Personal View

Future directions of acute ischaemic stroke therapy
Marc Fisher, Jeffrey L Saver
Lancet Neurol 2015; 14: 758–67
See Comment page 674
Department of Neurology,
Beth Israel Deaconess Medical
Center, Harvard Medical
School, Boston, MA, USA
(Prof M Fisher MD,
Prof J L Saver MD); and
Comprehensive Stroke Center
and Department of Neurology,
David Geffen School of
Medicine, University of
California, Los Angeles, CA,
USA (Prof M Fisher,
Prof J L Saver)
Correspondence to:
Prof Marc Fisher, Beth Israel
Deaconess Medical Center,
330 Brookline avenue, Boston,
MA 02215, USA
mfisher5@bidmc.harvard.edu

For several years, the only therapy with proven efficacy for acute ischaemic stroke was alteplase, which is approved for
use within 4·5 h after stroke onset in many countries, but only within 3 h in the USA. However, the recanalisation
rate with alteplase is modest. Several trials have shown substantial clinical benefit of neurothrombectomy within 6 h
of ischaemic stroke onset, which has initiated a new era of acute stroke therapy. As neurothrombectomy becomes part
of standard practice, additional trials will be needed to determine the best way to organise delivery of this care.
Continuing clinical trials with several types of advanced MRI and CT imaging to enhance patient selection are
investigating alteplase, other thrombolytic drugs, and novel endovascular devices, for use in later time periods from
stroke onset. Consequently, the organisation and implementation of future clinical trials will need to adapt to what
has been learned from the present generation of trials. The delivery of care to patients with acute stroke will also need
to incorporate newly proven therapies, and much additional work is needed to maximise outcomes in as many
patients as possible.

Introduction
The goal of acute ischaemic stroke treatment is to
improve patient outcome months and years after the
event and to have a reasonable safety profile. This
objective can be achieved by early recanalisation of an
occluded artery with use of a thrombolytic drug or
neurothrombectomy device to salvage ischaemic tissue
at risk of infarction and reduce the size of the infarct,
which leads to a better functional outcome. Physicians
should be aware of the novel evidence and treatment
options available from clinical trials of acute ischaemic
stroke therapy and how this information should inform
decision making for individual patients with stroke and
the organisation of regional or national care.
In this Personal View, we will provide a brief overview
of clinical trial evidence for the use of intravenous
alteplase and mechanical thrombectomy devices in acute
ischaemic stroke and present our opinion on how the
specialty is likely to evolve during the next 5–10 years. We
will also discuss the role of imaging in the selection of
patients with acute ischaemic stroke for therapy, the
potential use of adjunctive therapies to enhance the
benefits of reperfusion therapy, novel approaches to
intravenous thrombolysis, the need for new trial designs
for future acute ischaemic stroke trials, and, finally,
considerations of how to reorganise health-care delivery
systems to maximise the benefit of available and future
therapies.

