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Original research
Hyperdense vessel sign as a potential guide for the choice of stent retriever versus contact aspiration as first-line thrombectomy strategy
  1. Mahmoud H Mohammaden1,2,
  2. Diogo C Haussen1,2,
  3. Catarina Perry da Camara1,2,
  4. Leonardo Pisani1,2,
  5. Marta Olive Gadea1,2,
  6. Alhamza R Al-Bayati1,2,
  7. Bernardo Liberato1,2,
  8. Srikant Rangaraju1,2,
  9. Michael R Frankel1,2,
  10. Raul G Nogueira1,2
  1. 1 Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA
  2. 2 Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Atlanta, Georgia, USA
  1. Correspondence to Dr Raul G Nogueira, Marcus Stroke & Neuroscience Center, Grady Memorial Hospita, Emory University School of Medicine, Atlanta, GA 30303, USA; raul.g.nogueira{at}emory.edu

Abstract

Background The first-pass effect (FPE) has emerged as a key metric for efficacy in mechanical thrombectomy (MT). The hyperdense vessel sign (HDVS) on non-contrast head CT (NCCT) indicates a higher clot content of red blood cells.

Objective To assess whether the HDVS could serve as an imaging biomarker for guiding first-line device selection in MT.

Methods A prospective MT database was reviewed for consecutive patients with anterior circulation large vessel occlusion stroke who underwent thrombectomy with stent retriever (SR) or contact aspiration (CA) as first-line therapy between January 2012 and November 2018. Pretreatment NCCT scans were evaluated for the presence of HDVS. The primary outcome was FPE (modified Thrombolysis in Cerebral Infarction score 2c/3). The primary analysis was the interaction between HDVS and thrombectomy modality on FPE. Secondary analyses aimed to evaluate the predictors of FPE.

Results A total of 779 patients qualified for the analysis. HDVS and FPE were reported in 473 (60.7%) and 286 (36.7%) patients, respectively. The presence of HDVS significantly modified the effect of thrombectomy modality on FPE (p=0.01), with patients with HDVS having a significantly higher rate of FPE with a SR (41.3% vs 22.2%, p=0.001; adjusted OR 2.11 (95% CI 1.20 to 3.70), p=0.009) and non-HDVS patients having a numerically better response to CA (41.4% vs 33.9%, p=0.28; adjusted OR 0.58 (95% CI 0.311 to 1.084), p=0.088). Age (OR 1.01 (95% CI 1.00 to 1.02), p=0.04) and balloon guide catheter (OR 2.08 (95% CI 1.24 to 3.47), p=0.005) were independent predictors of FPE in the overall population.

Conclusion Our data suggest that patients with HDVS may have a better response to SRs than CA for the FPE. Larger confirmatory prospective studies are warranted.

  • stroke
  • thrombectomy
  • technique
  • CT

Data availability statement

The unpublished data from this dataset are held by Grady Memorial Hospital/Emory University and the corresponding author. Requests for data sharing would be required to be discussed with them directly.

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Introduction

Mechanical thrombectomy (MT) with stent retrievers (SRs) and/ or contact aspiration (CA) is now considered the treatment standard for selected patients presenting with large vessel occlusion stroke within 24 hours of stroke onset.1 The first-pass effect (FPE) has recently emerged as a key metric for the efficacy of thrombectomy.2 While many anatomical and technical factors affect the chances of achieving early and complete reperfusion, clot characteristics probably represent a critical aspect and may aid in determining the best initial reperfusion strategy.

As the hyperdense vessel sign (HDVS) on non-contrast head CT (NCCT) indicates higher clot content of red blood cells,3 4 it has the potential to serve as an imaging biomarker for device selection. Although previous studies have shown the association of HDVS with successful recanalization after mechanical thrombectomy (MT),5 6 the relationship between the choice of the initial thrombectomy modality and HDVS has not been well studied. We aimed to assess the predictors of FPE and evaluate whether HDVS modifies the treatment effect of SR versus contact aspiration (CA) as a first-line thrombectomy technique on FPE and as such may serve as an imaging biomarker for guiding first-line device selection in MT.

