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Original research
Predictors of poor clinical outcome despite complete reperfusion in acute ischemic stroke patients
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  1. Noel van Horn1,
  2. Helge Kniep1,
  3. Hannes Leischner1,
  4. Rosalie McDonough1,
  5. Milani Deb-Chatterji2,
  6. Gabriel Broocks1,
  7. Goetz Thomalla2,
  8. Caspar Brekenfeld1,
  9. Jens Fiehler1,
  10. Uta Hanning1,
  11. Fabian Flottmann1
  1. 1 Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg, Hamburg, Hamburg, Germany
  2. 2 Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  1. Correspondence to Mr Noel van Horn, Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg Eppendorf, Hamburg, Hamburg, Germany; no.vanhorn{at}uke.de

Abstract

Background In patients suffering from acute ischemic stroke from large vessel occlusion (LVO), mechanical thrombectomy (MT) often leads to successful reperfusion. Only approximately half of these patients have a favorable clinical outcome. Our aim was to determine the prognostic factors associated with poor clinical outcome following complete reperfusion.

Methods Patients treated with MT for LVO from a prospective single-center stroke registry between July 2015 and April 2019 were screened. Complete reperfusion was defined as Thrombolysis in Cerebral Infarction (TICI) grade 3. A modified Rankin scale at 90 days (mRS90) of 3–6 was defined as ‘poor outcome’. A logistic regression analysis was performed with poor outcome as a dependent variable, and baseline clinical data, comorbidities, stroke severity, collateral status, and treatment information as independent variables.

Results 123 patients with complete reperfusion (TICI 3) were included in this study. Poor clinical outcome was observed in 67 (54.5%) of these patients. Multivariable logistic regression analysis identified greater age (adjusted OR 1.10, 95% CI 1.04 to 1.17; p=0.001), higher admission National Institutes of Health Stroke Scale (NIHSS) (OR 1.14, 95% CI 1.02 to 1.28; p=0.024), and lower Alberta Stroke Program Early CT Score (ASPECTS) (OR 0.6, 95% CI 0.4 to 0.84; p=0.007) as independent predictors of poor outcome. Poor outcome was independent of collateral score.

Conclusion Poor clinical outcome is observed in a large proportion of acute ischemic stroke patients treated with MT, despite complete reperfusion. In this study, futile recanalization was shown to occur independently of collateral status, but was associated with increasing age and stroke severity.

  • stroke
  • thrombectomy
  • intervention

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Introduction

Recently, several randomized clinical trials have demonstrated the benefit and safety of mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke within the anterior circulation.1–3 Accordingly, successful recanalization graded by the Thrombolysis In Cerebral Infarction scale (TICI) is presumed to be one of the strongest predictors for favorable clinical outcome.1 In the HERMES (Highly Effective Reperfusion Using Multiple Endovascular Devices) meta-analysis, successful reperfusion was reported in up to 71% of patients.1 Results of the latest trials showed even higher reperfusion rates with up to 95% of patients achieving TICI 2b/3 recanalization.3–5 However, a substantial proportion of patients experience futile recanalization, defined as poor long-term outcome despite successful reperfusion. Recently, a meta-analysis showed that poor outcome (modified Rankin scale (mRS) at 90 days (mRS90) of 3–6) occurs in 45% of TICI 2b/3 cases.6 Yet another meta-analysis that pooled the results of five randomized clinical trials presented futile reperfusion rates of 54%.1 A clinical explanation for this finding of poor outcome in a considerable number of patients successfully treated with MT is currently missing in the literature. Indeed, the majority of analyses investigating futile reperfusion refer only to TICI 2b/3 reperfusion rates7–9; no studies on poor clinical outcome in patients achieving TICI 3 have been performed, despite known large differences in the outcome and safety profiles between TICI 2b and 3 reperfusion grades.6 10

This study presents the first investigation of the relationship between complete (TICI 3) reperfusion and subsequent long-term poor clinical outcome. We hypothesize that baseline clinical data, stroke severity, comorbidities and treatment circumstances are correlated with poor clinical outcome, despite angiographic results of TICI 3.