Management of acute ischaemic stroke
Until recently, the only therapy with proven efficacy was
intravenous alteplase. This drug was initially shown to be
beneficial when therapy was initiated within 3 h after
stroke onset in the two landmark National Institute of
Neurological Disorders and Stroke (NINDS) trials.1
Efficacy within 3 h was also supported by the subgroup
results of five additional trials,2 and the largest trial, the
3rd International Stroke Trial.3 Although the European
Cooperative Acute Stroke Study III (ECASS-3) trial
results supported the efficacy of alteplase when initiated
within 3–4·5 h of stroke onset,4 the extent of reduction in
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disability was slight and less robust than the effect when
given between 0 h and 3 h. This finding supports the
hypothesis that the earlier treatment of acute ischaemic
stroke is initiated, the greater the benefit to the patient.5,6
An individual patient-level meta-analysis6 of the alteplase
trials showed that treatment initiated within 3 h of stroke
onset was substantially more effective in improving late
outcome than treatment initiated between 3 h and 4·5 h;
by our calculations, the numbers needed to treat for
disability-free survival (modified Rankin Scale 0–1) are 11
versus 20. The American Heart Association treatment
guidelines7 recommended that alteplase should be given
up to 4·5 h after ischaemic stroke onset, and regulatory
authorities in many countries have approved the timewindow extension because they deemed the results of the
ECASS-3 trial to be sufficient.7 However, the US Food
and Drug Administration did not approve the timewindow extension, because of apparent concerns about
the robustness of the ECASS-3 results.8
Another widespread approach to revascularisation
therapy for acute ischaemic stroke is the use of endovascular
devices to remove clots (neurothrombectomy; figure 1). A
growing number of such devices have been tested in
patients with acute ischaemic stroke, including the Merci
coil retriever (Stryker Neurovascular, CA, USA) and
Penumbra (Penumbra Inc., CA, USA) aspiration devices
initially, and more recently the stent retrievers Solitaire
(Medtronic, MN, USA) and Trevo (Stryker Neurovascular,
CA, USA), and a direct aspiration first pass technique.9 All
of these devices have been cleared for use in patients with
acute stroke by regulatory authorities. The Merci and
Penumbra devices were moderately effective in recanalising
larger intracranial vessels.10,11 However, randomised trials of
endovascular recanalisation that permitted interventionalists
to use these devices or, in some studies, intra-arterial
delivery of fibrinolytics, did not show improved 90-day
outcomes when compared with standard medical care
(intravenous thrombolysis or supportive care alone).12–14
These neutral trials of first generation interventions were
limited by the failure to confirm vascular occlusions in all
enrolled patients, no penumbral imaging, too long a delay
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between randomisation and endovascular intervention,
and, most importantly, the devices had only slight technical
efficacy in reopening target occlusions. The Solitaire and
Trevo stent retriever devices were compared with the Merci
coil retriever in 8-h time windows in phase 2 clinical trials.
The stent retrievers showed superior efficacy in
recanalisation of occluded proximal intracranial vessels and
improved clinical outcomes, with recanalisation rates of
about 68% as compared with 30–40% with the Merci
retriever.15,16 Most recently, four concurrently conducted
randomised trials (MR CLEAN,17 ESCAPE,18 EXTEND IA,19
and SWIFT PRIME20) that tested neurothrombectomy
largely with Solitaire and Trevo stent retrievers reported
them to be superior to medical treatment alone. In all of
these superiority trials, a vascular occlusion had to be
documented by CT or magnetic resonance angiography
before enrolment and, except in the MR CLEAN trial, a
small baseline region of ischaemic injury should be seen on
plain non-contrast CT or CT perfusion. Speed from hospital
admission to baseline imaging, to groin puncture, and to
reopening of the initial vessel occlusion were also deemed
as important aspects to show efficacy. Patients in the
EXTEND IA and SWIFT PRIME trials had previous
intravenous alteplase therapy before enrolment; in the MR
CLEAN and EXTEND IA trials most of the patients had
been given intravenous alteplase before enrolment. In all
four trials, patients were randomly assigned to best medical
treatment versus endovascular therapy. Only the Solitaire
device was used in the EXTEND IA and SWIFT PRIME
trials; stent retrievers were used in 190 (97%) of 196 patients
in the MR CLEAN trial (one patient received alteplase intraarterially) and 27 (78%) of 35 patients in the EXTEND IA
trial. Subsequently, a fifth trial was published, the
randomised REVASCAT trial,21 which was similar in design
and outcome to the other four trials. Pooled analysis of
these trials is needed to analyse benefits and risks in patient
subgroups, but collectively they suggest that neurothrombectomy has become a proven intervention for the
treatment of acute ischaemic stroke.
Alteplase and endovascular therapy are best used in the
setting of an organised stroke-care system, which directs
patients to an appropriate hospital and incorporates
comprehensive stroke units that are adequately staffed.
Evidence in some countries suggests that enhancement
of regional care plans can lead to substantially higher
rates of alteplase use, reduced mortality, and improved
outcomes.22,23

Imaging and acute stroke therapy
Multimodal imaging should include the following: a
plain non-contrast head CT scan to exclude haemorrhage
and identify changes that could suggest early ischaemic
brain injury; CT angiography to show vascular occlusion;
CT perfusion imaging to assess the extent of tissue hypoperfusion; standard brain MRI, to exclude
haemorrhage; and magnetic resonance angiography,
to show vascular occlusion (diffusion-weighted and
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A

L

C

B

D

L

E

L

L

L

F

L

Figure 1: Highly effective recanalisation with a stent retriever
A man aged 62 years presenting with aphasia and right hemiparesis. Left
internal carotid artery angiogram (A) anterior–posterior and (B) lateral views
showing proximal left M1 middle cerebral artery occlusion. Solitaire stent
retriever deployed in target vessel (C) anterior–posterior view with partial
reperfusion during deployment. (D) lateral view of full recanalisation of middle
cerebral artery. (E) Anterior–posterior and (F) lateral views of substantial
reperfusion of distal field after one stent retriever pull. Images courtesy of
May Nour (David Geffen School of Medicine, University of California,
Los Angeles, CA, USA).

perfusion-weighted MRI to assess locations of ischaemic
brain injury and hypoperfusion are also available). CT
and magnetic resonance multimodal imaging have the
potential to identify subgroups of patients presenting
with stroke more than 3 h after onset who will still benefit
from treatment, by showing a persisting vascular
occlusion target for reperfusion therapy and by showing
the extent of the ischaemic penumbra (potentially
salvageable ischaemic tissue) and irreversibly injured
ischaemic tissue (the ischaemic core; figure 2). Patient
selection by advanced imaging, such as diff usionweighted imaging for the infarct core and perfusionweighted imaging for the ischaemic penumbra,24 is being
tested in several ongoing clinical trials, such as the
EXTEND (NCT01580839), DAWN (NCT02142283), and
POSITIVE (NCT01852201) trials, with time windows of
alteplase and device use longer than 3 h. If the results of
these trials show benefit, clinicians and regulatory
authorities might use these advanced imaging techniques
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DWI

