Arterial Tortuosity Is a Potent Determinant of Safety in Endovascular Therapy for Acute Ischemic Stroke

Authors: Hamidreza Saber, Geoffrey P. Colby, Nils Mueller‐Kronast, Mohammad Ali Aziz‐Sultan, Richard Klucznik, Jeffrey L. Saver, Nerses Sanossian, Frank R. Hellinger, Dileep R. Yavagal, Tom L. Yao, Reza Jahan, Diogo C. Haussen, Raul G. Nogueira, Michael T. Froehler, Osama O. Zaidat, David S. Liebeskind

Abstract

Background

Subarachnoid hemorrhage (SAH) associated with vessel injury during endovascular therapy for acute ischemic stroke is a known complication. Arterial anatomy may predispose to increased risk of SAH and technical safety, yet factors such as clot location, arterial size, and tortuosity have not been explored. We examined these anatomic factors with respect to SAH during thrombectomy.

Methods

Arterial anatomy at the site of occlusion and mechanical thrombectomy during device deployment was detailed by the STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) core laboratory. Luminal diameters, arterial branching, and segmental tortuosity were measured. Arterial tortuosity was quantified using the distance factor metric. Statistical analyses included descriptive variables of arterial anatomy, with univariable and multivariable modeling to predict SAH.

Results

Arterial tortuosity in each segment from the proximal cerebral arteries to the site of occlusion was quantified in 790 subjects treated with mechanical thrombectomy in STRATIS. Cumulative arterial tortuosity to the site of vessel occlusion was greater in distal lesions. SAH was clearly linked with more distal thrombectomy (*P *= 0.02), occurring in 19.0% of distal M2, 16.7% of M3, 7.3% of distal M1, 5.8% of proximal M2, 2.4% of distal internal carotid artery, and 2.1% of proximal M1. In multivariable analysis after adjusting for arterial diameter at the site of occlusion, arterial tortuosity was a significant predictor of SAH (upper tertile versus odds ratio, 3.08 [95% CI, 1.04–9.09]; *P *= 0.04), while arterial diameter was unrelated to SAH (*P *= 0.30) when accounting for tortuosity.

Conclusion

This novel analysis of arterial tortuosity and angiographic anatomy during mechanical thrombectomy establishes tortuosity as a determinant of SAH, providing insight for future techniques and innovative device designs.

Endovascular therapy (EVT) has been established as the standard of care for acute large‐vessel occlusion of the proximal anterior circulation. ^1^ , ^2^ , ^3^ , ^4^ , ^5^ Up to 30% to 40% of patients with acute ischemic stroke (AIS) harbor a distal arterial occlusion (distal‐vessel occlusion [DVO]), and a significant proportion of these patients may have poor outcomes. ^6^ , ^7^ , ^8^ Recent single‐ and multicenter cohorts have also evaluated the role of EVT for treatment of occlusions in medium‐vessel occlusions such as the M3 segments of the middle cerebral artery (MCA), the anterior cerebral artery, and the posterior cerebral artery. However, the safety of EVT in distal lesions remains controversial. Subarachnoid hemorrhage (SAH) associated with vessel injury during EVT for AIS particularly in the distal vasculature is a known complication. ^7^ Arterial anatomy may predispose to increased risk of SAH and technical safety, yet factors such as clot location, arterial size, and tortuosity have not been explored with respect to procedural safety.

Recent studies have suggested arterial tortuosity as a predictor of procedural complication following EVT. ^9^ Arterial tortuosity may represent a marker of vascular fragility, as well as technical difficulty and the possibility of device‐related vascular injury during thrombectomy. ^10^ As such, the arterial tortuosity index can represent a novel factor in the procedural risk stratification and prognostic assessment following EVT in AIS.

To address this topic and owing to the lack of randomized data, an ad hoc subanalysis of the STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) registry data was performed to investigate these anatomical factors with respect to SAH during thrombectomy. We hypothesized that increased vascular tortuosity is associated with an increased rate of SAH following EVT for DVO.

Methods

Study Population

The data that support the findings of this study are available from the corresponding author upon reasonable request. This study represents a retrospective ad hoc analysis of data collected from the STRATIS registry. The STRATIS registry is a prospective, multicenter, nonrandomized study that investigated outcomes following use of the Solitaire stent‐retriever device (96.9%; Medtronic, Dublin, Ireland) and Mindframe Capture Low Profile Revascularization (Mindframe; 3.1%) device. ^11^

The study inclusion criteria included (1) patients aged ≥18 years with AIS due to intracranial vessel occlusion; (2) National Institutes of Health Stroke Scale score of 8 to 30; (3) use of Medtronic market‐released neurothrombectomy device as the initial device; (4) baseline modified Rankin scale score of ≤1 before index stroke; and (5) treatment within 8 hours of stroke onset. Overall, 984 patients with AIS due to large‐vessel occlusion at 55 US centers between August 2014 and June 2016 were enrolled (Figure 1). The technical approach, including the use of a balloon guide catheter or intermediate large‐bore catheter, as well the choice of stent size, were not compulsory and were up to the treating neurointerventionist's choice. Details and results of the STRATIS registry are published elsewhere. ^11^ STRATIS is registered with https://www.clinicaltrials.gov (NCT02239640). ^12^ Ethics approval was obtained by the institutional review board at each center. Each subject provided written informed consent before enrollment into the registry. We adhered to the observational cohort guideline.

