Risk Factors for Unfavorable Angiographic Outcomes after Reconstructive Endovascular Treatments of Unruptured Vertebral Artery Dissecting Aneurysms
Article information
Abstract
Objective
To investigate the clinical and radiological features of unruptured vertebral artery dissecting aneurysms (uVADAs) treated with reconstructive endovascular techniques and to evaluate the risk factors associated with unfavorable radiological outcomes while focusing on the flow diversion effect.
Methods
We retrospectively reviewed 86 patients with uVADAs treated at a single tertiary center between January 2009 and December 2022. The patients were categorized into the flow diversion group (patients with uVADAs treated with a flow diverter or multiple stents) and the non-flow diversion group (patients with one or fewer stent insertion). Unfavorable angiographic outcomes were defined as 1) recurrence after coil insertion regardless of stent deployment or 2) no regression after stent insertion without coil packing. Univariate and multivariate analyses were performed to assess the related risk factors.
Results
We observed 37 uVADAs in the flow diversion group. Recurrence or no regression occurred in two of 37 (9.1%) and 13 of 49 (27.7%) uVADAs in the flow and non-flow diversion groups, respectively. The treatment without flow diversion effect (non-flow diversion group; odds ratio [OR], 8.04; 95% confidence interval [CI], 1.23–52.57; p=0.003) and hypertension (OR, 22.09; 95% CI, 2.51–194.2; p=0.005) were significantly associated with unfavorable angiographic outcomes.
Conclusion
The flow diversion effect using a flow diverter or multiple stents insertion, along with strict blood pressure control, may be an important factor in achieving favorable angiographic outcomes in uVADA treatment.
INTRODUCTION
Vertebral artery dissecting aneurysms (VADAs) are rare but clinically significant vascular lesions with an incidence of approximately 1 to 1.5 per 100000 people [1]. Often, they are characterized by a wide range of clinical manifestations, ranging from asymptomatic findings to dismal subarachnoid hemorrhage. Ruptured VADAs (rVADAs) have a high rebleeding rate after the initial hemorrhage, thus requiring immediate treatment. Parent artery occlusion (PAO), including the dissected segment, is a traditional treatment modality for rVADAs owing to its high complete occlusion and low recurrence rates [2]. PAO is regarded as the definitive treatment for rVADAs; however, this deconstructive technique can lead to severe ischemic complications [3].
Unruptured VADAs (uVADAs) may remain asymptomatic, and such cases can be resolved with conservative management. They require more aggressive treatment depending on the clinical and radiological status, including the initial size and shape, changes in size and shape over time, and related ischemic symptoms or mass effects. However, a consensus on the optimal treatment for uVADAs has not been established clearly. PAO is the most definitive treatment for uVADAs; nonetheless, physicians may be reluctant to treat uVADAs with PAO owing to the potential risk of ischemic complications [3-6]. Therefore, they prefer reconstructive endovascular techniques as primary treatment options for uVADAs. These interventions include coil embolization, stent-assisted coil embolization, multiple overlapping stenting, and flow-diverting stenting. In cases with a fusiform shape and posterior inferior cerebellar artery (PICA) incorporation, the use of detachable coils is technically difficult. The concept of flow diversion has become more prevalent in VADA treatment with the advent of stent technology. The flow diversion effect, which redirects the blood flow away from the aneurysm via multiple overlapping stents or flow-diverting stents strategically, can promote thrombosis inside the aneurysm and rebuild the neointima over the stents [7]. Some investigators have suggested the efficacy and safety of multiple overlapping or flow-diverting stents for uVADAs in case series [4,7-16]. However, they have not compared the clinical and radiological outcomes of various reconstructive methods for uVADA while focusing on the flow diversion effect.
Therefore, in this study, we aimed to investigate the clinical and radiological features of uVADA treated with various reconstructive endovascular techniques and to evaluate the risk factors associated with unfavorable radiological outcomes while focusing on the flow diversion effect.