Methods

Study population

In this retrospective single-center study, we evaluated 617 consecutive patients who underwent MT for acute LVO from a prospectively collected database from July 2015 to April 2019. In our clinic, patients with acute LVO routinely undergo MT according to the standard of care. MT is only withheld in patients with large early infarction lesions (Alberta Stroke Program Early CT Score (ASPECTS) <5) or those presenting within the late time window without evidence of perfusion mismatch.

The inclusion criteria of the present study were as follows: (1) acute ischemic stroke due to LVO within the anterior circulation, including the internal carotid artery (ICA) or middle cerebral artery (MCA); (2) complete reperfusion (defined as TICI 3); (3) known admission National Institutes of Health Stroke Scale (NIHSS) and ASPECTS; (4) known mRS90 days after stroke onset; (5) available collateral score on CT angiography (CTA); and (6) pre-mRS ≤2. Figure 1 demonstrates the stepwise patient inclusion process.

Figure 1

Flow chart demonstrating the number (n) of patients included in the analysis. inclusion of n=123 TICI 3 patients with anterior circulation stroke, known NIHSS, ASPECTS, mRS90, collateral score and pre-stroke mRS ≤2. ASPECTS, Alberta Stroke Program Early CT Score; LVO, large vessel occlusion; mRS, modified Rankin scale; mRS90, mRS after 90 days; MT, mechanical thrombectomy;NIHSS, National Institutes of Health Stroke Scale; TICI, Thrombolysis in Cerebral Infarction.

Patients underwent MT according to the standard protocol using stent-retrievers and/or aspiration catheters. All patients were under the supervision of an anesthesiologist during the procedure. Local anesthesia with optional conscious sedation was the standard anesthesiological management, and patients only underwent general anesthesia if deemed necessary.

All patient data and procedures conducted in this study were obtained in compliance with ethical guidelines of the leading ethics committee of the Ludwig-Maximilians University LMU, Munich (689-15) and in accordance with the Declaration of Helsinki. An informed consent was not mandatory according to the institutional review board approval and local regulations because all patient data obtained were already defined by national law for quality control reasons. Therefore, recruitment of patients undergoing MT was carried out without selection bias through an informed consent procedure.

Baseline characteristics and image analysis

Patient baseline clinical data and the following comorbidities were assessed: smoker status, arterial hypertension, atrial fibrillation, diabetes, and dyslipidemia. Stroke severity based on initial imaging was assessed with ASPECTS on non-contrast CT and/or on diffusion-/perfusion-weighted imaging. The diagnosis of ICA or MCA occlusion was verified on digital subtraction angiography (DSA) images in all patients. Intracranial collaterals were evaluated according to the Maas system.11 All images were analyzed by an experienced neuroradiologist (>5 years of experience).

Procedure and functional outcome

The following clinical, imaging and procedural data were collected: use of intravenous thrombolysis, time from onset to admission and to recanalization (if available), as well as time from puncture to reperfusion. The angiographic result was assessed on the final DSA image series and was classified according to the TICI scale; successful reperfusion was defined as TICI 3.

Experienced neurologists examined all patients, applying the NIHSS and pre-stroke mRS on admission and at 90 days follow-up. We defined a binary outcome with mRS90 0–2 as good and mRS90 3–6 as poor outcome.

Statistical analysis

The univariable distribution of metric variables is described by the median and IQR. Absolute and relative frequencies are given for categorical data. The association between clinical and radiological parameters and outcome was assessed by logistic regression analysis. Multivariable analysis was performed using a logistic regression model with unfavorable outcome at 3 months as the dependent variable. The variables included in the multivariable analysis as predictor variables included age, sex, baseline NIHSS, mRS, ASPECTS, time from groin puncture to recanalization, type of anesthesia, location of vessel occlusion, intravenous thrombolysis, comorbidities, and collateral score.

