Background
Mechanical
thrombectomy (MT) in combination with intravenous thrombolysis (IVT) is
the standard treatment for patients suffering from acute ischaemic
stroke (AIS) due to intracranial large vessel occlusion (LVO) in the
anterior circulation.1,2
The particular benefit of IVT in these patients is unknown. As a
result, various randomised controlled studies are currently being
conducted to determine if MT without IVT is equally effective
(SWIFT-DIRECT, NCT03192332; MR CLEAN NO IV, ISRCTN80619088; DIRECT MT,
NCT03469206). Recently, the randomised DIRECT-MT trial in China
indicated that MT was noninferior to the combined treatment.3
However, the ongoing SKIP trial in Japan could not establish that
skipping IVT was noninferior to the combined approach but was at least
associated with a lower risk of intracranial haemorrhage (ICH).4
Symptomatic
intracerebral haemorrhage is the main intracranial complication of IVT
with rates reported up to 8.8% according to the European Cooperative
Acute Stroke Study II (ECASS II) trial and associated with high
mortality rates.5,6
Nevertheless, in primary stroke centres (PSCs), the early initiation of
bridging therapy remains the only treatment for patients presenting
with AIS before admitting these patients to a MT-capable comprehensive
stroke centre (CSC). With increasing numbers of patients treated under
the ‘drip and ship’ paradigm, the occurrence of an IVT-associated ICH
prior to the endovascular procedure is becoming more likely.7
Studies analysing the benefit of MT in this subgroup are limited as
pre-interventional ICH remains an exclusion criterion for endovascular
therapy in clinical trials.8
Therefore, we aimed to report our multicentre experience with MT in
patients with AIS due to LVO suffering from IVT-associated ICH.
Methods
We
conducted a retrospective study of AIS patients undergoing MT at five
tertiary care centres in Germany between January 2010–September 2020.
All
patients included in the study were treated with MT due to LVO despite
the occurrence of an ICH after initiation of IVT. Inclusion criteria
were missing evidence of ICH on baseline imaging, application of IVT and
execution of additional imaging prior to the intervention (e.g. due to
deterioration of clinical symptoms) using multi-detector or
flat-detector computed tomography (CT) with detection of a newly
delimited ICH. Extent or location of ICH (parenchymal, subdural or
subarachnoid) were not exclusion criteria. Space-occupying effect of a
parenchymal haemorrhage was defined as any mass effect on adjacent brain
structures such as deep grey matter and gyri with narrowing of sulci,
midline shift or brain herniation. Early ischaemic damage was evaluated
using Alberta Stroke Program Early CT Score (ASPECTS) on first imaging
for the anterior and posterior circulation. In post-interventional
ASPECTS areas of intraparenchymal haemorrhage in the affected territory
were included in the assessment. Large vessel occlusion was defined as
any occlusion in cerebral arteries including distal internal carotid
artery (ICA), middle cerebral artery (MCA; M1 and M2 segments), distal
vertebral artery, basilar artery (BA) and posterior cerebral artery (P1
segment). Patient demographics, medical history, technical features,
angiographic and clinical outcome were noted. The aetiology of the
occlusion was based on the Trial of ORG 10172 in Acute Stroke Treatment
(TOAST) classification. In addition, the underlying aetiology for ICH
(e.g. neoplasm, aneurysm, cavernoma) and localization of the ICH
(in/outside the LVO affected territory) was reviewed. Any progression in
size with consecutive increase of perifocal oedema was defined as
aggravation of the ICH.
All patients received IVT and were treated
according to the widely accepted selection criteria with a weight-based
infusion of alteplase at 0.9 mg/kg over 60 min with a maximum dose of
90 mg. Ten per cent of the total treatment dose was given as a bolus
over 1 min. There were no limitations on procedural characteristics
including the use of different thrombectomy techniques, which were left
to the attending neuroradiologist’s discretion. Endovascular treatment
was performed with approved MT devices using stent-retrievers,
large-bore aspiration catheters or a combination of both.
Complete
reperfusion was defined as the Thrombolysis In Cerebral Infarction
(TICI) scale score of three. Successful reperfusion was defined as
TICI≥2b. Clinical efficacy outcome was the rate of functional
independence measured by the modified Rankin Scale (mRS) and defined as
0–2 at discharge and 90 days. National Institutes of Health Stroke Scale
(NIHSS) and mRS grades were assessed by a consultant neurologist.
Baseline NIHSS was collected at patients’ admission at the CSC.
According
to the guidelines of the respective local ethics committees, ethical
approval was given when necessary for this anonymous retrospective
study, which was conducted in accordance with the Declaration of
Helsinki. A patient’s consent for treatment was obtained according to
the individual institutional guidelines. Due to the retrospective nature
of the study, additional informed consent was deemed unnecessary.
Results
In
total, six patients from five tertiary stroke centres were treated with
MT due to LVO suffering from IVT-associated ICH. Procedural
characteristics per case are shown in Table 1.