MATERIALS AND METHODS
Study population and clinical characteristics
This study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital (IRB; IRB No. KC21RISI0565). Because this was a retrospective review of existing data, the IRB waived the requirement for informed consent. Between January 2009 and December 2022, 4807 cases of intracranial aneurysms were treated using endovascular techniques at a single tertiary center. Among them, 153 were diagnosed as VADA, 42 of which were ruptured. Among the 111 patients with uVADA, 25 were treated with PAO. We included 86 patients diagnosed with uVADA who underwent reconstructive endovascular treatment. Patients with a history of recent major trauma (within 3 months), such as head or cervical injury, were excluded during screening to reduce diagnostic ambiguity related to traumatic dissections. The baseline clinical characteristics included age, sex, medical history (hypertension, diabetes mellitus, and hyperlipidemia), and history of tobacco use. Hypertension was diagnosed if the patient was under antihypertensive medications and had a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg. Hyperlipidemia was defined as use of antihyperlipidemic medications or a total cholesterol level of 240 mg/dL.
Radiological evaluation and endovascular procedures
All the enrolled patients underwent digital subtraction angiography (DSA), including 3D rotational angiography. Detailed angiographic findings and endovascular treatment details were extracted from their medical records. The radiological characteristics, including recurrence or no regression, maximal size, shape of the uVADA, PICA involvement, vertebral artery (VA) dominance, and brainstem compression, were reviewed through DSA, magnetic resonance imaging (MRI), or computed tomography (CT) angiography with the consensus of two independent investigators. Based on the endovascular technique used, the patients were categorized into groups of flow diversion (treated with multiple overlapping stents or a flow-diverting stent) and non-flow diversion (treated with one or fewer stent insertion). The treatment modality was determined by discussions among the neurovascular team, which consisted of experienced neurovascular neurosurgeons and a neurointerventionist. We used two or three stents with a low-profile visualized intraluminal support (LVIS) Stent (MicroVention, Tustin, CA, USA) or Enterprise Stent (Codman Neurovascular, Miami Lakes, FL, USA) in the multiple overlapping stenting groups. In the multiple stenting groups, we deployed a laser-cut closed-cell stent as a scaffold, followed by braided stents in a stent-within-stent fashion in a single-session treatment [15]. In addition, we used a pipeline embolization device (PED) (Covidien/Medtronic, Irvine, CA, USA), flow-redirection endoluminal device (MicroVention), and Surpass Evolve Flow Diverter (Stryker Neurovascular, Kalamazoo, MI, USA) for the flow-diverting stent. Given our reimbursement system, we placed only one flow diverter without coil insertion for a single patient.
Outcome assessment
In our institution, we defined VADA when we found fusiform dilatation and/or irregular shape in the VA, along with an intimal flap, mural hematoma, or thrombus on MRI or CT images. We considered treatment for hemodynamically unstable intracranial cases, which change in shape and size on short-term follow-up images. Indications for treatment included a history of subarachnoid hemorrhage; increased dissection size or change shape at follow-up; and contrast stagnation sign with more than 10 mm in size, VADA >10 mm, and irregular shapes or blebs [17,20]. An irregular aneurysm surface was defined according to the following features based on DSA : 1) definite and large blebs on the main dilated segment or 2) a dilated segment consisting of multiple lobulations [17,20]. Aneurysm size was measured as the maximum distance between the neck and the dome or the height of the aneurysm on DSA. We defined PICA-involved aneurysms as those in which the PICA branch originated from the aneurysm and excluded those in which the dissection extended to the basilar artery. The location of VADA was also classified as dominant VA, hypoplastic VA, or codominant VA on DSA. Dominant VA was defined as 1) the only VA with no contralateral VA or 2) the VA with the larger diameter if the diameter of the ipsilateral VA was 0.3 mm larger than the contralateral VA [18]. In this study, unfavorable angiographic outcomes were defined as 1) recurrence after coil insertion regardless of stent deployment or 2) no regression after stent insertion without coil packing. Recurrence was defined as an increase in the aneurysm size caused by coil loosening or compaction after the initial treatment on follow-up angiography. No regression indicated marginal or no effect (O’Kelly-Marotta grading [OMG] scales C and D) after the insertion of a single stent, multiple overlapping stents, or a flow-diverting stent at the final follow-up. We used this scale for the angiographic assessment because it was explicitly designed for radiologic evaluation after flow-diverting stent placement. This system consists of four grades : A, complete (>95%); B, incomplete (5%–95%); C, neck remnant (<5%); and D, no filling (0%).
