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Abstract
Background First pass reperfusion (FPR) has been established as a key performance metric in mechanical thrombectomy (MT). The impact of FPR may be more relevant in fast progressors. We aim to study the impact of baseline Alberta Stroke Program Early CT Score (ASPECTS) on non-contrast CT and hypoperfusion intensity ratio (HIR) on CT perfusion on clinical outcomes after FPR.
Methods A prospective MT database was reviewed for patients with isolated occlusion of the intracranial internal carotid artery and/or middle cerebral artery M1 segment who underwent MT with complete reperfusion (modified Thrombolyis in Cerebral Infarction score 2c–3) from January 2012 to May 2019. The overall population was divided into ASPECTS >7 versus ≤7 and the subgroup of patients with baseline CT perfusion was divided into HIR <0.3 versus ≥0.3. Univariable and multivariable analyses were performed to establish the predictors of 90-day functional independence (modified Rankin Scale (mRS) ≤2) in each subgroup.
Results A total of 436 patients were included in the analyses. FPR was achieved in 254 (58.3%) patients. ASPECTS modified the effect of FPR on clinical outcomes, with FPR predicting good outcomes in patients with ASPECTS ≤7 (46% vs 29%, adjusted OR 3.748; 95% CI 1.590 to 8.838, p=0.003) while no significant effect was detected in those with ASPECTS >7 (62.3% vs 53.1%, adjusted OR 1.372; 95% CI 0.798 to 2.358, p=0.25). Similarly, FPR predicted good outcomes in patients with HIR ≥0.3 (54.8% vs 41.9%, adjusted OR 2.204; 95% CI 1.148 to 4.233, p=0.01) but not in those with HIR <0.3 (62.9% vs 52.8%, adjusted OR 1.524; 95% CI 0.592 to 3.920, p=0.38).
Conclusions The impact of FPR on functional outcomes is highly dependent on baseline imaging characteristics, with a more prominent influence in patients presenting with lower ASPECTS and/or higher HIR.
- stroke
- thrombectomy
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Introduction
Large vessel occlusion (LVO) may account for up to 40% of acute ischemic stroke (AIS).1 Mechanical thrombectomy (MT) has become the gold standard for LVO AIS.2 Although there are many predictors of outcome after MT, successful reperfusion remains one of the most important predictors of favorable functional outcomes.3 First pass reperfusion (FPR) has more recently emerged as a new metric that strongly correlates with improved functional outcomes.4
To our knowledge, previous studies on FPR did not consider the speed of infarct volume progression in their analyses. Due to their greater vulnerability to reperfusion time, the impact of FPR may be more relevant in patients with poor collaterals ('fast progressors').5 Baseline Alberta Stroke Program Early CT Score (ASPECTS) and CT perfusion (CTP) parameters strongly correlate with collateral flow and infarct growth rate.6 7 We aim to study the impact of baseline ASPECTS on non-contrast CT (NCCT) and hypoperfusion intensity ratio (HIR) on CTP on the clinical outcomes of patients after FPR.
Methods
Patient selection
We retrospectively reviewed a prospectively maintained MT database in a comprehensive stroke center from January 2012 to May 2019. Patients were included in the analysis if they had: (1) anterior circulation LVO with intracranial internal carotid artery (ICA) or middle cerebral artery (MCA) M1 occlusion; (2) good quality baseline NCCT; and (3) achieved complete reperfusion with modified Thrombolysis in Cerebral Infarction (mTICI) 2c–3. Patients with tandem cervical ICA occlusion were excluded. The study was approved by the Institutional Review Board.
Imaging protocol and analysis
All patients in the study had NCCT performed using a GE Revolution 256-slice CT scanner or a GE Lightspeed 64-slice CT scanner (GE Healthcare, Chicago, Illinois, USA). ASPECTS is maintained in our database for all patients. HIR was assessed on baseline CTP when available using an automated software program (RAPID, iSchemaView, Menlo Park, California, USA). HIR was defined by the proportion of the TMax >6 s lesion with TMax >10 s.7 All procedures were done by experienced neurointerventionalists using stentrievers, contact aspiration, or combined techniques according to the operator’s preference.
Outcome measures
Reperfusion scores were determined by the operators. FPR was defined as achieving mTICI 2c–3 after a single pass of the device.4 Non-FPR were cases in which the final mTICI 2c–3 was achieved with ≥2 passes. Good outcome was defined as functional independence at 90 days (modified Rankin Scale (mRS) 0–2). We evaluated the outcomes of FPR in the overall population, then classified the patients into two groups according to ASPECTS (>7 and ≤7); FPR outcomes were evaluated in each group. A subgroup analysis of patients who underwent pretreatment CTP was also performed. Patients were dichotomized according to HIR into two groups (<0.3 and ≥0.3).
