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Case Series
Relationship between reperfusion and intracranial hemorrhage after thrombectomy
  1. Shashvat M Desai1,
  2. Daniel A Tonetti2,
  3. Andrew A Morrison3,
  4. Bradley A Gross2,
  5. Brian Thomas Jankowitz4,
  6. Tudor G Jovin5,
  7. Ashutosh P Jadhav6
  1. 1 Neurology and Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  2. 2 Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  3. 3 University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  4. 4 Neurosurgery, UPMC, Pittsburgh, Pennsylvania, USA
  5. 5 Neurology, Cooper University Hospital, Camden, New Jersey, USA
  6. 6 Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  1. Correspondence to Dr Ashutosh P Jadhav, Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; jadhav.library{at}gmail.com

Abstract

Introduction Symptomatic intracerebral hemorrhage (sICH) is a devastating complication after endovascular thrombectomy. Prior reports have demonstrated that thrombolysis in cerebral infarction (TICI) ≥2 b reperfusion is protective against sICH. We aimed to further examine the relationship between reperfusion grade and sICH, to elucidate whether a difference between TICI 2b and 3 exists, and to determine whether this relationship holds true for patients undergoing delayed thrombectomy (6–24 hours).

Methods We performed a single-center retrospective review of prospectively-recorded data for patients undergoing endovascular thrombectomy for large vessel occlusion between January 2015 and February 2018. Multivariable logistic regression analyses were performed to identify predictors of parenchymal hematoma (PH) and sICH (NINDS—National Institute of Neurological Disorders and Stroke, SITS-MOST—Safe Implementation of Thrombolysis in Stroke Monitoring Study, ECASS III—European-Australian Cooperative Acute Stroke Study III criteria) and to identify the role of reperfusion grade. This analysis was repeated for delayed thrombectomy patients.

Results 528 patients were included; mean age was 71.5% and 43% were male. Median NIHSS (National Institutes of Health Stroke Scale) and time last seen well (TLSW) to treatment were 17 and 4.8 hours, respectively. Successful recanalization was achieved in 94%. On multivariable analyses, ASPECTS (Alberta Stroke Programme Early CT Score) was a predictor of PH (OR 0.7, 95% CI 0.57 to 0.87; p=0.002) for patients achieving any reperfusion grade. For patients achieving successful reperfusion, lower ASPECTS was a predictor of PH (OR 0.73, 95% CI 0.58 to 0.91; p=0.005) and of sICH (ECASS III) (OR 0.67, 95% CI 0.45 to 0.98; p=0.04); in addition, TICI 2b as compared with TICI 3 was a predictor of PH (OR 2.1, 95% CI 1 to 4.4; p=0.04) and of sICH (NINDS) (OR 7.5, 95% CI 1 to 57; p=0.045). TLSW to treatment was not an independent predictor of PH or sICH.

Conclusion Higher baseline ASPECTS and higher degree of reperfusion following endovascular thrombectomy is associated with reduced likelihood of PH and sICH.

  • angiography
  • hemorrhage
  • intervention
  • stroke
  • thrombectomy

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Introduction

Hemorrhagic transformation is a devastating complication after endovascular thrombectomy (ET) for acute ischemic stroke caused by large vessel occlusion, especially in the case of intracranial hematoma (ICH) with space-occupying effect (parenchymal hematoma (PH)) or when it results in acute neurological deterioration (symptomatic ICH (sICH)). Various predictors of hemorrhage after intravenous thrombolysis have been reported in the past two decades.1–4 More recently, retrospective studies have demonstrated that hypertension and a longer procedure duration are independent predictors of PH formation after endovascular thrombectomy, while hyperlipidemia and successful reperfusion are protective against PH.5 Furthermore, PH, as opposed to hemorrhagic infarction, has been demonstrated to be a predictor of poor clinical outcome.5

In a multicenter analysis of 1122 patients undergoing endovascular thrombectomy within 8 hours of symptom onset, PH was associated with worse functional outcomes and higher mortality.6 Furthermore, it has been demonstrated that thrombolysis in cerebral infarction (TICI) 2b or 3 reperfusion is independently associated with lower rates of ICH after adjusting for gender, National Institutes of Health Stroke Scale (NIHSS), tissue plasminogen activator (tPA) use, and time to angiography (OR 0.42, p=0.04).5 7 Taken together these results suggest that uncomplicated successful reperfusion is protective against ICH after thrombectomy.

