Introduction Studies comparing endovascular stroke treatment using mechanical thrombectomy (MT) with or without prior IV tissue plasminogen activator (tPa) have included only 30% of internal carotid artery terminus occlusions (ICA-O), a known predictor of recanalization failure with IV tPa.
Objective To carry out a retrospective multicenter analysis of prospectively collected data of consecutive patients to investigate the impact of intravenous thrombolysis on ICA-O by comparing patients treated with MT alone or bridging therapy (BT).
Material and methods Patients with ICA-O treated with MT alone or BT were retrospectively examined and compared. Demographic data, vascular risk factors, treatment modalities, complications, technical and clinical outcomes were recorded. A propensity score (PS) analysis was used to compare modified Rankin Scale (mRS) score at 3 months and intracerebral hemorrhage (ICH) between groups.
Results 141 consecutive patients (60% BT/40% MT) were included between January 2014 and June 2016. Baseline characteristics did not differ between the groups. There was no significant difference in the rate of Thrombolysis in Cerebral Infarction 2b/3, distal emboli, and median number of passes between the groups. There was a significant difference between BT and MT groups in the median time between imaging and groin puncture (median 97 min vs 75, p=0.007), the rate of ICH (44% vs 27%, p=0.05), but not for symptomatic ICH (18% vs 13%, p=0.49). With PS, there was a trend towards a higher rate of ICH (OR=2.3, 95% CI 0.9 to 5.9, p=0.09) in the BT group compared with the MT alone group, with no difference in mRS score ≤2 at 3 months (OR=1.6, 95% CI 0.7 to 3.7, p=0.29).
Conclusion There was no significant difference in clinical outcomes between patients receiving bridging therapy versus direct thrombectomy. Bridging therapy delayed time to groin puncture and increased ICH rate.
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Randomized control trials (RCTs) of endovascular treatment with mechanical thrombectomy (MT) for acute ischemic stroke included all patients with large vessel occlusions (LVOs) in the middle cerebral or internal carotid arteries with or without intravenous thrombolysis (IVT), but did not present subgroup analyses of specific occlusion locations like carotid-T occlusions.1
Recent retrospective studies comparing MT with or without IVT in LVOs report similar rates of technical and clinical outcomes, mortality, and symptomatic intracranial hemorrhage (sICH), suggesting that the benefit of MT does not depend on prior IVT.2–8 However, internal carotid artery occlusions (ICA-O) involving the middle cerebral artery (MCA), anterior cerebral artery (ACA; carotid-L), both (carotid-T), or neither (carotid-I) accounted for <30% of these occlusions. Yet, these occlusions possess greater challenges for IVT than more distal LVOs. Recanalization rates for ICA-O range from 6% to 20% with IVT alone, and are known to be significantly lower than for MCA occlusions.9 10 In another series, Legrand et al demonstrated that the thrombus burden extending from the ICA terminus was a predictor of recanalization failure with IVT.11 These very low recanalization rates counterbalance the global hemorrhagic risk of systemic thrombolysis.12 For ICA-O, the safety and benefit of IVT remain unclear.
We present a retrospective multicenter analysis of prospectively collected data of consecutive patients to investigate the impact of IVT on ICA-O by comparing patients treated with MT alone or with bridging therapy (BT).
Materials and methods
All patients presenting with acute ischemic stroke in ICA-O treated with MT alone or BT in eight neurointerventional centers (NICs) were included in this registry between January 2014 and June 2016.
Baseline characteristics recorded for all patients included age, gender, vascular risk factors, treatment modalities, times from symptom onset to diagnosis and treatment, bleeding complications, and clinical outcomes.
Stroke and imaging characteristics
An ICA-O was defined as an occlusion of at least the internal carotid artery terminus (C1 segment of the artery) on CT angiography or MRI, extending into the MCA or anterior cerebral artery (ACA; carotid-L), both MCA and ACA (carotid-T), or neither MCA nor ACA (carotid-I).
Anterior collaterality was defined as the visualization of the ipsilateral A2 segment on baseline imaging. Tandem cervical lesions, dissecting or atheromatous, were also recorded (table 1).
Stroke severity was evaluated by a neurologist using the National Institute of Health Stroke Scale (NIHSS) score, and the baseline extent of ischemia was assessed using the Alberta Stroke Programme Early CT (ASPECT) score on MRI or CT.
IVT eligibility before MT was evaluated by the neurologist and interventional neuroradiologist at each center, and was initiated within 4.5 hours after stroke onset at the peripheral hospital or on arrival at the NIC after patient transfer.
Times of periprocedural management were analyzed from stroke onset to door to imaging to groin puncture to recanalization.
Recanalization success and distal emboli in the same or previously unaffected vascular territories were assessed immediately after angiography using the modified Thrombolysis in Cerebral Infarction (mTICI) score by the treating physician.13 A score of 2B or more was considered a successful recanalization. The number of passes of the thrombectomy device was also recorded.