Sensitivity analysis
A sensitivity analysis was performed for the previous subgroups after matching for age, National Institutes of Health Stroke Scale (NIHSS) score and time from last known well (LKW) to puncture. A matching method based on Euclidean distances was performed to obtain a pair of individuals considered to be the nearest neighbors in a three-dimensional space of age, baseline NIHSS score and time from LKW to puncture using the University Edition of SAS statistical software (SAS Institute). The distribution of Euclidian distances was then studied and a threshold was determined as follows: Q75 +1.5 × (Q75 − Q25), where Q25 and Q75 are the 25th and 75th percentiles, respectively. Pairs with distances greater than the threshold were considered outliers and eliminated from further consideration.8
Statistical analysis
Categorical variables were expressed as frequencies and percentages. Chi-square and Fisher’s exact tests were used for categorical variables comparison. After normality testing through the Shapiro–Wilk test, continuous variables were expressed either as median (IQR) or mean±SD and compared with the Mann–Whitney U test or t-test as appropriate. On multivariable analyses, all variables with p˂0.1 were included to assess independent predictors of functional independence at 90 days in a logistic regression model. Given its strong association with clinical outcomes, we forced time from LKW to reperfusion into the model. Significance was set at p˂0.05. Analyses were performed using SPSS 26 software (IBM, Armonk, New York, USA).
Results
Among 1747 patients who underwent MT from January 2012 to May 2019, a total of 436 patients qualified for the analysis. In the overall cohort, median (IQR) age was 66 (54–77) years, ASPECTS was 8 (7–9), and the mean±SD baseline NIHSS score was 17.3±5.8. FPR was achieved in 254 (58.3%) patients. The group with FPR had shorter procedure duration (34 (26–48) vs 64.5 (45.8–89.3) min, p<0.001), trend to lower 90-day mortality (14.2% vs 20.9%, p=0.07), and significantly higher rates of good outcome (56.7% vs 44%, p=0.009) compared with the non-FPR mTICI 2c–3 group. No other significant differences were observed (online supplementary table I). On multivariable analysis, FPR (OR 1.703; 95% CI 1.103 to 2.629, p=0.016) remained an independent predictor of good outcome. Other predictors were younger age, lower baseline NIHSS score, higher ASPECTS, smoking, absence of diabetes mellitus, and pre-procedure IV tissue plasminogen activator administration (online supplementary table II).
Supplemental material
Primary analysis: effect of FPR in patients with baseline NCCT ASPECTS >7 versus ASPECTS ≤7
In the group with ASPECTS >7, patients with FPR had a significantly lower baseline NIHSS score, longer time from LKW to puncture, and a shorter procedure duration compared with the non-FPR group. There was no difference in the rate of 90-day mRS 0–2 (62.3% vs 53.1%, p=0.13, adjusted OR 1.372; 95% CI 0.798 to 2.358, p=0.25) across patients with and without FPR, respectively (table 1 and online supplementary table II).
Demographics, clinical, and procedure characteristics (group with ASPECTS >7)
In the group with ASPECTS ≤7, patients with FPR showed a trend for higher use of stent retrievers as the first-line technique, significantly shorter procedure duration, and higher rates of good outcome (46% vs 29%, p=0.03) compared with the non-FPR group. On multivariable analysis, FPR was independently associated with good outcomes (OR 3.748; 95% CI 1.590 to 8.838, p=0.003) (table 2 and online supplementary table II).
Demographics, clinical, and procedure characteristics (group with ASPECTS ≤7)
Subgroup analysis: effect of FPR in patients with HIR <0.3 versus ≥0.3 on baseline CTP
There were no differences in demographic, clinical, and imaging characteristics between the FPR and non-FPR groups. HIR modified the effect of FPR on clinical outcomes, with FPR predicting good outcomes in patients with HIR ≥0.3 (54.8% vs 41.9%, p=0.06; adjusted OR 2.204; 95% CI 1.148 to 4.233, p=0.01) (table 3 and online supplementary table II) while no significant effect was detected in those with HIR <0.3 (62.9% vs 52.8%, p=0.33; adjusted OR 1.524; 95% CI 0.592 to 3.920, p=0.38) (table 4 and online supplementary table II).
