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Original research
Intravenous thrombolysis pretreatment and other predictors of infarct in a new previously unaffected territory (INT) in ELVO strokes treated with mechanical thrombectomy
  1. Nitin Goyal1,
  2. Georgios Tsivgoulis2,
  3. Jason J Chang3,
  4. Konark Malhotra4,
  5. Juan Goyanes1,
  6. Abhi Pandhi1,
  7. Rashi Krishnan5,
  8. Muhammad F Ishfaq1,
  9. Daniel Hoit6,
  10. Christopher Nickele7,
  11. Violiza Inoa-Acosta8,
  12. Aristeidis H Katsanos9,
  13. Lucas Elijovich10,
  14. Andrei Alexandrov11,
  15. Adam S Arthur12
  1. 1 Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
  2. 2 Second Department of Neurology, “Attikon” Hospital, School of Medicine, University of Athens, Athens, Greece
  3. 3 Critical Care, MedStar Washington Hospital Center, Washington, District of Columbia, USA
  4. 4 West Virginia University Health Sciences Center Charleston Division, Charleston, West Virginia, USA
  5. 5 Neurology, University of Tennessee Health Science Center, College of Medicine Memphis, Memphis, Tennessee, USA
  6. 6 Neurosurgery, University of Tennessee, Memphis, Tennessee, USA
  7. 7 UTHSC, Department of Neurosurgery, Memphis, Tennessee, USA
  8. 8 Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee, USA
  9. 9 Department of Neurology, University of Ioannina School of Medicine, Ioannina, Greece
  10. 10 Semmes-Murphey Clinic, Memphis, Tennessee, USA
  11. 11 Surgery, University of Alabama, Birmingham, Alabama, Alabama, USA
  12. 12 UT Department of Neurosurgery/Semmes-Murphey Clinic, Memphis, Tennessee, USA
  1. Correspondence to Dr Nitin Goyal, Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA; ngoyal{at}uthsc.edu

Abstract

Introduction One uncommon complication of mechanical thrombectomy (MT) is an infarct in a new previously unaffected territory (infarct in new territory (INT)).

Objective To evaluate the predictors of INT with special focus on intravenous thrombolysis(IVT)pretreatmentbefore MT.

Methods Consecutive patients with emergent large vessel occlusion (ELVO) treated with MT during a 5-year period were evaluated. INT was defined using standardized methodology proposed by ESCAPE investigators. The predictors of INT and its impact on outcomes were investigated.

Results A total of 419 consecutive patients with ELVO received MT (mean age 64±15 years, 50% men, median baseline National Institutes of Health Stroke Scale score 16 points (IQR 11–20), 69% pretreated with IVT). The incidence of INT was lower in patients treated with combination therapy (IVTandMT) than in patients treated with MT alone, respectively (10% vs 20%; p=0.011). The INT group had more patients with posterior circulation occlusions than the group without INT (28% vs 10%, respectively; p<0.001). The rates of 3-month functional independence were lower in patients with INT (30% vs 50%; p=0.007). IVT pretreatment was not independently related to INT (OR=0.75; 95% CI 0.32 to 1.76), and INT did not emerge as an independent predictor of 3-month functional independence (OR=0.69; 95% CI 0.29 to 1.62) on multivariable logistic regression models. Location of posterior circulation occlusion was independently associated with a higher odds of INT (OR=3.33; 95% CI 1.43 to 7.69; p=0.005).

Conclusions IVT pretreatment is not independently associated with a lower likelihood of INT in patients with ELVO treated with MT. Patients with ELVO with posterior circulation occlusion are more likely to have INT after MT.

  • stroke
  • thrombectomy
  • thrombolysis
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Introduction

Several randomized clinical trials have shown that endovascular treatment with mechanical thrombectomy (MT) using stent retrievers is superior to standard therapy alone in treating patients with acute ischemic stroke with emergency large vessel occlusion (ELVO).1–7 Additionally, current guidelines recommend prompt treatment with intravenous thrombolysis (IVT) in patients eligible for MT without contraindications to tissue plasminogen activator (tPA).2

One uncommon complication of MT that has recently been described is an infarct in previously unaffected territory (infarct in new territory (INT)). INTs have been defined as an acute area of ischemia that is present in a vascular territory unrelated to the vascular distribution of the ELVO.5 8–10 INTs are typically identified on a follow-up non-contrast computed tomography scan or diffusion-weighted magnetic resonance imaging (DWI-MRI) performed within 24 hours of MT.8–10 Formal classifications for INTs were described by Goyal et al 7 using two classification parameters: size (types I, II, and III) and catheter manipulation across the ostium (types A and B) of the arterial territory.8

It has been hypothesized that the use of IVT before MT may reduce the incidence of INT. Proposed mechanisms are largely related to the creation of a fibrinolytic state, which may lead to easier detachment of clot, fewer passes with a stent-retriever, and dissolution of the target thrombus and any new thrombi that may have formed or embolized to other territories during this time.8–11 Reduction of INT incidence may improve functional outcome. However, there are contradictory10 12 13 and limited data supporting these hypotheses. Apart from potential association with IVT, other predictors of INT are largely unknown. In this study, we sought to evaluate the predictors of INT with special focus on IVT pretreatment before MT, in a high-volume tertiary care stroke center.