A CT or MRI scan was performed 24–72 hours after treatment or within 24 hours in the case of clinical deterioration. ICH and sICH were graded according to the Prolyse in Acute Cerebral Thromboembolism II study.14
The primary clinical endpoint for treatment efficacy was the modified Rankin Scale (mRS) score, assessed by a physician at 3 months: favorable outcome (0–2), poor outcome (3–6) and very poor outcome (4–6). For patients unable to present for a clinical examination at the hospital, the mRS score was assessed through a phone call interview performed by the investigators of each NIC.
Continuous data were presented as mean (±SD) or median (IQR) based on the distribution. Categorical variables were presented as counts (proportions). The Mann–Whitney U test was performed to test for statistical differences in continuous parameters between two groups. The χ2 or Fisher exact test (based on expected frequency) was used to compare categorical variables between groups. Outcomes variables at 3 months were mRS scores (favourable 0–2 vs poor 3–6), death and any ICH. A propensity score (PS) using the inverse probability of treatment weighting method was used to compare both groups.
The PS was obtained from a multivariate logistic regression model on 114 patients because of missing data.
For the mRS or ICH PS, the baseline clinical data used in the model were age, gender, wake-up stroke, hypertension, dyslipidemia, smoking, diabetes, obesity, imaging at the NIC, baseline NIHSS score, time from onset to imaging, baseline ASPECT score, cervical lesion, and anterior collaterality. We estimated the association between MT alone or BT and recanalization rate or clinical outcome with crude odds ratio (95% CI) and adjusted OR with PS. A 5% level of significance was used. The following data analysis software was used: SPSS version 19 and SAS version 9.4.
In accordance with the French legislation, institutional or ethics committee approval was not required for this study because it used only anonymized data, collected as part of routine clinical care.
A total of 145 consecutive patients from eight NICs presenting with ICA-O were treated with MT with or without prior IVT during the study period. Four patients with proved initial imaging after 4.5 hours were excluded owing to ineligibility for IVT. From the remaining 141 patients, 56 patients (40%) were treated with MT alone, 85 patients (60%) were treated with BT, and all had pre-stroke mRS score <2. Of these patients 49 (35%) had been transferred (table 1).
Baseline characteristics are presented in table 1. Both groups had similar demographics (except gender), vascular risk factors, cervical lesions, NIHSS score, ASPECTS, and anterior collaterality. In the BT group, significantly fewer patients (n=2) had prior anticoagulation medication compared with the MT group (p<0.0001).
In the MT group, contraindications for IVT were effective anticoagulation (n=17, 30%), recent surgery (n=4, 7%), recent stroke (n=6, 11%), or history of ICH (n=7, 12.5%). In a further 22 patients (39%), IVT was not given after consensus with the neurologist and interventional neuroradiologist based on age, ASPECTS, timing, and immediate availability of MT.
The time from stroke onset to groin puncture was significantly longer in the BT group than in the MT alone group (240 min, IQR 200–300 vs 200 min, IQR 140–280, p=0.002), imaging to groin puncture (97 min, IQR 60–170 vs 75 min, IQR 40–113, p=0.007), and stroke onset to recanalization (294 min, IQR 240–360 vs 270 min, IQR 203–340, p=0.03) (table 1).
On the other hand, both MT alone and BT groups achieved similar rates of successful recanalization (75% vs 80%), distal emboli (21% vs 27%), and median number of passes with thrombectomy device (3 vs 2), respectively (table 1).
Overall, the rate of ICH from any cause was higher in the BT group (44% vs 27%, p=0.05), while there was no significant difference in the rate of sICH (18% vs 13%, p=0.49). However, adjusted OR with propensity scores did not reach statistical significance (OR with PS 2.3 in favour of BT group, 95% CI 0.9 to 5.9, p=0.09) (table 2).
ICH was reported significantly more often in patients who were transferred (49% vs 25%, p=0.004), those who were older (70 years±10 vs 68 year±17, p=0.02), and required longer time to recanalization (321 min, IQR 253–378 vs 280 min, 210–340, p=0.03) (online supplementary table 1).
Supplementary file 1
Clinical outcomes were similar in both groups using unadjusted analysis (table 1). Adjusted OR with PS comparing the BT group with the MT alone group were 1.6 (95% CI 0.7 to 3.7, p=0.29) for favourable clinical outcome, and 1.2 (95% CI 0.5 to 2.9, p=0.66) for mortality (table 2, figure 1).
Favourable outcome at 3 months was related to younger age (66±16 years vs 72±13 years, p=0.002), anterior collaterality (92% vs 77%, p=0.03), successful recanalization (91% vs 69%, p=0.01), lower NIHSS score at admission (17, IQR 14–20 vs 19, IQR 16–23, p=0.004), higher ASPECT score (8, IQR 7–9 vs. 7, IQR 5–8, p=0.01), and earlier time to recanalization (270 min, IQR 210–330 vs 310 min, IQR 240–360, p=0.05). Any ICH (16% vs 52%, p<0.001) and sICH, (4% vs 24%, p=0.001) were related to poor clinical outcome at 3 months (table 3).