DWI (Tmax)

Figure 2: Malignant penumbral profile unfavourable for treatment more than 3 h after stroke onset
MRI scan with DWI showing large established infarct core (left; 143 cm³) and perfusion-weighted imaging showing
extremely large region of tissue at risk (right; 255 cm³). Although mismatch is present (ratio 1·8), and the patient
presented within the treatment window, the large size of the already completed infarct in the dominant
hemisphere shows reperfusion would probably be futile, because tissue loss sufficient to cause death or severe
dependency has already occurred. DWI=diffusion-weighted imaging. Tmax=time-to-maximum of the residue
function. Images courtesy of Greg Albers (Stanford University, School of Medicine, CA, USA).

to guide future use of alteplase and device therapies. The
two DEFUSE studies25,26 evaluated intravenous alteplase
alone or in combination with endovascular therapy and
showed that patients with a perfusion-weighted to
diffusion-weighted target mismatch of 20% or more
seemed to benefit when recanalisation occurred up to
6–8 h after stroke onset. The EPITHET study27 showed
that patients randomly assigned to alteplase or placebo in
the 3–6 h window and who had at least a 20% larger
lesion volume in perfusion-weighted imaging than
diffusion-weighted imaging were unlikely to benefit
from treatment with alteplase. However, when the study
was reanalysed to include only the portion of the initial
diffusion-weighted imaging lesion contained within a
region of perfusion-weighted imaging abnormality, the
alteplase group showed significantly reduced ischaemic
lesion growth (p=0·046). Other studies19,20 have suggested
that perfusion-weighted imaging might not be necessary
to identify patients with ischaemic stroke who are most
likely to benefit from alteplase or endovascular therapy.28
Patients with a proximal vessel occlusion shown on a
magnetic resonance angiography who had a baseline
lesion volume on diffusion-weighted imaging of less than
50–70 mL showed clinical improvement with treatment.
Although some regions with mild abnormality seen with
diffusion-weighted imaging might be salvageable,
assessment of diffusion-weighted imaging lesion volume
before treatment can provide a useful estimation of the
ischaemic core.29
Perfusion-weighted imaging might also provide
additional important information besides the target
perfusion-weighted and diffusion-weighted imaging
mismatch; in the DEFUSE studies, a malignant
mismatch pattern of a diffusion-weighted lesion or of a
severe hypoperfusion more than 100 ml was identified in
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patients with large severe perfusion-weighted imaging
lesions even though diffusion-weighted imaging lesions
were small or moderate in size (figure 2).30 Data are
presently not available to show whether diffusionweighted imaging lesions of a modest size (eg,
≤50–70 mL) are sufficient for including late time-window
patients in clinical trials.
An additional promising MRI strategy is to use the
mismatch between the diffusion-weighted imaging
lesion and the fluid attenuated inversion recovery lesion
to identify those patients with wake-up stroke who have
recent symptom onset and might benefit from
reperfusion intervention.31 Acute stroke MRI scans are
the best approach to identify the ischaemic core and
penumbra but are difficult to obtain in a timely manner
in many centres where CT is the most readily available
imaging modality. CT angiography and CT perfusion are
obtained for many patients with acute stroke at many
centres.32 CT angiography is clearly useful for the
identification of occlusions in large-to-medium size
vessels, such as the distal internal carotid artery or
proximal middle cerebral artery, and preliminary data
suggest that late-presenting patients with such occlusions
could be more likely to benefit from thrombolytic therapy
than patients without occlusions in these vessels. The
value of CT perfusion in acute ischaemic stroke is
controversial. An initial study33 suggested that the
ischaemic core could be identified by cerebral blood
volume measurements (blood volume in the capillaries
per unit brain volume) similar to those shown with
positron emission tomography. The usefulness of
cerebral blood volume measurements to identify the
ischaemic core is problematic because these
measurements might not reliably identify irreversibly
injured ischaemic tissue, and a more recent study34 has
used cerebral blood flow levels below 30% of the normal
contralateral hemisphere to identify the ischaemic core.
The penumbral region in patients with acute ischaemic
stroke has been estimated by use of cerebral blood flow
maps. A recent study35 has suggested that a threshold of
greater than 6 s, when comparing the arrival of the
contrast bolus with the normal contralateral hemisphere,
shows a hypoperfused volume that is similar to that seen
on perfusion-weighted imaging MRI (figure 3). CT
perfusion was used to select patients in a phase 2 trial of
intravenous tenecteplase, a thrombolytic drug that
showed greater efficacy than intravenous alteplase.36
Concerns persist that this approach might not reliably
identify the ischaemic penumbra and that the 30%
threshold of cerebral blood flow might not reliably
identify the ischaemic core. Several of these trials of latetime-window alteplase and endovascular interventions
are using CT perfusion identification of the ischaemic
core with a threshold of cerebral blood flow of less than
30% of the contralateral hemisphere to delineate the
ischaemic core and exclude patients with a large
ischaemic core. If these trials are successful in improving
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outcome, and identification of the ischaemic core and
penumbra with CT perfusion contributes to their
success, the usefulness of CT perfusion in acute
ischaemic stroke is likely to aid diagnosis, in view of the
much greater accessibility of CT compared with MRI in
the acute stroke setting.