Methods

Patient selection

We retrospectively reviewed a prospectively maintained comprehensive stroke center MT database between January 2012 and November 2018. Patients with a large vessel occlusion stroke involving the intracranial internal carotid artery or middle cerebral artery (M1 and M2 segments) and treated with either SR or CA as a first-line strategy were included. Only patients who underwent NCCT before the procedure at the treating site were included. Imaging studies with suboptimal quality were excluded. The study was approved by the institutional review board.

Imaging protocol and assessment of HDVS

All patients underwent NCCT imaging performed with a GE Revolution 256-slice CT scanner or GE Lightspeed 64-slice CT scanner (GE Healthcare; Chicago, Illinois, USA). A subjective determination of the presence or absence of HDVS by stroke neurologists was prospectively maintained in our MT database. HDVS was defined if the lumen of the occluded blood vessel appeared more dense than adjacent or equivalent contralateral arteries but non-calcified on NCCT scans reconstructed at 2.5 mm thickness.7

Endovascular procedure

SR thrombectomy: A 9 French/95 cm Concentric balloon guide catheter (BGC) was advanced over a 5 French/125 cm catheter and a 0.038 inch guidewire into the proximal or mid-internal carotid artery whenever applicable. The catheter and the guidewire were removed, then a microcatheter and microwire inside were navigated intracranially through the BGC up to the area proximal to the thrombus. The microcatheter with the microwire inside was advanced past the thrombus, then the microwire was removed and a selective angiogram through the microcatheter was obtained to ensure an intraluminal position. A SR was then advanced through the microcatheter and deployed across the occlusion. After waiting for 5 min to allow SR integration with the thrombus, the balloon on the BGC was inflated and the SR was pulled out.

CA technique: A BGC was used as mentioned above and a large-bore aspiration catheter with a microcatheter and a microwire inside were navigated intracranially through the BGC up to the area proximal to the thrombus. The microcatheter was removed and the aspiration catheter was brought into the proximal face of the thrombus. The BGC was inflated and the aspiration catheter was pulled out under manual aspiration using a Vac-u-lock 60 cc syringe or an aspiration pump, according to the operator’s preference. Continuous aspiration was applied to the BGC via the Vac-u-lock 60 cc syringe during the removal maneuver of the SR or the large-bore aspiration catheter in both techniques.

All endovascular procedures were performed by neurointerventionalists experienced in MT with SR and CA techniques. Decision between the two different modalities and the size/type of the devices was based on the operator’s preference. Cases including combined SR and CA as first-line technique were excluded from the analysis.

Outcome measures

Reperfusion rate was assessed by the operator using the modified Thrombolysis In Cerebral Infarction (mTICI) scale.8 FPE was defined as mTICI 2c/3 after a single pass of the selected device.2 Good outcome was defined as functional independence at 90 days (modified Rankin scale score 0–2). The primary analysis was the interaction between HDVS and thrombectomy modality on FPE. Secondary analyses aimed to evaluate the predictors of FPE.

Statistical analysis

Categorical variables were expressed as frequencies and percentages and compared using a chi-square test. Continuous variables were expressed as median and IQR after normality testing through the Shapiro-Wilk test, and compared with the Mann-Whitney U test. Multivariable analysis was performed using binary logistic regression analysis for all variables with p˂0.10 to assess independent predictors of FPE. Subgroup analysis was performed to study the interaction between the thrombectomy modalities and HDVS. Significance was set at p˂0.05. Analyses were performed using SPSS 26 software (IBM Armonk, New York, USA).

Results

During the period from January 2012 through November 2018, 1566 consecutive patients underwent MT at our comprehensive stroke center. After exclusion of patients with posterior circulation strokes (n=133), those who did not have on-site preprocedure NCCT or had a suboptimal scan (n=439), and patients who underwent combined SR and CA as a first-line technique (n=167), a total of 779 patients qualified for the study (figure 1 online data supplement). The median (IQR) age was 64 years (53–75) while the baseline National Institutes of Health Stroke Scale (NIHSS) score was 17 (12–21), and the baseline Alberta Stroke Program Early CT Score (ASPECTS) was 8 (7–9). The first-line treatment modality included SR in 631 (81%) and CA in 148 (19%) patients. HDVS and FPE were reported in 473 (60.7%) and 286 (36.7%) of the patients, respectively.