Statistical analysis of all data, including odds ratios and 95% confidence intervals (OR, 95% CI), were calculated using the SPSS statistical software (IBM, SPSS Statistics 25.0, Armonk, New York, USA) and R (R Core Team, 2019, Vienna, Austria12).

Results

Baseline characteristics of patients

Of 617 patients who underwent MT in the designated time period, the final TICI score was reported in 572 patients; 250/572 patients (43.7%) had complete reperfusion (TICI 3). The inclusion criteria were fulfilled by 123 patients (see patient selection flow chart, figure 1).

These patients had a median age of 75 years (IQR 67–81), a median NIHSS on admission of 16 (IQR 12–19), and a median ASPECTS of 8 (IQR 7–9). Twenty-three out of 123 (19%) patients received general anesthesia. The rate of futile reperfusion (mRS90 of 3–6) was 54.5% (n=67/123), with a median patient age of 78 years (IQR 70–83). The remaining 45.5% (n=56) had a median age of 69 years (IQR 62–78) and showed a favorable outcome 3 months after treatment (mRS90 of 0–2). Patient characteristics are displayed in table 1; 21% and 9% of patients with poor and good outcome, respectively, had collateral scores of 1, whereas 16% of patients with poor outcome and 18% with good outcome had a collateral score of 4. Overall, according to the scoring system developed by Maas,11 both patient groups (ie, those with poor and good outcome) showed comparable results, as seen in table 2.

Table 1

Baseline characteristics of TICI 3 patients

Table 2

Imaging and interventional findings

Interventional findings and treatment

Comorbidities, location of occlusion, intravenous thrombolysis, number of device passages, collateral score, and time from onset to recanalization did not have a significant impact on clinical prognosis. Data for time from onset to recanalization was available for 79 patients (64%). Detailed interventional results are displayed in table 2.

Results of multivariable statistical analysis are shown in table 3. Poor clinical outcome was significantly associated with the following parameters after adjusting for confounders: age (adjusted OR 1.10, 95% CI 1.04 to 1.17; p<0.001), admission NIHSS (OR 1.14, 95% CI 1.02 to 1.28; p=0.024) and ASPECTS on admission imaging (OR 0.6, 95% CI 0.4 to 0.84; p=0.007).

Table 3

Logistic regression analysis with odds ratio and p value for analyzed data

Discussion

This study was conducted to identify predictors for poor clinical outcome, despite best possible treatment results after MT. In our study cohort, approximately half (54.5%) of patients with complete reperfusion showed poor clinical outcome at 90 days. These findings are in line with those from previous studies conducted by Kaesmacher et al 6 and Lee et al,7 who reported futile recanalization rates of 45% and 51.4%, respectively.

Our study, along with several others,6 13 14 identified greater age, high NIHSS and low ASPECTS as independent predictors for unfavorable clinical outcome at the 3 month follow-up timepoint (mRS90 of 3–6). In contrast to previous studies also examining predictors of futile recanalization,7 8 15 we confined our analysis to completely recanalized patients with a TICI score of 3, justified by the significant differences in outcome observed between TICI 2b and TICI 3, as described in a recent meta-analysis.6