Given that the majority of patients with uVADA presented with minimal or no neurological deficits (baseline modified Rankin scale [mRS], 0–1), the change from baseline was minimal in most cases. Therefore, the final mRS score at follow-up was considered an appropriate and pragmatic indicator of good clinical outcome, defined as mRS ≤2.
Statistical analysis
Statistical analyses were performed using SPSS software (version 28; IBM Corporation, Armonk, NY, USA). Descriptive statistics are presented as mean±standard deviation or median (interquartile range) for the continuous variables and as frequencies (percentages) for the categorical variables. We performed a univariate analysis to assess the potential risk factors for unfavorable angiographic outcomes. Factors with a p-value <0.10 in the univariate analysis were further evaluated in the multivariate logistic regression analysis to identify the independent risk factors. We calculated each factor’s odds ratio (OR) with a 95% confidence interval (CI). A p-value <0.05 was considered statistically significant.
RESULTS
Baseline characteristics
Table 1 summarizes the clinical and angiographic characteristics of the 86 uVADAs in 86 patients treated endovascularly. The mean age was 52.9±11.9 years, and there were 45 men (52.3%). The most common presenting symptoms or signs of uVADAs were incidental findings (n=35, 40.7%), followed by headaches (n=33, 38.4%), dizziness (n=6, 7.0%), brainstem compression (n=5, 5.8%), recanalization (n=5, 5.8%), and cerebral infarction (n=2, 2.3%). Hypertension was the most common comorbidity in 40 patients (46.5%), followed by hyperlipidemia and diabetes mellitus (n=14, 16.3% and n=8, 9.3%, respectively). Approximately 20 patients (23.2%) had a history of tobacco use.
Baseline characteristics
The mean maximum aneurysm size was 11.7±6.2 mm. We identified 42 (48.8%) large aneurysms. The aneurysm shape was categorized as pearl and string (dilatation with stenosis, n=46; 53.5%), fusiform dilatation without stenosis (n=16, 18.6%), saccular dilatation without stenosis (n=19, 22.1%), and recanalized (n=5, 5.8%). The patients were treated without (stent ≤1 with or without [w/wo] coil : 49, 57.0%) and with flow diversion (stents ≥2 w/wo coil : 14, 16.3%) (flow diverter without coil : 23, 26.7%). Of the 14 patients, three underwent triple, and 11 underwent double stenting. The recurrence and retreatment rates were 15.1% (13/86) and 2.3% (2/86), respectively. Good clinical outcome (mRS score ≤2) was achieved in 85 patients (98.8%) after a median clinical follow-up period of 42.3±32.9 months and a radiological follow-up period of 35.7±25.5 months. The OMG scale was initially grade A in 0 patients, grade B in seven patients (8.1%), grade C in 18 patients (20.9%), and grade D in 58 patients (67.4%).
Clinical and radiological outcomes
Table 2 presents the clinical and radiological outcomes according to treatment modality. All the patients with uVADAs underwent endovascular procedures. Forty-nine patients underwent non-flow diversion treatment with one or fewer stent insertion, whereas 37 underwent flow diversion treatment with multiple overlapping stents or a flow-diverting stent. In the flow diversion group, 14 patients underwent multiple overlapping stent treatments, and 23 patients received a flow-diverting stent. The rates of concurrent coil use with a single, multiple overlapping, and flow-diverting stent were 89.9% (44 of 49), 42.9% (six of 14), and 0% (0 of 23), respectively. Most saccular aneurysms were treated without flow diversion (15 of 19), whereas fusiform aneurysms predominantly underwent flow diversion (10 of 16). The mean follow-up periods, according to treatment modality for the non-flow diversion group, was the longest (clinical 51.0±39.9, radiological 39.9±29.5), whereas the flow diverter group within the flow diversion group had a relatively short mean follow-up duration (clinical 16.4±15.4, radiological 13.2±14.8). The recurrence rate (no regression of the flow diverter) was significantly lower in patients treated with multiple overlapping stents (0.0%) and a flow-diverting stent (8.7%) than in those treated with one or fewer stent insertion (27.7%) (p=0.027). However, favorable radiological outcomes were not significantly different.