Out of six patients, five patients received IVT at a PSC and were
subsequently transferred to a CSC for endovascular treatment
(‘drip-and-ship’ paradigm). One patient was directly transferred to a
CSC (‘mothership’ paradigm’). Alteplase was administered as the full
dose in patients treated by the ‘drip-and-ship’ paradigm. Median age was
80 years (interquartile range (IQR) 76–85 years) and 4/6 (67%) patients
were female.
| Table 1. Detailed demographic, procedural and outcome parameters. |
|
Table 1. Detailed demographic, procedural and outcome parameters.
Large
vessel occlusion of the BA was detected in 3/6 (50%) patients, two
patients suffered from MCA M1 and one patient from distal ICA LVO,
respectively. Five out of six (83%) individuals demonstrated cerebral
intraparenchymal haemorrhage on pre-interventional CT. Of those, 3/5
(60%) patients suffered from space-occupying haematoma. In one patient,
additional subdural haematoma was observed, and one patient suffered
from isolated subarachnoid haemorrhage (SAH). Five out of six (83%) ICH
events were localised in the LVO affected territory (Figure 1).
Cardioembolic
cause was the most common aetiology for the LVO and found in 3/6 (50%)
patients, followed by large artery atherosclerosis (1/6; 17%). Stroke
aetiology remained unknown in two patients. The underlying aetiology for
the ICH remained undetermined in all patients except for one, for whom
further work-up revealed vital cancer, which might have increased the
bleeding propensity. Four out of six patients had previous medication
with antiplatelet agents.
Median baseline NIHSS at CSC admission
was 22 and median baseline ASPECTS on first imaging was eight. The
initial NIHSS at the primary stroke centre was not documented in 5/6
patients. The median interval between (a) onset and IVT was 80 min (IQR
53–165 min), (b) IVT and groin puncture was 107 min (IQR 94–193 minutes)
and (c) onset and groin puncture was 240 min (IQR 190–340 min),
respectively. The rate of pre-treatment functional independence (mRS≤2)
was 50% (3/6).
Procedural and functional outcome
The
median time interval from groin puncture to final reperfusion was 70
min (IQR 61–146 min) and the median number of thrombectomy manoeuvres
was three (range 1–8). Successful reperfusion was achieved in 4/6 (67%)
patients. None of the six patients were reperfused completely. The
median ASPECTS in post-interventional CT was six. In the majority of
cases (5/6, 83%), the IVT-associated ICH had aggravated in
post-interventional imaging with space-occupying oedema.
Procedure-related,
minor SAH had occurred in 1/6 (17%) patients. In one patient,
intracranial stenting was performed (Case 6). The patient presented with
an occlusion of the proximal BA at a PSC (Figure 2)
and after IVT was administered, the patient was transferred to the CSC.
As the patients’ status had become impaired, CT imaging was done at the
CSC with evidence of slight SAH. The patient was transferred in the
angiography suite and the occlusion was recanalised successfully with
one aspiration attempt. However, a high-grade stenosis was confirmed in
the proximal BA segment, which re-occluded instantly. The operator
decided to implant a self-expanding stent with subsequent balloon
angioplasty, resulting in good reconstitution of the vessel. As the
patient was already pretreated with a daily dose of 100 mg of aspirin,
an intravenous infusion of tirofiban was initiated. Four hours later the
patient demonstrated wide and fixed pupils bilaterally. An emergency CT
scan showed a massive haemorrhage with intraparenchymal, subarachnoid
and subdural components. Surgical evacuation was not attempted, and the
patient died 2 days later.
Overall, five
patients had died during hospital stay. The survivor initially presented
with a non-space occupying ICH and achieved a complete resorption of
the haemorrhage at discharge; at 90 days, the clinical outcome was
moderate an mRS=4 (pre-treatment mRS=2, Case 4).
Discussion
We
provide the first report of a series of AIS patients with LVO suffering
from IVT-associated ICH prior to MT. Our study revealed several
findings: (a) the procedure is technically feasible with an adequate
rate of successful reperfusion, (b) the mortality rate of these subgroup
of patients is high (83%), and (c) the underlying cause for the ICH
remains undetermined in most cases.
As the presence of an
intracranial haemorrhage currently represents an exclusion criterion for
MT, the decision-making was done individually. In three of the affected
individuals, the haemorrhage was not space-occupying (Cases 2, 4 and
6). One patient showed haemorrhage outside the affected territory (Case
1). One patient suffered from a basilar artery occlusion and clinical
outcome is known to be devastating if occlusion will not be recanalised
(Case 5). In another patient (Case 3), it was the decision of the
operator and the neurologist as the patient was in her 80s, but
functionally independent prior to the stroke.
