Key-words:
Intracranial aneurysm - stent-assisted coiling - wide neck
Introduction
The incidence of cerebral aneurysms, although difficult to estimate, is reported around
0.2%–7.9% in autopsy data.[[1]] The ratio of ruptured to unruptured (incidental) aneurysms is 5:3–5:6, making almost
50% of these aneurysm ruptures during life.[[1]] Morbidity and mortality in patients experiencing significant intraoperative rupture
are approximately 30%–35%,[[1]] thus making this pathology rather challenging to treat. Risk for rupture for incidental
findings depends on many factors. Among them, aneurysm diameter is mostly important,
with an estimated annual risk for aneurysms of diameter <10 mm at 0.05% and more than
1% for those with diameters >10 mm.[[1]]
The optimal treatment for unruptured intracranial aneurysms (UIAs) depends highly
on the patient's general condition, the anatomy of the aneurysm, and the surgeon's
experience and must be weighed against the natural history of the condition. Treatment
options include surgical clipping across the neck of the aneurysm or vascular bypass
to maintain flow distal to trapped segment.[[1]] At the same time, there have been considerable developments in the field of endovascular
technology concerning various methods for the cure of intracranial aneurysms. What
is more, the basic coil occlusion technique[[2]] has expanded in terms of use through the evolution of the soft and three-dimensional
coil technology, along with the Guglielmi coil first use in 1991.
The introduction of balloons and stents to the endovascular armamentarium[[2]] has allowed better efficacy during endovascular coiling, not only on small-to-medium-sized
aneurysms with narrow necks but also on wide-neck aneurysms' treatment. Stents with
additional use of the coils reduce the possibility of dissection or vessel rupture.
Implanting a stent across the neck area is used as a prop to the coil mass, thus collaborating
to a change in the local hemodynamic parameters. This results in directing the flow
and providing a substrate for endothelialization in that area,[[2]] while it is obvious that a self-expanding stent can be easily positioned in the
intracranial vessel.[[3]] As far as wide-necked aneurysms are concerned (namely aneurysms with an aspect
dome-to-neck ratio of <2 or with a neck size >4 mm), it should be noted that the latter
has the possibility to be coiled with the assistance of balloon-assisted techniques
or stent-assisted coiling (SAC).[[2]]
The aim of this systematic review and meta-analysis was to investigate the clinical
outcomes of SAC limited to the UIAs with wide neck. We explored the literature in
terms of case series, concerning the mortality and the morbidity, the complications,
the access, and the techniques of the method.
Materials and Methods
This meta-analysis was conducted using the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses guidelines. Google Scholar, PubMed, and Cochrane Collaboration
were systematically searched for relevant publications, while we followed a snowball
process in the reference lists of the eligible articles to retrieve additional relevant
articles.
We used the following terms for search purpose: stent-assisted coiling, intracranial
aneurysm, and wide neck. We searched for all scientific papers, without gender or
language restriction, until January 2019. We investigated studies focusing on SAC
limited to the UIAs with wide neck, including aneurysms with an aspect dome-to-neck
ratio of <2 or with a neck size >4 mm. Studies reporting on intracranial aneurysms
without wide neck and on ruptured intracranial aneurysms with wide neck were excluded.
Data extracted from eligible studies included the first author's name, study year,
country in which the study was conducted, total number of patients, number of male
or female patients, follow-up (months), the mean age of patients, inclusion and exclusion
criteria, vascular access (transfemoral), type of anesthesia applied, type of anticoagulation
used, type of endograft used, and description of complications during follow-up.
We also extracted the number of patients with outcomes, which were thereafter described
as early and late. Early outcomes were defined as outcomes during the periprocedural
period and late ones as those ones occurring beyond this period. Outcomes of interest
included the following: technical success, defined as stable device placement and
adequate function on computed tomography angiography, total periprocedural obliteration,
periprocedural rupture, total obliteration during follow-up, overall late rupture,
pooled in-stent stenosis, total mortality, any neurological complication, stroke,
and recanalization.