Adjunctive therapeutic approaches
A major task ahead is to accelerate delivery of proven
reperfusion therapies. Intravenous alteplase is rarely
administered in the first, so-called golden hour after
onset of symptoms, when it is most effective. Prehospital
thrombolysis in mobile stroke unit ambulances and
reorganisation of emergency department care to shorten
door-to-needle times can substantially reduce time to
treatment.37,38 Reorganisation of regional systems can
expand access to thrombolytic therapy in a timely manner
within the approved therapeutic time window by routing
patients eligible for alteplase to a facility capable of rapidly
initiating it.39 For endovascular therapy, an intensive
worldwide effort is needed to shorten door-to-clot times
for acute ischaemic stroke, similar to the successful doorto-balloon initiative for acute myocardial infarction.40
However, even when the delivery of reperfusion
therapy is optimised, the need for brain imaging before
thrombolytic treatment and neurocatheter laboratory
facilities for endovascular treatment will preclude therapy
delivery shortly after stroke onset. The need to preserve as
much of the ischaemic penumbra for as long as possible,
in as many patients as possible, until reperfusion is
achieved, has further intensified because the stent retriever
trials41 have shown efficacy in improving outcome more
than 4·5 h after stroke onset. This strategy is based on the
concept that device or drug recanalisation or reperfusion
provides clinical efficacy by salvaging a portion of the
ischaemic penumbra, reducing infarct size, and therefore
improving functional outcome.41
The availability of endovascular therapy with novel
devices at small-to-medium sized hospitals might be
restricted, and patients will need to be transferred quickly
to larger centres where endovascular therapy can be
administered. This availability will be a particular problem
in developing countries, where few, if any, centres have
endovascular therapy available. Some patients could
initially receive intravenous alteplase at their local hospital
and then be transferred to a large, tertiary centre, if they
have an occluded vessel that can be treated with
endovascular therapy. However, the recanalisation efficacy
of intravenous alteplase is slight; about 30–40% of patients
with ischaemic stroke receiving this thrombolytic therapy
are estimated to achieve radiographic-confirmed or
ultrasound-confirmed complete or substantial partial
recanalisation, and some patients will not receive
intravenous alteplase for reasons such as presenting too
late after stroke onset, concomitant use of anticoagulation
therapy, or the absence of appropriate infrastructure such
as urgent CT access or appropriate personnel to perform
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Acute CT
NCCT

CTP–CBF

CTP–Tmax

MRI at 24 h
Penumbra map

DWI

PWI–CBF

200

1500

2

0

0
1500

0

75

50

1000

–5

0

75

50

1000

200

–5

0

2

0

Figure 3: Favourable penumbral profile for treatment more than 3 h after stroke onset
Non-contrast CT scan (NCCT) shows only subtle loss of grey–white differentiation around the head of the caudate
nucleus. However, CT perfusion imaging of cerebral blood flow (CTP–CBF) to define tissue at risk and of maximal
delay of contrast uptake (CTP–Tmax), to define an infarct core, allows construction of a penumbra map showing
substantial tissue that is still salvageable (green) and only a small core (red). After successful recanalisation therapy,
MRI at 24 h shows a small residual infarct on DWI and restored perfusion (PWI–CBF). DWI=diffusion-weighted
imaging. PWI=perfusion-weighed imaging. CBF=cerebral blood flow. With permission from Christopher Levi and
Mark Parsons (University of Newcastle, Australia).

thrombolysis at the receiving hospital. Although a metaanalysis42 of the intravenous alteplase trials supports the
use of thrombolysis in patients with severe initial deficits,
time is brain and the ischaemic lesion will evolve during
the transport of patients to the endovascular centre.42
Despite the negative results from trials of neuroprotection
for acute ischaemic stroke, a potentially novel application
would be to try to slow down the conversion of tissue in the
ischaemic penumbra into ischaemic core (figure 4). In
animal models of stroke, high-flow oxygen, hypothermia,
and neuroprotective drugs, such as a postsynaptic
density-95 protein inhibitor, can almost freeze the
expansion of diffusion-weighted imaging lesions and
extend the time window during which intravenous
alteplase is beneficial by several hours.43–47 With the
completed phase 2 and phase 3 trials showing that
prehospital paramedic initiation of neuroprotective
therapy with magnesium therapy is feasible, it would be
appropriate to consider a trial of a neuroprotective therapy
with a strong preclinical efficacy and good safety profile, in
which the target of therapy is to preserve as much
ischaemic penumbra in as many patients as possible until
recanalisation or reperfusion therapy can be started.46
Many potential neuroprotective interventions might
need to be analysed to assess their effects on penumbral
arrest, because the ischaemic cascade in neuronal tissues
after vascular occlusion is multifaceted and complex. The
pathway or pathways that should be targeted for
penumbral freezing are still unknown, but additional
animal studies could inform future research. If a
neuroprotective therapy can be shown to preserve the
volume of the ischaemic penumbra between the primary
and tertiary centres, as seen on appropriate advanced
imaging on arrival at the tertiary care centre, the number
of patients who can be treated successfully with
endovascular therapy or intravenous alteplase will
probably substantially increase because the treatment
time window will be increased.
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Infarct area
Hypoperfused tissue
45 min–small infarct,
substantial tissue at risk