Methods

Study population and baseline characteristics

We performed a retrospective analysis of a prospectively collected database of consecutive patients with ELVO who underwent MT at a tertiary care stroke center during a 5-year period (2013–2017). For the purpose of this study, the cohort was divided into two groups: patients who developed INT versus no INT after treatment with MT, regardless of IVT. Baseline demographic and clinical variables were collected.

Collateral status was graded using American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology criteria. Stroke severity at hospital admission was documented using National Institutes of Health Stroke Scale (NIHSS) scores by certified vascular neurologists. Baseline characteristics, including demographics, vascular risk factors, history of prior stroke, admission NIHSS scores, admission Alberta Stroke Program Early CT Score (ASPECTS), pretreatment with IVT, admission serum glucose, admission systolic blood pressure and diastolic blood pressure levels, occlusion site (anterior vs posterior circulation occlusion), were recorded as previously described.14 Collateral scores were reported in a dichotomized fashion (good vs poor collaterals) for anterior circulation ELVO using a methodology that has been shown to predict clinical outcome.15 INT was defined using standardized methodology proposed by ESCAPE investigators.8 9 INT was diagnosed using DWI-MRI in the majority of patients. Non-contrast CT head was used to diagnose INT in a small proportion of patients with ELVO where MRI could not be performed. All infarcts located outside the immediate territory of the vessel implicated in the presenting stroke were defined as INT. Based on the size of infarcts on 24-hour MRI or follow-up CT head, INT was classified into types I–III. It was further divided into two subtypes based on whether catheter was probably manipulated past ostium of new territory (A, yes or B, no).8 9

Definition of outcomes

Recanalization at the end of endovascular procedure was defined by modified Thrombolysis in Cerebral Infarction (mTICI) grades, which were obtained from the reports of endovascular specialists. Complete recanalization was defined as mTICI grades 2b or 3.16 Symptomatic intracranial hemorrhage was defined as the presence of a parenchymal hematoma type 2 on brain CT and/or MRI gradient recall echo sequence accounting for deterioration with an increase in NIHSS score of ≥4 points within 36 hours from treatment.17 Functional outcome was evaluated at 3 months using the modified Rankin Scale (mRS) scores by certified vascular neurologists. Functional status was evaluated in person either from a post-hospital discharge clinic follow-up or from a hospital visit in all patients. Functional independence (FI) was defined as mRS scores of 0–2 at 3 months. Endovascular specialists grading the degree of reperfusion at the end of MT and vascular neurologists assessing NIHSS and mRS scores were unaware of the purposes of the study and performed treatments and assessments as part of their clinical duties.14

Statistical analyses

All binary variables are presented as percentages, while continuous variables are expressed according to the presence of normality in their distribution, either with their median values and corresponding interquartile ranges (IQRs) or with their mean values and corresponding standard deviations (SDs). Statistical comparisons between the two groups of patients were performed with Pearson’s χ2, Mann-Whitney or Student t tests, where appropriate. Univariable and multivariable binary logistic regression models were used to evaluate associations between baseline characteristics and the likelihood of INT after MT. Additionally, univariable and multivariable binary logistic regression models were used to evaluate associations between baseline characteristics, including INT, with likelihood of FI at 3 months. As candidate variables for inclusion in multivariable models, we used baseline characteristics that were found to yield a p value <0.1 in the initial univariable analyses. The resulting multivariable models were tested under a two-sided statistical significance hypothesis with a significance level of 0.05. The Stata Statistical Software Release 13 for Windows (College Station, StataCorp LP, Texas, USA) computer program was used for all statistical analyses.