Figure 1

Forest plot graph shows the effect size in the primary outcome variable (odds ratio for first-pass effect) across the different subgroups. Last known well (LKW) to puncture, baseline National Institutes of Health Stroke Scale (NIHSS) score, the Alberta Stroke Program Early Computed Tomography Score (ASPECTS), and pre-mechanical thrombectomy use of intravenous alteplase (IV-tPA). Age, baseline NIHSS score, and ASPECTS were divided into two groups based on their median values. HDVS, hyperdense vessel sign.

Primary analysis: impact of HDVS on FPE according to first-line thrombectomy modality

Tables 1 and 2 show the baseline, procedural, and outcome variables according to FPE status in HDVS and non-HDVS patients, respectively. The presence of HDVS significantly modified the effect of thrombectomy modality on first-pass reperfusion (p=0.01) (figure 1) with patients with HDVS having a significantly higher rate of FPE with stent retrievers (SR 41.3% vs CA 22.2%, p=0.001; adjusted OR 2.11 (95% CI 1.20 to 3.70), p=0.009) and non-HDVS patients having a numerically better response to contact aspiration (CA 41.4% vs SR 33.9%, p=0.28; adjusted OR 0.58 (95% CI 0.311 to 1.084), p=0.088). There was no significant interaction between age, time to treatment, baseline NIHSS score, baseline ASPECTS, and use of intravenous tissue plasminogen activator (IV-tPA) and the first-line treatment modality for FPE.

Table 1

Demographic, clinical and procedure characteristics of patients with HDVS with and without FPE

Table 2

Demographic, clinical and procedure characteristics of non-HDVS patients with and without FPE

Secondary analysis: predictors of FPE

Table 1 online data supplement and table 3 depict the univariable and multivariable analyses of predictors of FPE, respectively. Individuals with FPE were significantly older (65 (54–76) vs 63 (52.5–74) years; p=0.04), underwent treatment less commonly under general anesthesia (10.1% vs 18.1%), p=0.003), and more frequently with a BGC (89.2% vs 77.7%, p˂0.001), than patients without FPE. Patients with FPE had shorter times from puncture to first angiography (9 (6-14) vs 10 (7–15.5) min, p=0.047) and first angiography to reperfusion (24.5 (18–36.3) vs 55 (37.5–84) min, p˂0.001). There was a strong trend toward higher rates of FPE in SR vs CA (38.4% vs 29.7%, p=0.05). There was no statistically significant difference between groups for other demographic variables, comorbidities, clinical, and radiological characteristics. FPE was associated with significant higher chances of functional independence at 90 days (61.6% vs 49.4%, p=0.003) and a strong trend towards lower 90-day mortality (14.8% vs 21.1 %, p=0.05). On multivariable analysis, older age (OR 1.012 (95% CI 1.001 to 1.023, p=0.04) and the use of BGC (OR 2.077 (95% CI 1.242 to 3.473), p=0.005) were independent predictors of FPE (table 3).

Table 3

Multivariable regression analyses for FPE as an outcome

Table 3 shows the multivariable analysis for predictors of FPE according to HDVS status. Lower use of general anesthesia (OR 0.492 (95% CI 0.258 to 0.938), p=0.03) and use of SR as a first-line modality (OR 2.108 (95% CI 1.201 to 3.70), p=0.009) were independent predictors of FPE in patients with HDVS. Female gender (OR 1.63 (95% CI 1.008 to 2.634), p=0.04) and BGC (OR 2.632 (95% CI 1.208 to 5.694), p=0.015) were independent predictors of FPE in the non-HDVS group.