Measurements

An independent core laboratory examined angiographic data and the procedural reports to ascertain vascular tortuosity, clot location, vessel size, angiographic outcomes, and the number of stent retriever passes. Arterial occlusions in various segments of the intracranial vessels were adjudicated. Arterial tortuosity index was quantified using the distance factor metric (DFM), defined as the percent ratio of calculated shortest distance between the end points divided by actual length of the arterial segment considered ^13^ , ^14^ (Figure 2). The M1 segment of the MCA was defined as the arterial trunk from its origin at the internal carotid artery to the first bifurcation or trifurcation into the major branches. The M2 MCA was defined as occlusion beyond the major first branching of the M1 artery and to the apex of the circular sulcus. Proximal and distal M1 and M2 were defined by delineating the halfway distance of the entire respective segment. M3 was defined as the opercular segments extending laterally from the insula toward the cortex. The stent retriever sizes used included 4 mm × 15 mm, 4 mm × 20 mm, 4 mm × 40 mm, 6 mm × 20 mm, and 6 mm × 30 mm.

Degree of reperfusion was defined on the basis of the expanded Thrombolysis in Cerebral Infarction grading scale and was adjudicated by the independent STRATIS registry core laboratory.

Outcomes

The primary outcome was the presence of SAH on imaging 24 hours after thrombectomy using magnetic resonance imaging or computed tomography (CT). Imaging outcomes were adjudicated using the expanded Thrombolysis in Cerebral Infarction score system.

Statistical Analysis

Categorical variables were expressed as proportions and continuous variables as mean (±SD) or median (with interquartile range [IQR]). Differences between groups were examined using Pearson's χ^2^ test and Fisher's exact test for categorical data, and Student's t‐test and Wilcoxon's rank‐sum test for continuous variables as appropriate. All P values were 2‐sided and values ≤0.05 were considered significant.

Descriptive statistics were used to present the data using the mean, SD, and median with IQR or frequency distribution as appropriate. For 2‐group comparisons, t‐tests or the Wilcoxon rank‐sum test was used for continuous variables and the χ^2^ test or Fisher exact test for categorical variables as appropriate.

Results

Figure 1 shows the flowchart for study inclusion. Among a total of 844 patients with available imaging for mechanical thrombectomy using the Solitaire device, EVT was performed with various device sizes, including Solitaire 4 × 40 in 36.3% (306/844), Solitaire 6 × 30 in 31.4% (265/844), Solitaire 4 × 20 in 26.4% (223/844), unspecified in 3.8% (32/844), Solitaire 6 × 20 in 1.3% (11/844), and Solitaire 4 × 15 in 0.8% (7/844). During device deployment in STRATIS, median arterial diameter at the occlusion site was 2.4 mm (IQR, 1.9–3.4), 2.9 mm (IQR, 2.2–3.6) at the proximal stent marker, and 1.4 mm (IQR, 1.2–1.7) at the distal stent marker.

SAH and Arterial Tortuosity

Arterial tortuosity in each segment from the proximal cerebral arteries to the site of occlusion was quantified in 790 subjects treated with mechanical thrombectomy in STRATIS (Figure 1). Tortuosity measurement was not possible for 54 of 844 patients because of technical limitations (unavailability of optimal angiographic imaging views for calculating DFM). Figure 2 shows an example of tortuosity measurement in a patient with distal M2 occlusion.

SAH was associated with more distal thrombectomy (*P *= 0.02), with 19.0% of distal M2, 16.7% of M3, 7.3% of distal M1, 5.8% of proximal M2, 2.4% of distal internal carotid artery, and 2.1% of proximal M1 (Table 1). The cumulative arterial tortuosity index to the site of vessel occlusion was greater in distal lesions as compared with proximal lesion (Table 2). In univariable analysis, a higher arterial tortuosity index was a significant predictor of SAH (upper tertile versus odds ratio [OR], 4.12 [95% CI, 1.67–10.18]; *P *= 0.002; Table 3). In multivariable analysis after adjusting for arterial diameter at the site of occlusion, arterial tortuosity remained a significant predictor of SAH (upper tertile versus OR, 3.08 [95% CI, 1.04–9.09]; *P *= 0.04). Multivariate prediction of SAH revealed that arterial diameter was unrelated to SAH (*P *= 0.30) when accounting for tortuosity (Table 4).