Results

A total of 419 consecutive patients with ELVO received MT (mean age 64±15 years, 50% men, median NIHSS score 16 points (IQR 11–20)). Of these, 289 patients (69%) were pretreated with IVT and 130 (31%) did not received IVT before MT. However, owing to missing data on INT, only 408 patients were analysed in this study. Pretreatment with IVT was documented in 280 (68.6%) of 408 patients with complete data. INTs were documented in 54 (13.2%) of the 408 patients. In our cohort, a combination of distal aspiration and stent retriever was used as the most common technique (also called the ‘Solumbra’ technique) in 56% of cases. The second most commonly employed technique was the ADAPT (A Direct Aspiration First Pass Technique), and this was used in 20% of the study population. Stent retrievers without distal aspiration were used in 19% of patients. The remaining cases were mostly cervical or intracranial carotid occlusions in which acute angioplasty and/or stenting was employed. A balloon guide was used in 8% of cases. MT was carried under general anesthesia in 24% of cases while the remaining patients received conscious sedation (76%).

The baseline characteristics and outcomes variables of patients with ELVO with INT versus no INT when treated with MT with or without IVT are shown in table 1. Patients with INT had longer symptom onset to groin puncture time (median (IQR) 288 (200–440) min vs 246 (180–324) min) compared with those who did not have INT. The incidence of INT was lower in patients treated with combination therapy (IVT and MT) than in patients treated with MT, respectively (10% vs 20%; p=0.011). The INT group had lower rates of IVT pretreatment (54% vs 71%; p=0.011) than those who did not have INT. More patients in INT group had posterior circulation occlusions than those without INT (28% vs 10%, respectively; p<0.001). The rates of 3 month FI were lower in patients with INT (30% vs 50%; p=0.007)

Table 1

Baseline characteristics and outcome variables of patients with large vessel occlusion with and without infarct in new territory (INT) following treatment with mechanical thrombectomy

Univariable and multivariable associations of baseline characteristics with INT are displayed in table 2. The following variables were associated with INT on univariable analyses: IVT, good collateral status, hypertension, antiplatelet pretreatment, symptoms onset-to-groin puncture time (OTGPT), and location of posterior circulation occlusion. Multivariable analyses identified only posterior circulation occlusion location as associated with higher odds of INT after adjustment for potential confounders (OR=3.33; 95% CI 1.43 to 7.69; p=0.005). IVT pretreatment was not independently related to INT (OR=0.75; 95% CI 0.32 to 1.76) on multivariable logistic regression models adjusting for location of occlusion, collateral status, and OTGPT.

Table 2

Univariable and multivariable associations of baseline characteristics with infarct in new territory (INT) on logistic regression models

Univariable and multivariable associations of baseline characteristics with predictors of 3-month FI are displayed in table 3. The following variables were associated with 3 months FI on univariable analyses: age, history of stroke, INT, baseline NIHSS score, admission SBP, good collateral status, symptoms OTGPT, and location of posterior circulation occlusion. INT did not emerge as an independent predictor of 3-month FI (OR=0.69; 95% CI 0.29 to 1.62) on multivariable analyses. The following three variables were independently associated with 3-month FI on multivariable analyses: baseline NIHSS score, collateral status, and OTGPT.

Table 3

Univariable and multivariable associations of baseline characteristics with 3-month functional independence on logistic regression model

Subgroup analyses

We also performed subgroup analyses evaluating univariable and multivariable associations of baseline characteristics with INT in patients with anterior circulation occlusions (table 4). The only variable that tended to be associated with a lower odds of INT on univariable analyses was good collateral grade (OR=0.51; 95% CI 0.24 to 1.05). There was no association between IVT pretreatment and INT in the anterior circulation subgroup. We further conducted subgroup analyses evaluating univariable and multivariable associations of baseline characteristics with INT in patients with posterior circulation occlusions only (table 5). The following variables were associated with INT on univariable analyses: history of congestive heart failure, history of coronary artery disease, and number of passes during MT. Multivariable analyses identified that a higher number of passes during MT was associated with a higher likelihood of INT after MT in patients with posterior circulation occlusions (OR=1.95; 95% CI 1.03 to 3.68; p=0.039).

Table 4

Univariable and multivariable associations of baseline characteristics with infarct in new territory (INT) on logistic regression models in patients with anterior circulation occlusions (n=339)

Table 5

Univariable and multivariable associations of baseline characteristics with infarct in new territory (INT) on logistic regression models in patients with posterior circulation occlusions (n=69)

Discussion

Our study showed that INT was less frequent in patients pretreated with IVT in initial unadjusted analyses and was also related to worse functional outcomes in univariable analyses. However, the former associations did not retain statistical significance in multivariable and subgroup analyses. We also documented an independent association between posterior circulation occlusion and higher likelihood of INT. Furthermore, subgroup analysis in patients in posterior circulation occlusions identified a higher number of passes during MT as an independent positive predictor of INT in this subgroup of patients with ELVO.