Neuroprotection
to freeze penumbra

Standard
care

Neuroprotective
intervention

4 h–differential
infarct
progression

Reperfusion
intravenous or
intra-arterial
therapy

Final infarct size

Figure 4: Freezing the penumbra
Early after stroke onset, substantial hypoperfused tissue is at risk but only a
small established infarct exists. Without application of neuroprotective therapy,
the infarct progresses in size before reperfusion therapy can be started (left
side). Early neuroprotective intervention slows or prevents this progression, so
that more salvageable tissue persists to the time of start of reperfusion
treatment (right side). After successful reperfusion, final infarct size is larger
without (left side) than with (right side) bridging neuroprotection.

Successful recanalisation or reperfusion clearly
improves outcome after acute ischaemic stroke but might
also have disadvantages. Tissue injury after reperfusion,
so-called reperfusion injury, has been observed in the
heart, brain, and other organs, and might be mediated by
free radical production, inflammatory white blood cells,
apoptosis, and other factors.47–49 In acute ischaemic stroke,
the clinical outcomes of reperfusion injury are unknown.
In temporary occlusion stroke modelling studies, evidence
suggests that therapies targeted to the purported
mechanisms of reperfusion injury, such as inhibitors of
the inflammatory response and antioxidants, reduce
infarct size and improve functional outcome. Before
widespread use of thrombolytics and the advent of highly
effective neurothrombectomy devices, reperfusion
occurred in only a few treated patients. But now that reperfusion is actually being achieved in many patients with
ischaemic stroke, reperfusion injury is a possible target
for therapeutic development, where drugs targeted at
reperfusion injury are given to patients after imagingdocumented proof of recanalisation or reperfusion. Trials
investigating treatment of reperfusion injury will be large
and complex, and will need substantial sample sizes to
confirm improved functional outcome in addition to that
achieved by the initial thrombolytic or device therapy.
Further to adjunctive therapies delivered intravenously, the endovascular route will become an
important potential approach to deliver additional
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therapy, as current trials continue to establish the efficacy
of mechanical thrombectomy. Neurothrombectomy of
proximal occlusions often leaves embolic occlusions in
second-order and higher-order branches that are not
easily accessed by devices. Neurothrombectomy can also
cause occlusions in these vessels through embolisation.
Local and regional microcatheter infusion of fibrinolytics
can potentially remove these distal occlusions, but
clinical trials are needed to define when to pursue and
when to avoid this additional intervention. Also,
microcatheter delivery of drugs that are protective against
reperfusion injury, directly into the reperfused region, is
a promising strategy for diminishing reperfusion injury.
Microcatheter delivery can lead to higher concentrations
in target tissue than those achieved with systemic
administration.