However, these prior reports have largely focused on patients undergoing thrombectomy within 8 hours and have aggregated data for patients with “successful recanalization”, defined as TICI 2b or 3 reperfusion. In this report we aim to explore the relationship between TICI score and PH/sICH and stratify perfusion rates by TICI score to elucidate any difference between TICI 2b and TICI 3 recanalization. Furthermore, some studies have suggested that longer time from symptom onset to endovascular intervention is a predictor of increased risk of hemorrhagic transformation.6 8 As such, this report aims to focus on the predictors of sICH, particularly in the late time window (6–24 hours).9 10

Methods

A retrospective analysis of prospectively collected data was performed for all patients presenting to a tertiary care academic comprehensive stroke center with acute ischemic stroke between January 2015 and February 2018 using the Get-With-The-Guidelines database. Demographic characteristics, clinical and radiological data, treatment and procedural information were extracted and analyzed. This study was approved by the local Institutional Review Board. Data used to prepare this manuscript may be made available on reasonable request.

Patient selection

Acute ischemic stroke patients who presented to a single comprehensive stroke center and underwent endovascular thrombectomy (ET) during the study period were analyzed. Patients who received endovascular thrombectomy for occlusion of an anterior circulation artery (intracranial internal carotid artery (ICA), middle cerebral artery segment 1 (M1) and/or middle cerebral artery segment 2 (M2)) were included in the study. Occlusion location was confirmed by CT angiography, magnetic resonance angiography and/or cerebral angiography. The decision to offer endovascular therapy was based on the discretion of the vascular neurologist and treating neurointerventionalist, after detailed discussion with the patient and their family. Details of the procedural approach have been previously described but typically consist of manual aspiration as a first line approach, followed by stent retriever use in the event of refractory thrombus.11 12

Baseline characteristics

Baseline demographic (age, sex), clinical (stroke severity, time from symptom onset, risk factor profile), radiographic (Alberta Stroke Programme Early CT Score (ASPECTS), occlusion location) information and procedural technique and efficiency (TICI score13) were collected and analyzed by a vascular neurologist blinded to patient outcomes.

Outcomes

The primary safety outcome was sICH. The National Institute of Neurological Disorders and Stroke (NINDS) definition of sICH was hemorrhagic transformation temporally related to worsening in neurologic condition,14 the European-Australian Cooperative Acute Stroke Study III (ECASS III)15 definition of sICH was hemorrhagic transformation with resultant causal NIHSS increase of ≥4, and the Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST)16 definition of sICH was limited to PH type 2 on imaging obtained 22–36 hours after treatment with concomitant neurologic worsening of NIHSS ≥4. All post-treatment radiologic evaluation of ICH was conducted by a vascular neurologist blinded to patient-specific data. Secondary safety outcomes included stroke-related mortality within 90 days of treatment. Efficacy outcome was 90 day functional independence, defined as modified Rankin Scale (mRS) score 0–2.

Statistical analyses

Continuous variables are reported as mean±SD or median with interquartile range (as appropriate) and categorical variables are reported as proportions. Between groups comparison for continuous variables was performed using Student’s t-test and categorical variables using χ2 test or Fisher exact test, as appropriate. Univariable analysis was performed for baseline characteristics between ICH (PH-1/2, sICH) and non-ICH patient groups. Additionally, occurrence of ICH by groups of TICI scores included individual TICI groups and in successful versus non-successful recanalization groups. Multivariable logistic regression analysis was performed to identify predictors of ICH and adjust for known confounders. Variables with a p value <0.2 on univariable analysis were used for multivariable logistic regression. Associations are presented as odds ratios with 95% confidence intervals (OR, 95% CI). Significance was defined as p≤0.05. Statistical analysis was performed using IBM SPSS Statistics 23 (IBM-Armonk, NY).

