinical studies, the novel operator-independent
device showed no safety concerns, caused no disruption
of the bloodbrain barrier on sequential MRI imaging and
yielded recanalization rates comparable to the CLOTBUST
trial.
Since this operator-independent device can be quickly
mounted by medical personnel with no prior experience in
ultrasound, the device enables us to conduct large scale
sonothrombolysis trials at all levels of emergency rooms
capable of administering tPA as the standard of care. Thus,
sonothrombolysis for acute ischemic stroke enters testing in
the pivotal efcacy multi-national trial called CLOTBUSTER
(Combined Lysis of ThromBus using 2 MHz pulsed wave Ultra-
sound and Systemic TPA for Emergent Revascularization,
NCT01098981). Briey, all patients will receive 0.9 mg/kg
intravenous tPA therapy (10% bolus, 90% continuous infu-
sion over 1 h, maximum dose 90 mg) as standard of care
according to national labels (i.e. within 3 or 4.5 h from
symptom onset). All patients with National Institutes of

Table 1 Clinical trials of microsphere-potentiated sonothrombolysis for acute ischemic stroke using trancranial ultrasonography
(modied from Ref. [34]).

Trial F Microspheres Design Recanalization Asymptomatic Symptomatic Outcome

ICH ICH

Molina et al. 2 MHz Galactose- tPA/TCD/S vs 55% 23% 3% 56% (mRS 02)
[23] based tPA/TCD vs tPA
Alexandrov 2 MHz Perutren- tPA/TCD/S vs 42% 25% 0% 40% (mRS 01)
et al. [24] lipid tPA/TCD
TUCSON [25] 2 MHz Perutren- tPA/TCD/S 2 doses 67% 17% 0%, 27% 75% (mRS 01)
lipid vs tPA
Larrue et al. 2 MHz Galactose- tPA/TCCD/S vs tPA 48% 78% 0% N/A
[28] based
Perren et al. 2 MHz Phospholipid tPA/TCCD/S vs tPA 63% N/A 9% N/A
[26] encapsulated
sulphur
hexauoride
Nicoli et al. 2 MHz Phospholipid tPA/TCD/S vs 86% N/A 5.7% N/A
[29] encapsulated tPA/TCD
sulphur
hexauoride
F frequency of ultrasound; ICH intracerebral hemorrhage; tPA tissue plasminogen activator; TCD transcranial Doppler; S
microspheres; mRS modied Rankin scale; TCCD transcranial color-coded duplex; N/A not available.
Current trends in sonothrombolysis for acute ischemic stroke
Health Stroke Scale (NIHSS) scores 10 points are eligible
and after signing a written informed consent they will wear
an operator-independent ultrasound emitting device for 2 h.
The proprietary device (Cerevast Therapeutics, Redmond,
WA) exposes traditional transcranial Doppler bone windows
for sequential insonation of the 12 proximal intracranial
segments that most commonly contain thrombo-embolic
occlusions causing disabling strokes. Patients will be ran-
domized 1:1 to continuous exposure to 2 MHz PW ultrasound
versus sham exposure. No pre-treatment proof of a proximal
arterial occlusion would be required since angiography is not
a standard of care for evaluation of tPA-eligible patients at
most institutions. Furthermore, NIHSS 10 points identify
severe cerebral ischemia caused by proximal occlusions in
>80% of patients [32,33].
Safety will be determined by the incidence of sICH within
24 h of treatment. Functional recovery will be determined
by modied Ranking scores (primary end-point mRS 01) at 3
months. CLOTBUSTER is a large simple efcacy clinical trial,
the rst of its kind for sonothrombolysis.
Once CLOTBUSTER establishes safety and efcacy of an
operator-independent 2 MHz PW ultrasound device, the next
phase clinical trials can commence combining experimen-
tal microspheres with regulatory-approved tPA therapy and
safe ultrasound exposure. This exposure is needed to acti-
vate microspheres, however a proof of safety and efcacy of
ultrasound is required before a complex combinatory treat-
ment with or without tPA can be tested any further in the
clinical setting.
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