Statistical analysis
The outcome rates in patients with SAC in UIAs with wide neck were estimated for each
study and reported as the proportion of patients with the corresponding outcome among
all patients with SAC in UIA with wide neck. Values of the concomitant outcomes were
subsequently appropriately calculated, expressed as proportions and 95% confidence
intervals (CIs), and thereafter transformed into quantities according to the Freeman–Tukey
variant of the arcsine square-root transformed proportion. The pooled effect estimates
were calculated as the back-transformation of the weighted mean of the transformed
proportions, using DerSimonian–Laird weights of a random-effects model, and expressed
as percentage proportions. One meta-analysis was conducted taking into account all
case series.
Formal statistical test for heterogeneity using the I2 test was performed. Publication
bias was assessed using the Egger test for small-study effects as well as visual inspection
of funnel plots. We used Stata statistical software version 14 (StataCorp LP, College
Station, TX, USA) for the analyses.
Results
Study characteristics
We identified 886 potentially eligible studies after a literature search [[Figure 1]]. We excluded a total of 82 duplicate records, as well as 17 articles which were
referred to in vitro experiments and in vivo ones based on laboratory animals. Further,
76 case reports and 3 articles were referred to children and were also excluded. Review
of the titles and abstracts evidenced that 201 articles were irrelevant. We also removed
323 articles because they were reviews and not original articles or they did not refer
to aneurysms with wide neck. A total of 184 articles were further evaluated. Among
them, 130 and 28 articles including both ruptured and unruptured aneurysms with wide
neck or only ruptured ones, respectively, were excluded. Finally, 26 articles were
deemed relevant to be included in the systematic review. However, 11 articles were
further excluded as they were referred to endovascular treatment of UIAs with wide
neck using flow diverters or temporary stent, as well as 2 articles, because of overlapping
population. Eventually, 13 articles participated in the meta-analysis,[[4]],[[5]],[[6]],[[7]],[[8]],[[9]],[[10]],[[11]],[[12]],[[13]],[[14]],[[15]],[[16]] corresponding to a total of 976 patients who underwent SAC of their UIAs with wide
neck [Supplemental Table 1].
Figure 1: Flowchart of eligible studies
The included eligible studies in the systematic review were published from 2005 to
2017. Among 976 patients included in our systemic review, 384 were females (72.6%).
For another 447 patients, the gender was not specified. The access vessel was noted
in 466 of 976 patients. Among them, the device delivery system was advanced transfemorally.
Neuroform and Enterprise devices were used in the majority of the patients. The procedure
took place under general anesthesia in 460 cases (47.1%), whereas the type of anesthesia
was not reported for the remaining patients. The age of the study sample ranged from
18 to 80 years, with an average age of 50 years, and the median follow-up ranged from
6 months to 2 years. The majority of the patients had also aneurysms placed in the
anterior circulation. It is worth noting that the majority of the aneurysms in the
posterior circulation were located on the basilar tip, while 69 patients with paraclinoid
aneurysms were included in our review study. Studies on patients with blister aneurysms
were excluded. Moreover, studies on fusiform (n = 500 patients), dissecting (n = 384
patients), mycotic/traumatic (n = 116 patients), or saccular (n = 116 patients) aneurysms
were also excluded from our meta-analysis. Finally, antiplatelet drugs were routinely
administrated during the periprocedural and postprocedural period along with intravenous
heparin during procedure.
Meta-analysis
Our meta-analysis found that the technical success of the method was 98.43% [95% CI:
95.62–99.95; [[Figure 2]]]. Among the other early outcomes, total periprocedural obliteration was at 50.20%
[95% CI: 36.09–64.30; [[Figure 3]]], while periprocedural rupture was zero. The pooled rate for total obliteration
during follow-up was 63.83% (95% CI: 45.80–80.18), while overall late rupture was
estimated at 0.41% (95% CI: 0.00–2.38). However, this figure was estimated from only
four studies,[[4]],[[7]],[[9]],[[12]] corresponding to only 4 events out of 365 patients, as these studies were the only
which provided with corresponding data. Similarly, the pooled in-stent stenosis rate
was 1.24% (95% CI: 0.02–3.63), and it was estimated from six studies,[[5]],[[8]],[[10]],[[12]],[[14]],[[15]] with 8 events out of 261 cases during follow-up.