Results

Patient demographics

A total of 528 patients with acute ischemic stroke due to anterior circulation artery occlusion underwent ET at a single comprehensive stroke center during the study period. Mean age was 71.5±14.3 years and 43% (n=227) were males. The median NIHSS score and time from last known well to treatment (IQR) were 17 (13–21) and 4.8 (3–10) hours, respectively; 37.8% (n=200) of patients underwent thrombectomy beyond 6 hours of last known well. The median ASPECTS score was 9 (8–10), and 35.6% (n=188) received intravenous tissue plasminogen activator (tPA).

Internal carotid artery occlusion was found in 29.4% (n=155), middle cerebral artery segment 1 (MCA-M1) occlusion in 56.4% (n=298), and the rest were middle cerebral artery segment 2 (MCA-M2) occlusions (14.2%, n=75). Successful recanalization (TICI ≥2 b) was achieved in 94.1% (n=497) (TICI 2b in 78.2% (n=413) and TICI 3 in 15.9% (n=84)). Recanalization rates of TICI 2a were achieved in 4.5% (n=24), TICI 1 in 0.6% (n=3) and TICI 0 in 0.8% (n=4).

Incidence of ICH and baseline characteristics

PH type 1 or type 2 (PH-1/2) was noted in 20.4%, while sICH per ECASS III and NINDS criteria was noted in 5.8% (n=31) and 6.8% (n=36), respectively. Incidence of PH-2, PH-1/2 as well as sICH per SITS MOST, ECASS III and NINDS criteria are described in table 1 and their baseline demographic, clinical and radiological characteristics have been compared in univariable analyses.

Table 1

Incidence and baseline characteristics

ICH and degree of recanalization

Occurrence of different types of ICH post thrombectomy grouped by degree of recanalization (final TICI score) are described in table 1 and depicted in figure 1. An inverse relation exists between degree of recanalization and incidence of ICH. While patients with TICI <2 a did not experience PH-1/2, it was observed in 33.3% patient with TICI 2a, compared with 21.3% in TICI 2b and 13.2% in TICI 3 groups (p for all groups=0.15 and p for 2B vs 3=0.09). Similar trends were noted in sICH across all definitions (table 2A).

Figure 1

Intracerebral hemorrhage and TICI. ECAS III, European-Australian Cooperative Acute Stroke Study III; NINDS, National Institute of Neurological Disorders and Stroke; PH, parenchymal hematoma; sICH, symptomatic intracranial hemorrhage; SITS MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring Study; TICI, thrombolysis in cerebral infarction.

Table 2

Intracerebral hemorrhage and TICI

Predictors of ICH

Independent predictors of different types of ICH were tabulated (table 3). Among all patients, ASPECTS (OR 0.56, 95% CI 0.57 to 0.87; p=0.002) was the only independent predictor of PH-1/2. Similarly, ASPECTS (OR 0.67, 95% CI 0.45 to 0.98; p=0.03) and NIHSS score (OR 0.85, 95% CI 0.75 to 0.97; p=0.01) predicted sICH per ECASS III criteria. Among patients with successful recanalization (TICI 2B or more), ASPECTS (OR 0.73, 95% CI 0.58 to 0.89; p=0.005) and TICI score (OR 2.1, 95% CI 1 to 4.4; p=0.04) predicted PH-1/2, ASPECTS (OR 0.67, 95% CI 0.45 to 0.99; p=0.04) predicted sICH per ECASS III, and TICI score (OR 7.5, 95% CI 1 to 57; p=0.045) predicted sICH per NINDS definition.