New approaches for recanalisation
The modest recanalisation efficiency of intravenous
alteplase is related to clot location and burden.50,51 Therefore,
about 60% of patients treated with intravenous alteplase
will not benefit from lytic treatment, as recanalisation and
subsequent reperfusion are needed for favourable clinical
outcomes.52 Several other thrombolytic drugs with better
fibrin specificity and fewer neurotoxic effects than alteplase
have been developed and tested in clinical trials.
Desmoteplase, a thrombolytic derived from bat saliva,
has undergone extensive preclinical and clinical
evaluation. Two initial small clinical studies53,54 showed
better reperfusion than placebo in patients with acute
ischaemic stroke, but a larger phase 2b trial55 did not
show improved clinical outcome on the modified Rankin
scale compared with placebo in patients who were
enrolled up to 8 h from stroke onset. The results of a
phase 3 trial (DIAS-3)56 showed safety of desmoteplase
given 3–9 h after ischaemic stroke in patients with
occlusion or high-grade stenosis in major cerebral
arteries. In this study, although the clinical outcome of
patients treated with desmoteplase was not significantly
different from that of patients treated with placebo in the
intention-to-treat analysis, in the per-protocol analysis
patients treated with desmoteplase tended to have a better
outcome than the placebo-treated group.
Tenecteplase is another thrombolytic drug, and
preclinical data suggest that its thrombolytic efficacy is
greater than that of alteplase.57 A small clinical study58 of
tenecteplase compared with alteplase, which was stopped
prematurely, did not show a difference in clinical
outcome. A more recent small trial59 that included
penumbral imaging in the patient selection criteria
showed that when the two tenecteplase arms of the study
were combined and compared with the alteplase arm,
tenecteplase was associated with a significantly (p<0·001)
better functional outcome at 24 h as assessed by
improvement on the National Institutes of Health stroke
scale. A large phase 3 trial (NCT02101606) comparing
tenecteplase with alteplase in the 0–4·5 h time window is
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underway; this study also includes penumbral imaging in
the patient inclusion criteria.
Another approach to intravenous thrombolysis is to
combine alteplase with another drug. Argatroban, a direct
thrombin inhibitor that augments alteplase by improving
microcirculatory flow and preventing reocclusion, was
given intravenously to 65 patients in a safety study.
Argatroban was infused for 48 h after initial treatment with
intravenous alteplase.60 At 2 h after initiation of argatroban,
29 (62%) of 47 patients had complete or partial recanalisation
on transcranial Doppler studies. The proportion of clinically
significant intracerebral haemorrhage was 4 (6%) of 65.
Although no control group receiving only intravenous
alteplase was reported, the recanalisation efficacy of
argatroban after alteplase seems to be better than that
previously observed with alteplase alone.
Annexin-A2 has binding site receptors for both
plasminogen and endogenous tissue plasminogen
activator.61 Annexin-A2 can therefore bring alteplase into
close proximity with plasminogen and potentially
enhance the thrombolytic efficacy of tissue plasminogen
activator. In an animal model of stroke, the combination
of a low-dose (2·5 mg/kg) of alteplase and annexin-A2
showed greater radiographical reperfusion efficacy and
fewer haemorrhagic side-effects than standard dose
10 mg/kg alteplase.62 In another preclinical animal
experiment, the combination of annexin-A2 and alteplase
dissolved clots more rapidly and completely in the middle
cerebral artery than alteplase alone, as shown in vivo by
MRI.63 Annexin-A2 plus alteplase has not yet been
studied in clinical trials but could be a promising drug
combination for future exploration.
A non-pharmacological approach to the enhancement
of the thrombolytic efficacy of alteplase is to use transcranial Doppler ultrasound sonothrombolysis. The precise
mechanism by which ultrasound energy enhances clot
lysis is unclear but could increase the penetration of
alteplase into clots and promote clot fragmentation.64
These effects of ultrasound energy might be further
enhanced by the injection of microbubbles of varying
sizes. In the CLOTBUST study,65 the largest study (n=126)
of ultrasound-enhanced thrombolysis, the proportion of
patients achieving complete recanalisation and a better
clinical outcome as assessed by the National Institutes of
Health stroke scale was increased with the combination of
ultrasound for 2 h and alteplase versus alteplase alone
(31 [49%] of 63 patients vs 19 [30%] of 63 patients; p=0·03).
A meta-analysis of sonothrombolysis clinical studies
suggested that this therapeutic approach combined with
alteplase was safe and had significantly (p<0·0001) better
clinical outcomes than with alteplase alone.66 A definitive
phase 3 trial (NCT01098981) is underway to confirm these
observations.

Novel approaches to test new therapies
In light of the positive current generation of neurothrombectomy and endovascular recanalisation studies,
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and now that intravenous fibrinolysis has become the
standard treatment approach for acute ischaemic stroke,
future trial designs for stroke studies will need to be
modified. Additionally, several trial designs that have
infrequently been used in acute stroke investigation
should become more common (table).
Active comparator trials will be needed to compare
different combinations of approved intravenous and
endovascular therapies. Studies should test new
hypotheses, such as whether, for certain vascular targets
(eg, internal carotid artery occlusions), a pure endovascular
strategy will be more effective than a combined
intravenous-endovascular or pure-intravenous approach.
Additionally, for other vascular targets (eg, distal middle
cerebral artery occlusions), a pure intravenous strategy
might be more effective than a combined intravenous and
endovascular approach. Trials with designs like the one in
SYNTHESIS-Expansion,13 in which the investigators used
different active treatment strategies in a head-to-head trial,
will probably become more common.
Regional systems of care trials will also need to become
more widespread, as has occurred with cardiovascular
interventions. These trials will need to compare different
approaches for embedding intravenous and endovascular
interventions in existing systems of care. For example,
drip and ship trials (in which patients receive intravenous
alteplase at an outlying hospital and are then transferred
to a tertiary centre) versus mothership (tertiary care
centre) trials should test emergency medical system
routing of patients with severe deficits after stroke.
Patients with potential large artery occlusions will first
be taken to the nearest primary stroke centre or
telestroke facility for intravenous alteplase, with the
option for later transfer for endovascular intervention.
This scenario should be compared with direct transport
to a comprehensive stroke centre where both treatments
are immediately available on site.
The number of trials of prehospital thrombolysis in
mobile stroke unit ambulances versus thrombolysis on
hospital arrival should increase to assess the effects on
final clinical outcome, rather than just process endpoints
such as onset-to-treatment time.67,68 Cluster randomisation
designs, rather than random assignment of individual
patients, will be a necessary design element of studies in
which the intervention is at the level of local or regional
systems of care.
Novel endpoints, such as the range of outcomes on
the modified Rankin Scale, substantial early deficit
improvement, or clot resolution by the time of catheter
angiography will be needed to detect signals of efficacy of
adjunctive therapies in small phase 2 trials of treatments
that are given in addition to recanalisation but that
include only several hundred patients. However,
improved final functional outcomes in the study control
arms (ie, patients who receive an active comparator) will
make late clinical endpoints less informative than in
present trials.
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Novel aspect in trial design