Figure 2: Forest plot presenting the meta-analysis of technical success based on event rates
for the use of stent-assisted coiling of unruptured intracranial aneurysms with wide
neck. Event rates in the individual studies are presented as squares with 95% confidence
intervals presented as extending lines. The pooled event rate with its 95% confidence
intervals is depicted as a diamond
Figure 3: Forest plot presenting the meta-analysis of total periprocedural obliteration based
on event rates for the use of stent-assisted coiling of unruptured intracranial aneurysms
with wide neck. Event rates in the individual studies are presented as squares with
95% confidence intervals presented as extending lines. The pooled event rate with
its 95% confidence intervals is depicted as a diamond
Total mortality was estimated with a pooled rate of 0.02% (95% CI: 0.00–0.51). Any
neurological complication and stroke rates were found to be 4.33% [95% CI: 2.03–7.23;
[[Figure 4]]] and 3.94% (95% CI: 1.48–7.33), respectively. Finally, regarding recanalization,
the pooled rate was 7.07% (95% CI: 4.35–10.26).
Figure 4: Forest plot presenting the meta-analysis of any neurological complications based
on event rates for the use of stent-assisted coiling of unruptured intracranial aneurysms
with wide neck. Event rates in the individual studies are presented as squares with
95% confidence intervals presented as extending lines. The pooled event rate with
its 95% confidence intervals is depicted as a diamond
Discussion
The meta-analysis was derived from a comprehensive review of 13 case series and provided
pooled outcome rates for patients treated with SAC for intracranial aneurysms with
wide neck. Although high-risk patients constituted our study cohort, a high technical
success rate of 98.4% was recorded.
Concerning anatomical results, our rate of immediate complete occlusion was lower
(50.20%) than in a meta-analysis for stand-alone coiling (86.1%).[[17]] This can be explained by the fact that coil packing after stent placement maneuverability
and the use of dual antiplatelet therapy and heparin during the procedure may limit
thrombosis around coil mass. The low rates of complete occlusion underline potential
difficulties of SAC in relation to aneurysmal morphology, such as the size and localization.
It was observed that, contrary to comparatively nonsatisfactory instant anatomical
results, complete occlusion was achieved at follow-up reaching 63.83%. The thrombosis
that is in progress could be further made clear through various speculations and theories.
Primarily, certain computational and animal studies indicated that conventional self-expanding
stents provoke a lessening of the flow velocity to the aneurysm and secondary wall
shear stress.[[18]],[[19]],[[20]],[[21]] It is also noteworthy that an arterial angular remodeling with migration and narrowing
of the flow impingement zone along with a decrease in apical pressure are caused by
intracranial stents. Certain alterations to the inflow to the sac that might result
in thrombosis[[22]] could also be caused by the straightening. Finally, it should be highlighted that
the stent struts that are connecting the aneurysmal neck might as well function as
a bioactive scaffold for neointimal growth.[[22]] For the same reasons that promote progressive aneurysm occlusion, the rate of recanalization
of intracranial aneurysms by SAC is low, as also confirmed by our study (7.07%). This
rate is also significantly lower than in meta-analyses for a stand-alone coiling (24.4%).[[17]]
The mortality and neurological complication rates (0.02% and 4.33%, respectively)
reported in our meta-analysis also compare favorably with those reported in the meta-analysis
for stand-alone coiling (1.2% and 4.8%, respectively) and for clipping (1.7% and 6.7%,
respectively),[[17]],[[23]] as well as with those mentioned in the studies for balloon-assisted coiling of
intracranial aneurysms using the Eclipse 2L double-lumen balloon (0% and 3.2%, respectively)
and for low rates of recanalization for wide-necked aneurysms treated with stenting
after balloon-assisted coiling (4.6% and 2.3%, respectively). However, we should highlight
that in the aforementioned studies for balloon-assisted embolization, the initial
complete occlusion rate was approximately 95% higher than this in our study (50.20%).