Since the publication of landmark endovascular trials,2 use of pretreatment tPA for patients with ELVO has been questioned and is a topic of ongoing debate. Several concerns, including number of exclusion criteria for tPA therapy, its cost, delay in initiation of MT, and safety considerations, have supported the question of whether tPA should be routinely given in patients going to MT.18–21 A retrospective study demonstrated that the tPA pretreatment did not improve outcomes of patients with ELVO and the combined therapy (tPA + MT) was associated with significantly higher total and direct hospital costs than endovascular therapy alone.20 Another study postulated that for those patients eligible for both tPA and MT presenting to comprehensive stroke centers with efficient workflow processes, there may be better patient value and overall healthcare benefit if they proceed directly to MT without IVT pretreatment.22 Contrary to these studies, several other single and multicenter non-randomized studies23 24 have shown that tPA pretreatment improves functional outcomes in ELVO and also leads to successful recanalization in 1 of 10 patients with ELVO, negating the need for additional endovascular reperfusion therapy.25 Di Maria et al 10 and Ganesh et al 9 showed that pretreatment with IVT might lead to a fibrinolytic environment that decreased INT incidence by facilitating dissolution of pre-existing thrombi or clots that had embolized to different territories during MT.9 10

Our findings are at odds with these two previous studies and the potential disparities in the study populations may account for these discrepant results. First, the two previous studies conducted post hoc analyses in datasets that included only anterior circulation strokes.9 10 In our report, 25% of the study population had posterior circulation strokes. The higher rate of INT in patients with posterior circulation occlusions can be explained by the hypothesis that the recanalization of basilar or vertebral artery occlusions may lead to potential multi-territory anterior circulation strokes via posterior communicating arteries. Future studies evaluating INT and posterior circulation strokes should focus on the integrity of collateralization provided by the circle of Willis. Additionally, breakdown of aortic arch atheroma leading to emboli in different vascular territories can also explain higher rates of INT in patients with posterior circulation. The larger number of INTs noted in our study 13% in comparison with Ganesh et al 9 (approximately 4–5%) may also reflect our inclusion of posterior circulation strokes in our analysis. Moreover, INT may be one of the causative factors for poor outcomes typically seen in patients with posterior circulation ELVO.

Second, Di Maria et al did not include collateral grading in their outcomes analysis.10 Ganesh et al did not differentiate collateral status as all of the patients from the ESCAPE cohort had ‘good collaterals’ in order to optimize the clinical outcome which would be present from the inevitable delay in treatment associated with MT.9 In our study, we found that in accordance with the existing literature, good collaterals were strongly associated with a higher odds of functional independence.26 27 Consequently, it may be postulated that collateral status might have confounded the association of INT with functional outcomes in our multivariable analyses.

Prior studies have demonstrated lower rates of INT with contact aspiration thrombectomy than with stent retriever techniques.28 29 In our study, we were unable to evaluate this hypothesis as the majority of patients underwent thrombectomy with combination of contact aspiration and stent retriever techniques.

Certain limitations of the current report need to be acknowledged, including the post hoc analyses and the inherent non-randomized design. Another methodological shortcoming is related to potential confounding by unmeasured variables that were not included in multivariable models. Moreover, patients were not randomized for the use of IVT and those who underwent MT alone usually had a contraindication for IVT that might have affected their outcomes. Finally, the sample size was small with a total of 54 patients with INTs. Consequently, the present dataset may have been underpowered to identify independent associations between baseline variables and INT.

In conclusion, INT may complicate MT in one out of eight patients with ELVO treated with MT. Although previous reports have showed that IVT pretreatment may affect the incidence of INT after MT and improve functional outcomes,9 30 our results indicated only the presence of univariable association between IVT pretreatment and INT, which did not retain its statistical significance on multivariable and subgroup analyses. Additionally, our study demonstrated that posterior circulation occlusion is an independent predictor of INT after MT. This preliminary observation requires independent confirmation in larger, prospective, multicenter datasets.

References

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Footnotes

  • Contributors NG: study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. GT, AHK: analysis and interpretation, critical revision of the manuscript for important intellectual content. JJC, KM, DH, CN, VI-A, LE, AA: critical revision of the manuscript for important intellectual content. JG, AP, RK, MFI: acquisition of data, critical revision of the manuscript for important intellectual content. ASA: study supervision, critical revision of the manuscript for important intellectual content.

  • 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 None declared.

  • Ethics approval The study was approved by the university of Tennessee institutional review board (15-04168-XP). Considering the retrospective nature, the board waived the need for the patient’s consent.

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

  • Patient consent for publication Not required.

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