Example comparisons

Target patients

Reperfusion strategies

Active comparator

Intravenous therapy plus intra-arterial
therapy vs intra-arterial therapy alone;
intravenous therapy plus intra-arterial
therapy vs intravenous therapy alone

Patients with ICA occlusions;
patients with M2 occlusions

Regional systems of care

Cluster randomisation

EMS routing—PSCs first vs CSCs
first (drip and ship); prehospital
thrombolysis in mobile CT vs
emergency department thrombolysis
(mothership)

Patients who are probably have
large artery occlusions based on
prehospital deficit profile; patients
<4·5 h since stroke

Prehospital neuroprotection

Imaging and clinical endpoints at admission NA1, hypothermia, or nitroglycerin vs
to emergency department will be more
control
directly informative than final outcome

Patients who are transported by
emergency medical services

Prevention of reperfusion injury

Serum and imaging biomarkers will be the
most informative phase 2 endpoints

Free radical scavengers vs control

Patients after successful TICI 2b
or TICI 3 reperfusion

Neurothrombectomy devices

Revert back to reperfusion as a surrogate
endpoint

Stent retriever A vs stent retriever B;
aspiration vs stent retriever

Patients with large artery
occlusions

Diverse approaches in one trial

Large sample sizes; registry based trials;
Hypothermia vs normothermia
linear outcome scales; preserve study power
(when mechanical thrombectomy is an
effective intervention in control arm)

Patients with large artery
occlusions

Imaging selection

Physiological-based (extensive multimodal
imaging) selection vs time-based
(brief imaging) selection

Patients considered for intravenous
therapy; patients considered for
intra-arterial therapy

NCCT vs CT angiography and
perfusion CT

ICA=internal carotid artery. M2=distal middle cerebral artery. EMS=emergency medical system. PSC=primary stroke centre. CSC=comprehensive stroke centre.
TICI=thrombolysis in cerebral ischaemia. NCCT=non-contrast CT.

Table: Future trial designs in acute ischaemic stroke

In studies of prehospital neuroprotection, useful
endpoints include differences in the development of
deficits from the field to the hospital, evidence of more
penumbra being preserved, and less progression to
infarct core on arrival, as seen with multimodal imaging.45
For trials of drugs to avert reperfusion injury, serum and
imaging markers of reperfusion injury will serve as
important endpoints.69
An important, and paradoxical, evolution is expected
to occur in the design of clinical trials of novel
neurothrombectomy techniques. For the past decade,
the major emphasis of neurothrombectomy trials has
been to progress beyond studies with technical efficacy
endpoints, such as reperfusion rates, to trials with final
functional outcomes as primary clinical endpoints, to
confirm that these interventions do improve patient
clinical course. However, now various trials have shown
that neurothrombectomy compared with no endovascular intervention does improve outcomes, future
neurothrombectomy trials will revert backwards. Tests
of new generation neurothrombectomy techniques,
with comparisons of innovative versus standard devices,
will generally need to use only early recanalisation and
other technical efficacy outcomes as primary endpoints.
Early recanalisation assessment will be crucial, as late
reperfusion is often futile and sometimes harmful.
Once analysis of proof of clinical efficacy in recently
reported trials70,71 is complete, early recanalisation is
likely to be established as an appropriate surrogate
outcome measure for device trials to predict improved
clinical outcomes. Additionally, only technical-endpoint
764

trials will have sufficient power to show superiority of
rapidly evolving device types.
Mechanical thrombectomy is expected to become the
standard of care in the intervention and control arms of
clinical trials; this will lead to improved outcomes in the
control group, necessitating much larger sample sizes in
phase 3 trials with final clinical outcomes as the primary
endpoint. As a result, phase 3 trials will need to have
large-scale, organised networks of stroke centres with
efficient mechanisms to contract patients and gain
approval from the institutional review board. Trial
designs that take advantage of electronic medical records
and large registries for data collection will be needed for
large scale, cost-effective trials.72 Increasingly, data
pooling across studies will also be needed to achieve
adequate power to address key issues such as sample
size, adjustment for baseline variables, and subgroup
analyses, and could be helped by use of open repositories
of data from completed clinical trials.73,74 Improvement of
study power by use of informative clinical endpoints and
statistical analytical approaches will become even more
important. An increase in uptake of linear, instead of
ordinal, outcome scales on the basis of item response
theory will be an efficient approach to outcome
assessment.75,76 Additionally, use of shift analyses and
sliding dichotomy, instead of simple dichotomy, when
analysing outcome spectrums will be more efficient.77,78
The survival advantage gained from early reperfusion is
likely to increase with longer follow-up of patients after
3 months, through to 1 or more years.79 Long-term
survival studies of endovascular interventions will also
www.thelancet.com/neurology Vol 14 July 2015