Our analysis reveals that patients presenting with greater age and with advanced focal neurological deficits are more likely to have developed functional dependency by the 3 month follow-up (mRS90 of 3–6). Greater age is frequently associated with poor neurological outcome after stroke, supposedly due to pre-existing physical and/or cognitive disabilities, higher frequency of complications during hospitalization, and therefore overall lower potential for neurological rehabilitation.16–18 The association between greater age and poor clinical outcome has been previously described by several studies,16 19 20 with noticeably worse clinical outcomes observed for patients between the ages of 60–70 years compared with their younger counterparts, despite similar recanalization and intracranial hemorrhage rates.19 This is in line with our findings, which show that younger patients (<55 years) with higher admission NIHSS (>20) are more likely to benefit from complete reperfusion than the elderly (figure 2A). This of course does not imply that endovascular therapy is not indicated in older patients. A recent study conducted by Lee et al 7 found that an increase in baseline NIHSS led to increased rates of futile reperfusion, but the clinical benefit of successful reperfusion after MT still outweighed the risks. Nevertheless, it is important to consider the results of the HERMES collaboration, a meta-analysis of five randomized trials, which showed only little therapeutic benefit in patients with initially low NIHSS (≤10).1

Figure 2

(A) Three-dimensional surface plot demonstrating the impact of NIHSS at admission (x axis) and age (z axis) on probability for poor clinical outcome after 90 days (mRS 3–6 after 90 days, y axis). A higher NIHSS and greater age lead to an increasing probability of an mRS ≥3–6. (B) Three-dimensional surface plot demonstrating the impact of age (x axis) and ASPECTS (z axis) on probability for poor clinical outcome after 90 days (mRS 3–6 after 90 days, y axis). Greater age and lower ASPECTS lead to an increasing probability of an mRS ≥3–6. ASPECTS, Alberta Stroke Program Early CT Score; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale.

In this study cohort, collateral status, as detected on single-phase CTA, was not significantly associated with clinical outcome, contrary to previous findings.21 Bang et al analyzed multiple randomized trials (eg, ESCAPE, SWIFT, PRIME, REVASCAT, BRASIL, DEFUSE, etc) and reported that an evaluation of collateral status may be beneficial to patients within an extended time window (>4.5 hours for intravenous thrombolysis and >6 hours for MT), who would otherwise not be treated.22 However, these studies included patients both with and without successful reperfusion. Because reperfusion success is more likely in patients with a good collateral score,23 the positive effect on clinical outcome is possibly indirect. Nevertheless, no validated scoring system currently exists that sufficiently predicts patient outcome.24 Relatively quick, easy and reproducible CTA-based methods exist for the quantification of collateral status and its influence on ischemic lesion dynamics.25 We conclude that collateral status has a negligible effect in this group of patients, which is in agreement with an MRI-based study that reported collaterals were not a significant predictor of clinical outcome when correcting for reperfusion status.26 In addition, patients in this study had, on average, rather high ASPECTS, which is known to be correlated with good collateral status.26 Therefore, the majority of patients with poor collateral status may not have been included in this study.

Our analysis also shows that futile recanalization is significantly associated with lower ASPECTS on admission. ASPECTS has been validated for assessment of an early infarct lesion of the anterior circulation and is often employed to select patients who would most likely benefit from MT, thus helping to improve clinical prognosis in such patient collectives.27–29 Results from the HERMES meta-analysis provided strong evidence for the efficiency of MT with an ASPECTS ≥6.1 Nevertheless, an ASPECTS <6 is not representative of a definitive treatment threshold. A 2014 study provided evidence for an extension of the cut-off for endovascular treatment to an ASPECTS of ≥5, whereas a very low ASPECTS (0–4) was associated with higher mortality rates (55%) and led to an increased incidence of intracranial hemorrhage after recanalization.28 This study demonstrates that achieving TICI 3 reperfusion with low initial ASPECTS (<5) is much more promising in younger patients (<55 years) than in the elderly (>90 years) (figure 2B).

Other retrospective studies reported an increased risk of poor clinical outcome in patients who underwent general anesthesia.30 In contrast, a meta-analysis of a recent randomized controlled trial reported no significant differences in clinical outcome between general anesthesia and conscious sedation.31 We also found no significant association between general anesthesia and poor clinical outcome, although the result was borderline (p=0.052). The tendency towards poor outcome after general anesthesia in retrospective studies is most likely caused by a selection bias, as more critically ill patients are more likely to undergo general anesthesia.