Endovascular treatment of LVO strokes in the anterior circulation is now well established. The focus is shifting towards optimizing workflow and treatment strategies. In patients presenting with ICA-O, it remains unclear whether IVT continues to be beneficial and safe when treated with MT.8 15 In the broader category of all LVOs, IVT does not seem to affect clinical outcome positively or negatively according to a recent meta-analysis by the HERMES group of five RCTs,1 and further supported by more recent studies.2–8
To our knowledge, we examined the largest cohort of patients with ICA-O treated with MT alone (without IVT) or BT (with IVT), showing no difference in clinical outcome, but increased time delay and possible complications.
In addition to the clear evidence that IVT alone offers low rates of recanalization9 10 in ICA-O, this series reported greater tendency for ICH (p=0.09), and significantly increased delay from imaging to groin puncture due to IVT administration (p=0.007) for patients in the BT group. Similar findings were described by Weber et al, showing a 36 min delay from imaging to groin puncture due to IVT prior to MT in all LVOs.
Patients given IVT require specialized medical transfer from imaging suites to angiography suites. Time to organize this specialized team probably explains the time delays found in the BT group. For the same reason, increased delays can occur more often in patients who are transferred. However, in our study, the proportion of patients arriving directly at the NIC versus patients transferred was similar in both the MT alone and BT groups (table 1).
Furthermore, adjusted OR with propensity scores shows a trend towards a higher risk of hemorrhage in the BT group (OR=2.3, 95% CI=0.9 to 5.9, p=0.09) (figure 1) that might also be due to the delays caused by IVT. This is in line with previous reports linking delays to treatment with increased risk of ICH.16 17 Both asymptomatic and symptomatic ICH can compromise the benefit of vessel recanalization on clinical outcomes in patients with acute ischemic stroke.12
Some authors have hypothesized that IVT before MT could improve MT success by partially dissolving or ‘softening’ the clot.2 4 18 In this series of ICA-O with large clot burden, adjunctive IVT did not improve revascularization success or reduce the number of passes required to recanalize the vessel in the BT group.
According to Kaesmacher et al, IVT before MT could reduce the rate of distal emboli.19 However, in this series, the rate of distal emboli was similar in both groups.
Despite a greater delay to recanalization in the BT group, clinical outcomes remained similar in both groups. This could be explained by the microvascular effects of IVT described by Desilles et al. Using a rat model, they demonstrated that downstream microvascular thrombosis occurs immediately after artery occlusion and contributes to brain damage.20 Furthermore, early IVT administration before recanalization improved ischemic stroke outcome by preserving cerebral microvascular perfusion downstream to the arterial occlusion.20 This hypothesis is further supported by another study which showed that IVT can promote recanalization in small vessels in the microvascular structure which are inaccessible to thrombectomy devices.21
Analysis of predictors of good clinical outcome showed expected results: younger age, lower NIHSS score, higher ASPECTS, successful and faster recanalization, and fewer bleeding complications. In addition, good anterior collaterals were also a significant factor. Indeed, this configuration of the circle of Willis offers a collateral supply from the ipsilateral anterior cerebral artery that is no longer possible in the case of anterior communicating artery agenesis. Collaterality has been well described as a key factor related to clinical outcomes at 3 months.22 23
This study is the first to present results of MT with or without IVT in a large number of patients with very proximal occlusion—that is, carotid terminus occlusion and high clot burden. Multicenter recruitment allowed for a large sample size from a broad spectrum of centers that reflects standard everyday practice of endovascular thrombectomy in stroke, although ICA-O remain a subgroup of LVOs.1
Our study has some limitations. It is a retrospective analysis of a non-randomized, observational study. However, we used statistical analysis and propensity scores to limit confounding bias. We opted for the inverse probability of treatment weighting method, which seems most appropriate.24
In the BT group, significantly fewer patients (n=2) had prior anticoagulation medication than in the MT group (p<0.0001). This is expected since previous effective anticoagulation treatment is one of the main contraindications for IVT in Europe.
Owing to multiple imaging modalities (CT or MRI) used in the eight different centers, clot characteristics were not analyzed, which might have influenced recanalization rates and clinical outcomes.25 26
The sample population included only patients with stroke who were treated with MT with or without prior IVT. Although MT is now well established for treating LVOs, patients who experienced ICH or a spontaneous recovery before groin puncture might have been excluded. Also, we did not report the occlusion status at the start of the MT procedure. Since all patients included required MT, we assume that a proximal occlusion remained (even M1 or M2) on the first DSA imaging.
Lastly, angiographic results were adjudicated in the center where the procedure was performed without independent core-laboratory evaluation of the final mTICI score and procedural complications.
IVT provided no apparent benefits to patients receiving MT who had carotid terminus occlusions (whether they involved the MCA, ACA, both, or none), but may delay care and increase the risk of symptomatic ICH. Future large RCTs will probably provide more insight into the best strategy to use in proximal occlusions.
CP and HD contributed equally.
Contributors RB conceived the idea for the study, collected data, and wrote the manuscript. P-LA collected data and wrote the manuscript. GM, FE, BK, SB, SS collected data. BG, HD critically reviewed the manuscript. BD-G performed the statistical analysis. MM critically reviewed the manuscript and corrected the spelling and grammar.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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