Discussion

Our study suggests that the HDVS may serve as an imaging biomarker for device selection in MT. Non-invasive imaging can provide important insights into clot composition. On NCCT, HDVS correlates with higher red blood cell (RBC) content, while its absence is associated with fibrin structural predominance.3 Similarly, susceptibility vessel sign (SVS) in T2* MRI indicates RBC-dominant thrombi, whereas a lack of SVS is indicative of fibrin-dominant clots.9–11 The value of these findings for their applicability to predict treatment response and tailor medical interventions is being explored by an ongoing clinical trial that compares a first-line strategy combining SR and CA with CA alone in the presence of SVS.12

There is conflicting evidence regarding the relationship between clot density in NCCT or the presence of SVS in T2* MRI and the recanalization effect of IV-tPA. Some studies have reported that higher clot density13 14 or the presence of SVS15 16 are predictors of poor response to intravenous thrombolytic agents. This might be explained by the effect of IV-tPA to lysis fibrin more than RBC-rich clots. Conversely, many other studies have reported that the higher the density of the clot, the higher is the likelihood of recanalization after IV-tPA.17 18

For MT, there is accumulating evidence suggesting that RBC-rich clots are easier to recanalize than fibrin-rich clots. A recent study analyzed clot composition as a function of the number of SR passes and showed that the relative fibrin content increases after the first two passes, supporting its more refractory nature.19 Other studies have demonstrated higher endovascular recanalization in the presence of HDVS5 6 17 or SVS.9–11

Three main mechanical characteristics have directly opposite behaviors across RBC-rich versus fibrin-rich thrombi and might interfere with the response to SR versus CA modalities: deformability (ie, degree to which applying a force can make a solid change its shape), friction (ie, the resistance to motion of one object moving relative to another), and friability (ie, the tendency of a solid substance to break into smaller pieces under pressure or contact). The fibrin network structure and clot mechanical properties are altered by incorporation of erythrocytes. RBC-rich thrombi are more deformable than fibrinous clots,20 and this more deformable nature allows for the SR struts to more easily permeate the clot, resulting in greater device–clot interaction and optimization of the retrieval process.21 Conversely, as fibrin-rich clots do not deform as much, the SR does not move into the clot matrix but rather remains constrained between the clot and the vessel wall. Fibrin-rich clots are less deformable and also have high friction coefficients than their RBC-rich counterparts.22 The combination of poor device–clot incorporation and high friction makes the fibrin-rich clots roll over the SR as opposed to being retrieved by it.23 The mode of device–clot interactions of SR and CA largely differ. SR interacts with the clot along most of its longitudinal aspect, whereas the CA interaction is restricted to the proximal transverse aspect of the clot. In the case of poorly deformable fibrin-rich clots, CA allows for lower dispersion of the attenuated device–clot interaction forces by concentrating the retrieval force across the shorter axis of the clot and more closely aligning it with the vector of movement. The thromboaspiration catheter can then more easily 'cork' and retrieve harder clots.

However, the use of CA as a first-line approach is affected by the high friability of RBC-rich clots, which seem to be the most common types of clots. A recent study demonstrated that clots with higher RBC content have an increased level of fibrin rupture on mechanical manipulation, which probably results in an increased propensity for fragmentation.21 An experimental in vitro study has demonstrated that, even though CA may result in rapid and reliable recanalization, it is associated with increased risk of distal embolization, particularly in the setting of red clots.24 As CA primarily approaches the clot by its proximal aspect, it fails to control any fragmentation that might happen across its longer longitudinal axis. In contrast, SRs more completely engage the whole length of the clot and, therefore, have higher chances of capturing more distal fragments that may form during the retrieval process. In another words, CA grabs the clot by its 'head' but fails to control its 'tail'. This is typically not a problem when dealing with the more cohesive fibrin-rich clots, but makes CA more prone to distal embolization when retrieving the more friable RBC-rich clots. This is the most likely explanation for the recent ASTER Trial analysis demonstrating lower rates of full perfusion (mTICI 2c/3) with CA versus SR in the setting of occlusive thrombi with SVS, which presumably have a higher RBC content.25 In our analysis, HDVS was associated with higher FPE with SR than with CA, whereas non-HDVS patients had similar if not better results with CA.