So far, there is one
case report about a successful MT in a 75-year-old patient with MCA
occlusion and pre-interventional IVT-associated ICH.8
The underlying cause for the ICH was probable cerebral amyloid
angiopathy and the patient was released with an excellent neurological
outcome (mRS=0). In comparison with our study, the patient had lower
NIHSS at admission (NIHSS=7) and was reperfused completely. In addition,
the IVT-associated ICH appeared not to be space-occupying.
The rate of successful reperfusion in our study was lower compared to the current literature5
and might be due to several factors. First, the median age of the
included patients was 80 years and all patients had arterial
hypertension with increased likelihood of difficult vascular access
resulting in longer procedure times, lower recanalization rates and
poorer outcome.9
Second, half of the occluded vessels were localised in the posterior
circulation. A recent study reported that futile recanalization occurred
more frequently in BA occlusions, and predictors of futile
recanalization included age, stroke severity, manoeuvre count and
intracranial stenting.10
In
our study, the mortality rate was high with 83% compared to patients
with LVO receiving IVT in the anterior circulation with rates up to 15%
in the interventional arm (MT and IVT) of the HERMES meta-analysis.5
It remains unclear whether the devastating clinical outcome in our
study was caused by the LVO or the ICH itself. Since the ICHs were
space-occupying in the majority of cases, it might have been attributed
most likely to the neurological aggravation. However, it has to be
mentioned that two of the patients were not reperfused successfully
(TICI=2a each), which is also accompanied with poor clinical outcome.11
In contrast to the deceased, the survivor in our cohort suffered from
an M1 occlusion and a small parenchymal haemorrhage, which had resorbed
completely at discharge. Although two other patients also showed
non-space-occupying ICHs on pre-interventional CT, the clinical outcome
was poor due to underlying BA occlusion and an aggravation of the ICHs
during the hospital stay. Although the presented number of patients is
low, it is conceivable that the extent of baseline ICH and expansion
after MT might influence patients’ outcome.
In this context, blood
pressure (BP) control might be one important factor affecting the
outcome. On the one hand, moderately elevated BP is associated with good
collateral circulation in AIS patients.12 On the other hand, high BP levels around reperfusion therapy carry an increased risk of ICH.13 In the status of vessel occlusion, low BP levels may lead to hypoperfusion of ischaemic tissue resulting in greater infarction.14
In the unlikely event of both, ICH and simultaneous cerebral LVO, the
optimal target BP remains indeterminable, since both variations provoke
poor neurological outcome.
In a meta-analysis risk factors for ICH
in AIS patients treated with IVT were identified including higher age,
higher stroke severity and higher glucose level.15
The study showed that there was approximately a doubling of the odds of
ICH with the presence of a visible acute cerebral ischaemic lesion on
pretreatment brain imaging.15
Some of these baseline factors are also reflected in our cohort
regarding high median age, high median baseline NIHSS, a median
ASPECTS=8 on baseline imaging, previous antiplatelet agents and
comorbidities. From this point of view, it might be reasonable in this
subgroup of patients, and more particularly in patients treated by the
‘drip and ship’ paradigm, to enforce a flat detector CT
pre-interventionally in case of deterioration of the patients’ status.
The
underlying cause for the IVT-related ICH was undetermined in most
cases. This might be due to the fact, that in most patients advanced
imaging including post-interventional magnet resonance imaging has not
been executed.
In patients with LVO based on an intracranial
atherosclerotic disease the treatment of the underlying stenosis is
challenging. In our study, one individual suffered from a slight
pre-interventional SAH and an acute high-grade stenosis of the BA. At
this point, the risk of progressive bleeding due to the necessity of
potent antiplatelet medication must be weighed against re-occlusion of
the vessel. The patient in our study was treated with intracranial
stenting and peri-interventional administration of tirofiban, which led
to a massive intracranial haemorrhage. In these specific cases,
alternatively a percutaneous transluminal balloon angioplasty might be a
reasonable treatment option with waiving of glycoprotein IIB/IIIA
inhibitors administration.
The main limitation of our study is the
retrospective nature including inherent selection bias and the usage of
different thrombectomy equipment and techniques. The lack of a control
group is a further limitation. As highlighted previously, the presented
number of patients is too low to draw definitive conclusions, especially
as half of the patients suffered from BA occlusion, which by itself is
accompanied with a poorer outcome compared to anterior circulation
strokes and might serve as a possible confounder. However, this
multicentre study includes the largest number of endovascularly treated
LVOs following IVT-associated ICHs in the literature so far.
Conclusion
Mechanical
thrombectomy in patients with IVT-associated ICH is technically
feasible. The clinical outcome of these patients appears to be
devastating with high mortality and only carefully selected patients
might benefit from endovascular treatment. However, until we have data
from larger trials, it will always be an individual decision but,
finally, it should be the goal to not leave individuals behind that
might benefit from endovascular treatment in this particular situation.
Yu Cui
Xin-Hong Wang1, 
Li-Hua Wang
Hui-Sheng Chen