Discussion

In this large, multicenter study, we examined the arterial tortuosity index and vessel size at the site of arterial occlusion. Arterial tortuosity was an independent predictor of SAH irrespective of vessel size at the site of occlusion following stent retriever thrombectomy for acute stroke. These findings provide insights for optimization of techniques and innovative device designs in future DVO studies.

Arterial tortuosity includes the presence of abnormal twists and turns of 1 or several arteries on the vessel pathway and has been associated with older age, female sex, high blood pressure, and other cardiovascular risk factors. ^10^ The recent identification of arterial tortuosity as a predictor of procedural complication rates following EVT for AIS have shed new light on this phenotype. ^9^ Arterial tortuosity may also represent a marker of vascular fragility and underlying arteriopathies and thus are an intermediate factor in procedural complication beyond technical difficulties accessing these vasculatures. ^15^ , ^16^ , ^17^ As such, the arterial tortuosity index can be seen as a novel factor in the procedural risk stratification and prognostic assessment following EVT in AIS. However, incorporation of this arterial phenotype into clinical practice requires standardization in terms of definition, measurement, and normalcy criteria, as well as further evaluation in retrospective and prospective studies involving neuroendovascular practitioners. Our analysis provides a useful and practical approach for quantification of the cerebrovascular tortuosity index in patients with acute stroke undergoing EVT and can be incorporated and obtained via preinterventional imaging modalities.

Tortuosity may affect various segments of cerebral vasculature from carotid segments to distal cortical branches, and can be localized to a single vessel or widespread along the cerebrovascular tree. Various terms have been used to describe different types of arterial tortuosity. Weibel et al proposed a classification for the morphological variation of the internal carotid artery, defined as an S‐ or C‐shaped elongation or undulation, kinking as an acute angulation, with its severity ranging from mild (angle ≥60°) to moderate (angle between 30° and 60°) and severe (angle <30). ^18^ In addition to the intrasegmental tortuosity, the cumulative tortuosity naturally increases toward distal vessels as progressing into natural anatomic segments. Prior research on vascular pathology has shown that aging, along with mechanical factors, such as blood pressure, blood flow, axial tension, and wall structural changes are major underlying contributors to the vascular tortusity. ^19^ Tortuosity is more commonly encountered in the more distal occlusions, and therefore it can be considered as an epiphenomenon in the more distal lesions. However, the degree of the tortuosity is variable across different DVOs according to the underlying anatomic variations. We believe that the actual tortuosity measurement would provide a more accurate marker for the risk of SAH in distal occlusions as compared with the segmental location of the occlusion alone.

Measuring and reporting the tortuosity index of cerebral vasculature is a challenging task in the absence of a standardized, universally accepted methodology. Common methods include qualitative approaches with visual estimation of a vessel's tortuosity, most often used in clinical settings after reviewing CT angiography, magnetic resonance angiography, or preinterventional digital subtraction angiography. More refined, quantitative methods in cerebral vasculature are not standardized or widely adopted. In this study, we used the distance metric or DFM approach, defined as the percent ratio of calculated shortest distance between the end points divided by actual length of the arterial segment considered.

Until recently, distal‐ or medium‐vessel occlusions were not a frequent target of endovascular intervention. However, with technologic advances, experience with EVT for DVO stroke is beginning to expand. ^7^ , ^8^ A recent multicenter case–control study of M3/anterior cerebral artery strokes demonstrated the benefit of EVT with higher rates of excellent outcomes following DVO interventions in patients presenting with severe deficits. ^20^ Previous studies of distal intracranial occlusion strokes, including anterior cerebral artery, M3 MCA, and posterior cerebral artery occlusions, have reported that EVT was effective in achieving successful reperfusion. ^21^ , ^22^ SAH is a known complication following endovascular therapies, particularly in more distal lesions. In a study of 111 patients with M1 thrombectomy for stroke, authors concluded that MCA tortuosity (evaluated by finding the top‐to‐bottom distance of the M1 segment on anterior–posterior view angiograms) was associated with postthrombectomy hemorrhage. ^23^ In a study of 209 isolated M2 thrombectomies with an observed sulcal SAH rate of 15.8%, Kim et al ^24^ reported that SAH was more frequently associated with distal M2 occlusion, superior division, or acute M2 angulations. Ng et al ^25^ also reported that the distal location of vessel occlusion was associated with a higher probability of SAH. In this analysis, we demonstrated that the vascular tortuosity index is correlated with the rates of SAH complications following intervention independent of vessel size at the site of occlusion. There is growing evidence that arterial tortuosity has considerable potential as a marker of procedural difficulty and complication rates following EVT. However, its incorporation requires adoption of a standardized approach to measurement, terminology, and reporting. This will require a uniform terminology for describing tortuosity, and a common approach to measurement and reporting of tortuous vessels in cerebral vasculature. It should also be noted that the clinical impact of postprocedural SAH following distal stroke thrombectomy is not well known, and future studies will be needed to evaluate the correlation of SAH with clinical outcomes in this subgroup. Newer devices with smaller diameters and low‐profile thrombectomy devices are being developed for distal‐ and medium‐vessel occlusions. ^26^ , ^27^ Further research will then be required to work toward optimization of endovascular techniques for treatment of distal/tortuous vascular anatomy.