Our results are consistent with a recent meta-analysis showing that the SR technique might be prone to retrieving high-density thrombus, whereas an opposite tendency was seen with CA.26 Despite the similar workflow and inherent imaging advantages of MRI over CT,27 CT has broader availability and cost advantages over MRI. Thus, our findings may provide a more pragmatic and generalizable approach to MT device selection. The idea that imaging may provide guidance for choice of technique has also been explored on the simple basis of the angiographic findings. Indeed, the ASTER investigators have recently demonstrated that the presence of an irregular shape occlusion on angiography seems to correlate with a better response to SR than to CA as first-line approach.28

Our results indicating that the use of BGC predicts FPE have been previously demonstrated in the literature.29 We showed that older patients have a higher chance of FPE, which may be related to different stroke etiologies resulting in different thrombus composition across age groups. Jadhav et al 30 reported that patients with FPE were significantly older; however, age was not an independent predictor of FPE in their cohort, which studied only SR and did not include CA.

Our study has all the typical limitations inherent of any single-center retrospective analysis. In addition, the CA group had a relatively small sample size, which limited the power and generalizability of our analysis. Moreover, we included cases from 2012 to 2018 and over this period the CA technology has evolved significantly. We did not evaluate other clot characteristics, including clot length, and it is important to acknowledge that there is no formal standardization on how to optimally evaluate for the presence of HDVS. Finally, there was no adjudication by an independent core laboratory of the imaging data; however, the assessment of HDVS and reperfusion rates was done blindly. The strengths of our study include its large number of patients, the consistency of the internal techniques in a single center, and the simplicity and applicability of the use of HDVS in clinical practice.

In conclusion, our data suggest that patients with HDVS may have a better response to SRs than CA for FPE. This may constitute a practical and effective approach for device selection in MT. Larger confirmatory prospective studies are warranted to confirm our findings.

Data availability statement

The unpublished data from this dataset are held by Grady Memorial Hospital/Emory University and the corresponding author. Requests for data sharing would be required to be discussed with them directly.

Ethics statements

Ethics approval

IRB obtained through Emory University, IRB00090915.

References

Footnotes

  • Twitter @PerrydaCamaraMD, @pisanileonardo

  • Contributors MHM: acquisition of data, design of the work, interpretation of data, drafting of the manuscript. DCH: interpretation of data, critical revision of the manuscript, CPdC, LP, MOG, ARA-B, BL, SR, MRF: critical revision of the manuscript. RGN: study conception, design of the work, interpretation of data, drafting of the manuscript. All authors gave final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests RGN reports potential conflicts with Stryker Neurovascular (DAWN Trial principal investigator–no compensation, Trevo Retriever Registry Steering Committee–no compensation, Trevo-2 Trial principal investigator–modest; Consultant–modest), Medtronic (SWIFT [SOLITAIRE FR With the Intention for Thrombectomy] Trial Steering Committee–modest; SWIFT-Prime Trial Steering Committee–no compensation; STAR [Solitaire Flow Restoration Thrombectomy for Acute Revascularization] Trial Angiographic Core Lab–significant), Penumbra (3D Separator Trial Executive Committee–no compensation), Cerenovus/ Neuravi (ENDOLOW Trial principal investigator, EXCELLENT Registry principal investigator, Analysis of Revascularization in Ischemic Stroke with EmboTrap (ARISE-2)-2 trial Steering Committee–no compensation, Physician Advisory Board, modest), Phenox (Physician Advisory Board, modest), Anaconda (Physician Advisory Board, modest), Genentech (Physician Advisory Board–modest), Biogen (Physician Advisory Board–modest), Prolong Pharmaceuticals (Physician Advisory Board–modest), Allm Inc. (Physician Advisory Board– no compensation), IschemaView (speaker, modest), Brainomix (Research Software Use–no compensation), Sensome (Research Device Use–no compensation), Viz.AI (Physician Advisory Board–stock options), Philips (research software use–no compensation, speaker–modest), Corindus Vascular Robotics (Physician Advisory Board–stock options), Vesalio (Physician Advisory Board–stock options), Ceretrieve (Physician Advisory Board–stock options) and Astrocyte (Physician Advisory Board–stock options). DCH is a consultant for Stryker and Vesalio and holds stock options at Viz.AI.

  • Provenance and peer review Not commissioned; externally peer reviewed.