This may have resulted from balloon-assisted technique because the technique can enable
denser packing of the aneurysm fundus and neck region or help mold the coil mass to
improve its interface with the parent vessel.[[24]],[[25]]
Regarding the rate of stroke, this was almost 4%. Several factors may explain our
low rate of stroke. Primarily, a tight antiplatelet protocol was pursued by the people
in treatment. Furthermore, since a progressive thrombosis of the sac is anticipated
because of a stent placement, we do not usually dare to acquire neither an immediate
occlusion nor a very dense packing. As a third step, it should be mentioned that ruptured
intracranial aneurysms with a high chance of being linked to an elevated stroke risk
were not incorporated. The latter is due to the fact that ensuing subarachnoid hemorrhage
induces vasospasm.[[2]] In addition, the interventional neuroradiologists usually make an attempt to get
a denser packing with a view to succeed in obtaining complete occlusion and further
reduce bleeding chances. As a result, there is an elevated chance of coil protrusion
at the area of the neck or in the parent artery than in unruptured aneurysms. The
coil protrusion might end up in causing thromboembolic events (TEs). Finally, it should
be noted that there is a possibility that the availability of the intracranial stents
assists in the reduction of the percentage of symptomatic TE complications of coiling
used as a rescue therapy to treat coil protrusion or instability and clot formation
at the neck.[[26]]
In our series, we did not observe intraprocedural aneurysmal ruptures, while this
rate was 2.6% according to the meta-analyses for stand-alone coiling.[[17]] The zero rate of aneurysmal rupture may be partially related to the fact that,
when possible, the authors of studies in our review did not place the guidewire in
the sac but tried to gently advance a microcatheter through the stent. It is worth
noting that the overall late rupture was only 0.41%, which could be explained partially
by the fact that additional treatment with coils was decided in some cases[[11]] and the discontinuance of the antiplatelet therapy after some months according
to the protocols.
A usual aggravation in-stent stenosis is atheromatous stenosis that is less important
to endothelial and fibroelastic reaction. Despite the fact that not a major intimal
damage could occur due to self-expanding stents used for stent coiling (SAC), the
latter definitely takes place and most possibly causes stability or improvement of
the occlusion of intracranial aneurysms with SAC. What is more, this could further
cause a certain kind of intrastent stenosis, something which was not common in our
series (1.25%). This could be explained by the fact that surgeons administrated routinely
antiplatelet therapy including aspirin (325 mg the usual dose) and clopidogrel (75
mg the usual dose) mainly 5 days prior to surgery in combination with 5000 iu heparin
intravenous bolus periprocedural which continued usually for additional 6 months for
aspirin and 3 months for clopidogrel postprocedural since acute in-stent stenosis
often elicits ischemic complications. However, as the premature or excessive prevention
of in-stent stenosis may result in hemorrhagic complications before coil embolization,
additional treatment for acute in-stent stenosis being delivered after its occurrence
could be an option. It is also important to mention that in our study, even this negligible
percentage for in-stent stenosis could be justified by aspirin or clopidogrel resistance.
The platelet reactivity units should be measured as well as the appropriate dose of
other drugs should be determined as an interaction is possible.
Among the SAC limitations are the necessity for double antiplatelet therapy, which
is advisable to be kept for a period of 1 month at least. However, this might change
in light of coated or absorbable stents.[[15]] Our findings highlight that SAC is a considerable technical progress in the management
of endovascular intracranial aneurysms. It is associated with low rates of morbidity,
further enabling a safer treatment of wide-necked UIAs, which is supported by the
large number of 976 patients who participate in our meta-analysis.
Our study has some limitations. First, in the meta-analysis, we included mainly retrospective
studies that did not directly compare different techniques. Second, follow-up images
were homogeneous as they were mainly magnetic resonance angiography (MRA) and digital
subtraction angiography. However, MRA has been reported to be highly effective and
reliable for the follow-up of SAC.[[27]] Third, heterogeneous aneurysm morphology and location can contribute to treatment
bias since they are related to difficulties of endovascular techniques. Similarly,
the modality of treatment including different choices of stents by physicians in different
institutions is related to treatment bias. Other limitations of the eligible studies
included in the meta-analysis were that not all patients complied with treatment during
follow-up, along with the fact that some results were attributed to small number of
cases, which were referred during follow-up. These two aforementioned limitations
might have introduced an indirect publication bias in our study. Finally, in our series,
morbidity was associated with TEs. This may have reflected the importance of adequate
antiplatelet agent preparation before and even after the successful procedure. Practically,
checking for antiplatelet agent resistance on a regular basis would be helpful, but
it was not available in the eligible studies.
Conclusions
Our review and meta-analysis pooled together outcome rates of relevant studies and
highlighted the feasibility and safety of SAC of UIAs with wide neck. SAC is a relatively
new technique, and we might need more experience before sound conclusions can be drawn.
In spite of the fact that it might still be premature to make a generalization of
the results, it seems that this technique might assist in the treatment of UIA with
wide neck and SAC represents an acceptable alternative to surgical clipping.