Table 3

Intracranial hemorrhage predictors

Predictors in late window (>6 hours) thrombectomy patients

Two hundred patients were treated beyond 6 hours. The rate of successful recanalization was 91.5% (n=183). Predictors of PH-1/2 include ASPECTS (OR 0.7, 95% CI 0.57 to 0.87; p=0.002) and of sICH per ECASS III include ASPECTS (OR 0.55, 95% CI 0.32 to 0.96; p=0.03) and NIHSS score (OR 0.85, 95% CI 0.75 to 0.97; p=0.01) (table 3).

Predictive value of different types of ICH

PH-1 or 2 within 24 hours of thrombectomy is the most sensitive measure for mRS 3–6 (25%) and mortality (31%) at 90 days. All definitions of sICH have a 100% specificity for mRS 3–6 at 90 days and sICH per SITS MOST has the highest specificity (98.4%) and positive predictive value (66.7%) for 90 day mortality (98.4%) ().

Discussion

In this retrospective study of 528 patients undergoing mechanical thrombectomy for anterior circulation large vessel occlusion stroke, we report higher rates of parenchymal and symptomatic hemorrhage rate in patients with partial recanalization (TICI 2a and 2b) and lower rates in patients with no recanalization (TICI 0 and 1) and complete recanalization (TICI 3). The overall rate of PH in this study (PH-1—11%, and PH-2—9.7%) was 20.5%, whereas the rates of sICH per SITS MOST criteria (3.4%), ECASS III criteria (5.9%) and NINDS criteria (6.8%) were predictably lower. Among those with TICI 2b or higher reperfusion, after controlling for age, initial NIHSS and ASPECTS, TICI 3 was an independent negative predictor of both PH (OR 2.1, p=0.04) and sICH per NINDS criteria (OR 7.5, p=0.05) on multivariable logistic regression analyses. Furthermore, patients with TICI 3 reperfusion had lower rates of sICH per ECAS III criteria than those who only achieved TICI 2b (1.5% vs 6.7%, p=0.029). Interestingly, patients with TICI 1 or 0 had zero percent incidence of PH-1/2 and sICH. This finding should be explored further with a larger and more heterogenous sample size (including large volume strokes).

Thrombectomy for acute large vessel occlusions has been established as safe and efficacious.17–21 One major risk of revascularization via either thrombolysis and/or thrombectomy remains sICH,1–4 22 which has been reported in 4.4% of patients undergoing thrombectomy in pooled data of large randomized trials23 but as high as 16% in multicenter registries.24 Predictors of sICH in patients undergoing thrombectomy include pretreatment ASPECTS, treatment interval after symptom onset, tPA use, and multiple passes with a stentriever.22 24 25 Recently, nomograms have been proposed to predict the risk of sICH after thrombectomy that are predicated on NIHSS, onset-to-end procedure time, age, and degree of collateralization.26 Additionally, numerous prior reports have established that successful reperfusion, generally defined as TICI 2b or higher, is protective against the development of PH.5 7 This is clinically relevant because patients who suffer sICH after thrombectomy have higher rates of 90 day mortality than those who do not.24

sICH after thrombectomy beyond 6 hours

Prior reports analyzing predictors of sICH after thrombectomy have evaluated patients who have entirely or predominantly undergone early (<6 hours) thrombectomy. Hao et al identified cardioembolic stroke, poor collaterals, delayed endovascular treatment, multiple passes, and lower ASPECTS as predictors of sICH in patients treated within 6 hours24. Lee et al found that PH for patients undergoing anterior circulation thrombectomy in the first 6 hours after symptom onset was predictive of poor outcome.5 Some studies have suggested that longer time from symptom onset to endovascular intervention is a predictor of increased risk of hemorrhagic transformation.6 8 We aimed to evaluate this by analyzing a subset of patients who underwent thrombectomies >6 hours after symptom onset.