Demographics, clinical, and procedure characteristics (group with HIR ≥0.3)
Demographics, clinical, and procedure characteristics (group with HIR <0.3)
Sensitivity analysis
After matching for age, baseline NIHSS score, and time from LKW to puncture, FPR predicted good outcomes in the group with ASPECTS ≤7 (n=118; 47.5% vs 27.1%, p=0.02; adjusted OR 3.858; 95% CI 1.218 to 6.707, p=0.016) while no significant effect was detected in those with ASPECTS >7 (n=196; 62.2% vs 52%, p=0.15; adjusted OR 1.382; 95% CI 0.730 to 2.617, p=0.32). Similarly, FPR predicted good outcomes in a matched cohort with HIR ≥0.3 (n=170; 60% vs 42.4%, p=0.02; adjusted OR 2.218; 95% CI 1.149 to 4.284, p=0.018) but not in those with HIR <0.3 (n=68; 64.7% vs 52.9%, p=0.32; adjusted OR 1.692; 95% CI 0.598 to 4.788, p=0.32) (see online supplementary tables III–VII).
Discussion
The concept of first pass effect (FPE) was first proposed in a subgroup analysis of the North America Solitaire Acute Stroke (NASA) registry,4 which demonstrated that FPE was significantly associated with higher rates of good outcomes. This study was limited by the fact that the authors compared FPE (mTICI 2c–3) with non-FPE (mTICI 0–3), which presumably biased the results by comparing fully reperfused FPE patients with patients without significant reperfusion. However, subsequent studies reinforced the clinical relevance of the FPE when comparing groups with a similar degree of final reperfusion.9–11
The mechanism underlying the benefits of FPR is probably multifactorial. There is an increased risk of vessel wall injury and distal embolization with every additional device pass.12–14 Even small clot fragments not visible on imaging may still disrupt microcirculatory perfusion and significantly affect the outcome.15–17 Finally, with every device pass there is an inherent increase in time to reperfusion and consequently smaller chances of functional recovery.18
Our study corroborates the literature on FPR being a powerful predictor of good outcome.9–11 We herein demonstrate that the benefit of rapid and full reperfusion is significantly modified by both baseline ASPECTS on NCCT and HIR on CTP, presumably reflecting the individual differences in rate of infarct growth among patients with AIS.5 A key element in determining the rate of infarct growth is the leptomeningeal collateral blood flow, where poor collateral grades correlate with fast progressors and vice versa.19 20 Strong associations exist between collateral status, baseline ASPECTS and the speed of infarct growth, where good collateral flow correlates with higher ASPECTS, and slower stroke progression.21–23 The subgroup analysis of the present study further supported this hypothesis by demonstrating that FPR has a more prominent impact in patients with lower ASPECTS and higher HIR, both of which are strongly associated with worse collaterals, reinforcing the fine balance that exists between time to reperfusion and collateral flow.
The idea behind the concept of HIR is to provide a more objective and continuous linear measurement for collateral flow with lower HIR reflecting better collateral status.7 24 25 Previous studies have identified different thresholds of HIR that better correlate with dichotomous collateral status. The DEFUSE 2 investigators showed that a threshold of ≥0.4 strongly correlates with poor collaterals and rapid infarct volume growth.7 Subsequently, Guenego et al 24 reported that HIR ≥0.5 strongly correlates with infarct core growth and poor collateral status. In the present study we found that HIR ≥0.3 defined collaterals that created a stronger and definite dependence on FPE. Similarly, the DEFUSE 3 investigators reported that HIR >0.34 optimally predicted substantial infarct growth at 24 hours.26 These variations in HIR thresholds between studies is probably explained by the differences in the studied populations.
To our knowledge, this is the first study to evaluate the interactions between baseline imaging and FPR on clinical outcomes. Our study has all the known limitations inherent to single-center retrospective analysis. Moreover, reperfusion (mTICI scores) was not assessed through a core laboratory. The strengths of our study include the use of NCCT ASPECTS which, despite some limitations,27 28 is a well-established, pragmatic, and widespread method for MT patient selection, as well as the robust sample size and the inclusion of only fully reperfused patients.
Conclusions
The effect of FPR on functional outcomes is highly dependent on baseline imaging characteristics including ASPECTS on non-contrast CT and HIR on CTP. The more prominent influence of FPR in patients presenting with lower ASPECTS and/or higher HIR further reinforces their characterization as 'fast progressors'.
References
Footnotes
Twitter @Mahmoudneuro, @pisanileonardo, @PerrydaCamaraMD, @nirav_r_bhatt
Contributors MHM: study conception, acquisition of data, interpretation of data, drafting of the manuscript. DCH, LP, ARA-B, CPdC, NB, SRB, BBL, NB, AMA, MRF: critical revision of the manuscript. RGN: study conception, design of the work, acquisition of data, 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.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. The data that support the findings of this study are available from the corresponding author on reasonable request.