Comparison of clinical and radiological characteristics according to treatment modality
Risk factors associated with recurrence or no regression
Table 3 summarizes the results of the univariate and multivariate analyses of the risk factors associated with recurrence or no regression in uVADAs. The multivariate logistic regression analysis demonstrated that hypertension (OR, 22.09; 95% CI, 2.51–194.2; p=0.005) and treatment without flow diversion effect (OR, 8.04; 95% CI, 1.23–52.57; p=0.030) were significantly associated with recurrence or no regression. We observed no statistically significant differences among the other variables.
Univariate and multivariate analyses of risk factors associated with recurrence or no regression of unruptured vertebral artery dissecting aneurysms
To address concerns regarding the heterogeneity within the flow diversion group, we performed a subgroup analysis among : 1) patients with multiple overlapping stents without coil insertion (true multiple stents), 2) those with multiple overlapping stents with coil insertion, and 3) those with flow diverter without coils. Notably, recurrence did not occur in any of the multiple stent subgroups, regardless of coil usage, while the flow diverter group had a no regression rate of 8.7%. These results suggest that the flow diversion effect itself—whether through multiple stents or a flow diverter—was independently effective, and the presence of coil packing may have had a supportive but not primary role.
We further stratified the multiple stent group by the number of stents used. Among 14 patients, 11 received double stenting and three received triple stenting. Recurrence was not observed in either group.
DISCUSSION
In this study, we demonstrated that the flow diversion effect using a flow-diverting stent or multiple overlapping stents deployments may be an important factor in achieving favorable angiographic outcomes in uVADA treatment. A flow-diverting stent has a high metal coverage rate and can alter blood flow into the aneurysm. This, in turn, can promote endothelial growth over the aneurysm neck, resulting in intra-aneurysmal thrombus formation and gradual aneurysm size reduction [13]. Some studies have reported good results in using a flow-diverting stent to treat uVADA, with favorable occlusion rates (56–91%) and safety outcomes (0–17%) [4,8-12]. Gölitz et al. [10] reported that a flow-diverting stent may stabilize the dissection flap against the wall and prevent further progression of VADAs. Similarly, the concept of multiple overlapping stents was adopted from an isolated case series in previous studies. Lim et al. [24] reported that overlapping the enterprise stent with the LVIS Blue stent increased the metal coverage surface area by up to approximately 33% in a straight vessel, such as VA. VA often has a relatively straight morphology compared with other anterior circulation vessels, which may explain why multiple stents in the VA have shown good results in the current study. This result is comparable with the nominal metal surface coverage ratio of the PED, which ranges from 30% to 35% [14]. As illustrated by our representative case in Fig. 1, deploying multiple overlapping stents in a 38-year-old man with an uVADA resulted in complete occlusion and favorable vascular remodeling, underscoring the effectiveness of this approach.
Illustrative case of unruptured VADA treated with multiple stenting. A 38-year-old man presented with sudden posterior neck pain. A : 3D-RA showing pearl-and-string-shaped unruptured VADA involving dominant right VA. B : Pre-procedural DSA. C : Follow-up 3D-RA after triple stenting showing complete occlusion and vascular remodeling. VADA : vertebral artery dissecting aneurysm, 3D-RA : 3D rotational angiography, VA : vertebral artery, DSA : digital subtraction angiography.
Moreover, by deploying a stent within the stent across the neck of the aneurysm, the operator can reduce the porosity of the stent construct. However, flow diverters and other braided stents (such as LVIS) have potential limitations, particularly in transition zones where porosity may increase; therefore, we usually deploy a laser-cut closed-cell stent as a scaffold. This was followed by deploying braided stents, such as LVIS, with a higher metal coverage rate as a stent-within-stent technique. We guessed that this method of using multiple stents might have contributed to better outcomes than solely using flow diverters because it effectively addresses the issue of increased porosity in transition zones. Furthermore, this method may alter the flow within the aneurysm, straightening the parent vessel and increasing radial force, promoting stasis and immediate thrombosis, and allowing for subsequent neointimal endothelial formation [16,19]. Kim et al. [18] reported that the deployment of multiple stents significantly altered the hemodynamic parameters of patient-specific aneurysms. After multiple overlapping stent placements, the area of low wall shear stress (WSS) increased in the dome of the aneurysm. The elevated WSS area was reduced significantly by double stenting (54.8–70.4%) and triple stenting (21.8–24.3%). Wang et al. [35] reported a significant reduction in the WSS (63.88%) and velocity (46.05%) in the double-LVIS stents. A single pipeline caused less reduction in WSS (51.08%) and velocity (37.87%) than a double-LVIS stent. The double-pipeline stents resulted in the greatest reduction in WSS (72.37%) and velocity (54.26%). Therefore, the multiple overlapping stents technique can be used to cover VADAs with a flow diversion effect.