Personal View

be important, particularly in countries with information
readily available from central mortality registries.
Positive trials of multimodal imaging, to select latepresenting patients who are suitable for reperfusion
intervention, would also change the landscape for future
trials. Initial trials are likely to recruit so-called sweetspot patients with very large penumbral and small-core
volumes, who are most likely to respond to therapy.80
Subsequent trials of increasingly large scale would be
needed to define the penumbra and core volume
thresholds at which benefits disappear and harms
accumulate. Additionally, more trials of imaging techniques will be done, in which the imaging strategy,
rather than the treatment strategy, is the randomised
variable; for example, patients could be assigned to brief
versus extensive imaging, as in the recently launched
PRACTISE trial (NCT02360670), which compares noncontrast CT alone versus combined non-contrast CT and
CT angiography and perfusion CT in patients treated
with alteplase.

Evolution in systems of care
In many countries, the introduction of intravenous
fibrinolysis drove the development of organised regional
systems of acute stroke care. These regional systems are
largely single tier, with direct delivery of patients by
ambulance to primary stroke centres or to outlying acutestroke ready centres. The advent of proven endovascular
or late-imaging guided reperfusion therapies should
rapidly further substantial development in these regional
systems of care. Comprehensive stroke centres, which
provide endovascular interventions and multimodal
imaging, will become more widespread,81 with each
endovascular centre hub being associated with
3–10 hospitals.82 The emergency medical service would
route selected patients directly to comprehensive stroke
centres, especially those who are 3·5 h or longer from
stroke onset, and after the time window for standard
intravenous fibrinolysis, and those with the most severe
deficits, who are more likely to have large artery
occlusions (or intracerebral haemorrhage).83,84 Telestroke
systems are also expected to move from emergency
departments to mobile, often wearable, devices carried
by paramedics. These devices will enable real-time
surveillance, routing, and treatment decision making by
neurologists throughout the prehospital encounter.

Conclusions and future directions
The development of acute stroke therapies has been
challenging, with many disappointing trial outcomes and a
few successes. A new era of acute stroke therapy has
arrived, and planning must begin to implement the clinical
benefit with later-time-window endovascular therapy and
intravenous alteplase into routine practice to enhance how
acute ischaemic stroke care is organised and delivered.
Regional and national systems of acute stroke care centred
on stroke care units will need to be initiated in some
www.thelancet.com/neurology Vol 14 July 2015

Search strategy and selection criteria
We identified references for this review by searching PubMed
between Jan 1, 2000, and March 1, 2015. The following
search terms were used: ”ischaemic stroke”, “therapy”, “brain
imaging”, “endovascular”, and “clinical trials”. Articles were
restricted to those in English. Additional papers were
identified by searching of the authors’ personal files.

countries, and existing systems will need to be improved in
other countries. Many additional clinical trials will need to
be implemented and directed at novel therapeutic targets,
such as penumbral freezing, prevention of reperfusion
injury, enhanced recanalisation efficacy, and improvement
of endovascular devices. Trial design, implementation, and
outcome assessment will need to evolve to adapt to the new
reality of more therapeutic options of proven clinical
benefit at late time points. Advanced imaging is likely to
play an increasingly important part in clinical trials and
practice. Investigations will be needed to determine which
imaging approach is most helpful, particularly in clinical
settings and individual patient scenarios. The confluence
of better therapies, enhanced imaging capability to identify
the target of acute therapy in individual patients, and
enthusiastic, well trained, and motivated caregivers
worldwide bodes well for future advancements. Healthcare workers are poised to move from the end of the
beginning of acute ischaemic stroke therapy development
to an era of increasing treatment efficacy for many more
patients than can be helped at present. Now is the time to
begin considering the future and how to continue the
development of acute stroke treatment.
Declaration of interests
MF receives compensation from the American Heart Association for
serving as the Editor-in-Chief of Stroke. JLS is an employee of the
University of California (CA, USA). The University of California,
Regents receive funding for JLS’s services as a scientific consultant
regarding trial design and conduct to Covidien, Stryker, BrainsGate,
Pfizer, and St Jude Medical. JLS has served as an unpaid site
investigator in multicentre trials run by Lundbeck for which the
University of California Regents received payments on the basis of
clinical trial contracts for the number of patients enrolled. JLS is as an
unpaid consultant to Genentech advising on the design and conduct
of the PRISMS trial; neither the University of California nor JLS
received any payments for this voluntary service. The University of
California has patent rights in retrieval devices for stroke.
Contributions
MF and JLS created the concept, reviewed the literature, and wrote the
Review. JLS created figures 1 and 4 and the table.
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