Limitations

Our study has all the limitations inherent to a retrospective analysis and nonrandomized nature of registry data. EVT approach included only stent‐retriever thrombectomy using Solitaire devices, and does not represent experience with the newer stent‐retriever devices or the Direct Aspiration First‐Pass technique for thrombectomy. DFM measurements were not available in 45 patients, although the missing data are considered to be at random. Most registries cannot ensure the consecutive enrollment of patients, which can lead to biases. Moreover, we have based our evaluation of standard CT or magnetic resonance imaging techniques. New CT imaging modalities may improve the accuracy of SAH definition. A previous study has demonstrated that post‐EVT dual‐energy CT evaluation may change the ICH diagnosis to contrast staining only in about one‐third of the patients. ^28^ Nonetheless, post‐EVT contrast extravasation on dual‐energy CT has been shown to be associated with higher risks of hemorrhagic transformation and poor outcomes. ^29^ While the DFM represents an important step in the standardization of tortuosity measurements in EVT, it might not fully capture the challenges associated with short segments of tight angulations that could represent additional difficulties for the thrombectomy procedures. ^30^ Finally, lack of randomization or a broad set of clinical and radiographic covariates that may result in bias. Future large prospective studies will be needed to quantify the independent role of arterial tortuosity on hemorrhagic outcomes following mechanical thrombectomy.

Summary

This novel systematic analysis of arterial tortuosity and angiographic anatomy during mechanical thrombectomy establishes tortuosity as a determinant of SAH, providing insight for future techniques and innovative device designs.

Sources of Funding

This study was sponsored by Medtronic.

Disclosures

Dr Mueller‐Kronast serves as a scientific consultant regarding trial design and conduct to Medtronic. Dr Zaidat serves as a consultant to Medtronic, Stryker, and Penumbra. Dr Froehler serves as a scientific consultant to Medtronic, Stryker, and Blockade and has received a National Institutes of Health grant. Dr Colby reports to other from Stryker, Microvention, and Medtronic. Dr Aziz‐Sultan is an expert witness for BMC and serves as a scientific consultant to Medtronic. The University of California Regents receive funding for Dr Jahan's services as a scientific consultant regarding trial design and conduct to Medtronic/Covidien and is an employee of the University of California, which holds a patent on retriever devices for stroke. Dr Klucznik is on the Speakers’ Bureau for Medtronic. Dr Haussen is consultant for Stryker, Vesalio, and Cerenovus and has stock options with VizAi. Dr Nogueira reports to other from Stryker Neurovascular, Anaconda (physician advisory board), Genentech (physician advisory board), Biogen (Cirara in large Hemispheric infarction Analyzing modified Rankin and Mortality [CHARM] trial [BII093; glibenclamide]), Brainomix (physician advisory board, stock options), Viz‐AI (physician advisory board, stock options), Corindus Vascular Robotics (physician advisory board), Vesalio (physician advisory board), Ceretrieve (physician advisory board), Astrocyte (physician advisory board), Cerebrotech (physician advisory board), and Imperative Care (Imperative trial principal investigator). Dr Hellinger is on the Speakers’ Bureau for Medtronic and serves as a consultant to Penumbra and Cordis Neurovascular (J&J). Dr Yavagal has received honoraria from Medtronic and serves as a scientific consultant to Medtronic, Neuralanalytics, Inc. Dr Yao serves as a consultant/proctor to Medtronic. Dr Liebeskind reports to other from Cerenovus, Genentech, Medtronic, Stryker, and Vesalio outside the submitted work. Dr Saver reports personal fees from Medtronic, Stryker, Cerenovus, Boehringer Ingelhiem (prevention only), and Rapid Medical outside the submitted work; and The University of California has intellectual property rights in retriever technology for stroke. Other authors report no relevant disclosures. Osama O. Zaidat, Raul G. Nogueira, and David S. Liebeskind serve on the Editorial Board of Stroke: Vascular and Interventional Neurology. Editorial board members are not involved in the handling or final disposition of submissions.