The present study confirms the well-known outcome predictors in acute LVO ischemic stroke, where TICI 3 reperfusion has often been proposed as the therapeutic goal.32 Understanding why a large subset of these successfully reperfused patients still experience poor outcome could help to identify new targets for therapy and thereby further improve patient outcome. For example, hyperglycemia is a common phenomenon in patients suffering from acute ischemic stroke and is associated with poor clinical outcome.33 34 Blood platelet count serves as another potential biomarker that is correlated with poor functional outcome, as well as stroke recurrence and higher mortality rates.35 The recently discussed topic of net water uptake in ischemic lesions, calculated in acute multimodal and follow-up CT, is another quantitative imaging parameter that is associated with poor clinical outcome after TICI 2b/3 reperfusion.36 More sophisticated imaging analyses of early ischemic signs are also possible on common non-contrast CT scans. For example, automated software applied on non-contrast CT was able to identify future ASPECTS regions (as later verified by CT perfusion) by comparing relative Hounsfield units between the symptomatic and asymptomatic cerebral hemisphere.37 The number of device passes could also be included in future studies to investigate possible effects on clinical follow-up.38 So far, these findings have not been correlated to TICI 3 reperfusion rates, and comprehensive data as well as more in-depth analyses are needed to better understand the clinical course of these patients.

Our study is subject to some limitations as our dataset represents a retrospective registry observation of prospectively collected data from a single center. It would be interesting to match our findings with those of transregional medical centers with the intent of unmasking similarities and dissimilarities in clinical outcome. Although our standard of care in treating acute ischemic stroke is widespread, there are nevertheless differences in the preferences of the intervening neurointerventionalist in terms of MT technique and material, which may lead to differing results. The dichotomization used in this study for clinical outcome neglects differences between mRS 3, 4, 5 and 6. An extended, more in-depth analysis including a greater number of TICI 3 patients is needed to identify potential minor differences.

Conclusion

While the benefit of MT has been repeatedly demonstrated in various trials and meta-analyses, a considerably large number of patients with acute LVO have a poor clinical prognosis despite successful flow restoration. Our findings suggest that advanced age and increased stroke severity are independent predictors for an unfavorable clinical outcome following complete reperfusion, independent of collateral status.

References

Footnotes

  • Twitter @noelvanhorn

  • UH and FF contributed equally.

  • Correction notice Since its online publication, this article has been updated to show that authors 'Uta Hanning' and 'Fabian Flottmann' are equally contributing.

  • Contributors NVH, HK, UH, and FF made substantial contributions to the conception and design of the work. Data acquisition was performed by NVH, HK, HL, RMD, MD-C, GB, GT, CB, FF, and UH. NVH, HK, and FF performed the data analysis. Interpretation of the data was done by NVH, FF, HK, JF, GT, UH, GB, and HL. NVH and FF drafted the manuscript and all of the other authors revised it critically for important intellectual content. All authors approved the final version to be published. They 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 manuscript 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 JF: Consultant for Acandis, Boehringer Ingelheim, Codman, Microvention, Sequent, Stryker. Speaker for Bayer Healthcare, Bracco, Covidien/ev3, Penumbra, Philips, Siemens. Grants from Bundesministeriums für Wirtschaft und Energie (BMWi), Bundesministerium für Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), European Union (EU), Covidien, Stryker (THRILL study), Microvention (ERASER study), Philips. GT: Consulting fees from Acandis, grant support and lecture fees from Bayer, lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo, and consulting fees and lecture fees from Stryker. Grants from Bundesministerium für Wirtschaft und Energie (BMWi), Deutsche Forschungsgemeinschaft (DFG), European Union (EU), German Innovation Fund, Corona Foundation.

  • Patient consent for publication Not required.

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

  • Data availability statement Data are available upon reasonable request. Data supporting the findings are available from the corresponding author upon reasonable request.

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