In this study, 37 (43%) uVADAs were treated in conjunction with the flow diversion effect, including multiple overlapping stenting (n=14) and flow-diverting stent techniques (n=23). We achieved a high rate of favorable clinical outcomes (37/37 patients, 100.0%) and angiographic outcomes (no recurrence or no regression : 34/36 patients, 94.4%) at the final follow-up. Previous studies have reported a recurrence rate of 11.1% to 50% and retreatment rate of 5.9% to 11.1% [22-26]. The overall recurrence and retreatment rates of the current study were 15.1% and 2%, respectively; compared with other studies, our study demonstrated reasonable rates of recurrence and retreatment. Our findings align with those of studies that suggested that recurrence rates were lower when the flow diversion effect was used than when the flow diversion effect was not used [27,28]. This phenomenon may be attributed to the superior capacity of the flow diversion effect of uVADAs to induce intra-aneurysmal thrombosis and promote neointimal growth over the aneurysm neck, which consequently leads to complete and sustained aneurysm occlusion [29].
Moreover, we identified hypertension as a significant risk factor for unfavorable angiographic outcomes. Hypertension is an established risk factor for the formation and rupture of intracranial aneurysms [30,31]. It promotes atherosclerosis and postinflammatory vascular remodeling, possibly enhancing aneurysm progression [21,32,33]. Systemic hypertension and abnormal hemodynamic stress can activate the local renin-angiotensin system in the vessel wall, leading to vascular remodeling. This process may influence smooth muscle migration and proliferation within aneurysms, thereby contributing to wall instability [34,35]. Sustained hemodynamic stress induced by hypertension can lead to repeated injury and arterial wall remodeling. Therefore, hypertension can contribute to the recurrence or lack of uVADA regression. Our findings underscore the importance of effective blood pressure control in managing patients with uVADAs.
Our study had a few limitations. First, we performed this retrospective study at a single institution, which may have introduced an inherent bias. Second, our sample size was relatively small, which may have affected the statistical power of the results. Third, the shorter follow-up period for the flow diverter group may have led to underestimating its effectiveness compared to multiple stents. Thus, a longer follow-up period seems necessary to fully assess the outcomes of the flow diverter group. Fourth, we included a small number of patients who underwent reconstructive endovascular treatment for previously treated, recanalized uVADAs. Although these cases were managed using the same reconstructive principles as treatment-naïve aneurysms, their inclusion could introduce some heterogeneity. However, a sensitivity analysis excluding these patients showed no significant change in the overall results, thereby supporting the robustness of our main conclusions. Further multicenter prospective studies with larger patient cohorts are necessary to validate our findings and to identify the additional risk factors associated with the angiographic outcomes of uVADAs treated with reconstructive endovascular techniques.
CONCLUSION
The flow diversion effect with the use of a flow-diverting stent or multiple overlapping stents may be a crucial factor in achieving favorable angiographic outcomes in uVADA treatment. In addition, diligent management of hypertension is paramount. Our findings could provide a practical guide for clinicians to tailor uVADA treatment strategies and optimize patient outcomes.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Informed consent
This type of study does not require informed consent.
Author contributions
Conceptualization : JHC, YSS; Data curation : KHH, HJL; Formal analysis : JHC; Funding acquisition : JHC; Methodology : JHC, WCC; Project administration : JHC; Visualization : KHH; Writing - original draft : KHH; Writing - review & editing : JHC
Data sharing
The data supporting the findings of this study are available from the corresponding author upon reasonable request. However, due to patient privacy and ethical restrictions, the datasets are not publicly available.
Preprint
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Acknowledgements
This study was supported by the Research Fund of Seoul St. Mary’s Hospital, The Catholic University of Korea.