In 200 patients treated ≥6 hours of symptom onset, 91.5% were successfully recanalized. In our cohort, ASPECTS was an independent predictor of hemorrhagic infarction across multiple categories including PH-1, PH-2, and sICH per SITS-MOST and ECASS III criteria. Furthermore, NIHSS was an independent predictor of sICH per ECASS III criteria (p=0.01). The findings from these 200 patients constituting a ‘late-window’ cohort are similar to findings published elsewhere in patients treated within 6 hours of symptom onset,8 24 and reinforce the value of ASPECTS and NIHSS. For patients undergoing thrombectomy later than 6 hours, we find ASPECTS to be the strongest predictor of sICH. The presence of ICH can assist in outcome prediction; this has been well documented previously and incorporated in the Pittsburgh Outcomes after Stroke Thrombectomy (POST) Score.27 In this study, PH-1 or PH-2 have the maximum sensitivity (25%) and all definitions of sICH have excellent specificity for mRS 3–6 at 90 days.

Taken together, the data reported here suggest that achieving the highest degree of reperfusion possible is protective against hemorrhage after thrombectomy. We report higher rates of sICH in patients with partial recanalization (TICI 2a and 2b) with lower rates in patients with no reperfusion and complete reperfusion, concordant with prior literature.5 7 For the first time, we find that this relationship holds true even among “successful” reperfusion grades, as TICI 3 patients had a significantly lower rate of sICH than TICI 2b (1.5% vs 6.7%, p=0.029). In light of this finding, in some patients undergoing mechanical thrombectomy it may be worthwhile to continue thrombectomy until TICI 3 reperfusion is achieved, including addressing primary distal vessel occlusions or emboli in new or distal territories. Also, new non-mechanical methods may be explored to achieve TICI 3 recanalization. This must be determined on a patient-specific basis by the factors that govern thrombectomy safety, and ultimately the risk versus benefit ratio depends on the preferences and experience of the neurointerventionalist.

Study limitations

Our study is limited by its retrospective design subjecting it to the biases inherent to this type of analysis. Bias has been mitigated by collecting data prospectively and by standardizing thrombectomy technique and clinical data acquisition. Because this analysis is retrospective, this is not a valid analysis of whether pursuing recanalization until TICI 3 is achieved is beneficial. However, in a cohort of patients in which TICI 3 reperfusion is achieved, there is a lower rate of sICH than in patients with lower reperfusion grades. Additionally, our cohort is limited by the small sample of patients with <TICI 2B recanalization.

The determination of reperfusion grade is made by the neurointerventionalist at the time of the thrombectomy and lacks external confirmation. With meticulous review and scrutiny of post-thrombectomy angiography utilizing multiple views, we have stringent criteria to confirm patency of all distal vessels before making a determination of TICI 3 reperfusion. Utilizing these strict criteria for TICI 3 reperfusion, the rates of complete reperfusion reported here are generally lower than some rates from other centers reported in the literature.

Conclusion

A higher degree of reperfusion following endovascular thrombectomy is associated with reduced likelihood of parenchymal hemorrhage, symptomatic hemorrhage and mortality, and increased likelihood of functional independence at 90 days.

References

Footnotes

  • Twitter @shashvatdesai, @ashuPjadhav

  • Contributors Drafting the article: DAT, SMD. Acquisition of data/data analysis: SMD. Reviewed and revised article prior to submission: All authors. Study supervision: APJ.

  • 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 BTJ: Consultant: Medtronic; MWB: Investor: Penumbra, Inc; BAG: Consultant: Microvention; TGJ: Consultant: Stryker Neurovascular (PI DAWN-unpaid), Ownership Interest: Anaconda, Advisory Board/Investor; FreeOx Biotech, Advisory Board/Investor; Route92, Advisory Board/Investor; Blockade Medical, Consultant; Honoraria: Cerenovus.

  • Patient consent for publication Not required.

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