Impact of Strategy on Clinical Outcome in Large Vessel Occlusion Stroke Successfully Reperfused: ETIS Registry Results
Abstract
Background and Purpose:
Approximately half of the patients with acute ischemic stroke due to anterior circulation large vessel occlusion do not achieve functional independence despite successful reperfusion. We aimed to determine influence of reperfusion strategy (bridging therapy, intravenous thrombolysis alone, or mechanical thrombectomy alone) on clinical outcomes in this population.
Methods:
From ongoing, prospective, multicenter, observational Endovascular Treatment in Ischemic Stroke registry in France, all patients with anterior circulation large vessel occlusion who achieved successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b-3) following reperfusion therapy were included. Primary end point was favorable outcome, defined as 90-day modified Rankin Scale score ≤2. Patient groups were compared using those treated with bridging therapy as reference. Differences in baseline characteristics were reduced after propensity score-matching, with a maximum absolute standardized difference of 14% for occlusion site.
Results:
Among 1872 patients included, 970 (51.8%) received bridging therapy, 128 (6.8%) received intravenous thrombolysis alone, and the remaining 774 (41.4%) received MT alone. The rate of favorable outcome was comparable between groups. Excellent outcome (90-day modified Rankin Scale score 0–1) was achieved more frequently in the bridging therapy group compared with the MT alone (odds ratio after propensity score-matching, 0.70 [95% CI, 0.50–0.96]). Regarding safety outcomes, hemorrhagic complications were similar between the groups, but 90-day mortality was significantly higher in the MT alone group compared with the bridging therapy group (odds ratio, 1.60 [95% CI, 1.09–2.37]).
Conclusions:
This real-world observational study of patients with anterior circulation large vessel occlusion demonstrated a similar rate of favorable outcome following successful reperfusion with different therapeutic strategies. However, our results suggest that bridging therapy compared with MT alone is significantly associated with excellent clinical outcome and lower mortality.
REGISTRATION:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03776877.
Graphical Abstract
Despite successful reperfusion, 40% of patients with stroke due to anterior large vessel occlusion (LVO) treated with reperfusion therapy did not achieve functional independence in the previous randomized trials.1 We aimed to assess the influence of the reperfusion strategy (bridging therapy, intravenous thrombolysis [IVT] alone, or mechanical thrombectomy [MT] alone) on clinical outcomes of patients achieving angiographic successful reperfusion in current clinical practice.
Methods
The authors declare that all supporting data are available within the article and its Supplemental Material.
Study Design and Population
Patients enrolled in the prospective, multicenter, Endovascular Treatment of Ischemic Stroke registry between January 2015 and November 2019 were included in this study. The inclusion criteria were the following: (1) prestroke modified Rankin Scale (mRS) score 0–2; (2) acute anterior circulation LVO (M1 or M2 segment of the middle cerebral artery or internal carotid artery); (3) achievement of a successful reperfusion, defined as modified Thrombolysis in Cerebral Infarction grade 2b-3 proven by catheter angiogram, after one of the 3 following strategy: IVT alone, MT alone, or bridging therapy. Additional details, including RECORD guideline checklist and flow diagram (Figure I in the Supplemental Material).
Data collection and analyses were approved by local institutional review boards.
Outcomes
The primary outcome was favorable outcome (90-day mRS score 0–2). Secondary outcomes included excellent outcome (90-day mRS score 0–1), 90-day all-cause mortality, and hemorrhagic complications (parenchymal hematoma and symptomatic intracranial hemorrhage according to the European Cooperative Acute Stroke Study 2 classification).
Statistical Analysis
We compared the effect of IVT alone and MT alone to bridging therapy on the primary and secondary outcomes after adjusting for potential confounders using the propensity score-matching method. Magnitude of between-group differences at baseline was assessed by calculating the absolute standardized difference (ASD) and considered ASD>10% as meaningful difference. Using bridging therapy as a reference, we estimated the odds ratio and 95% CI as treatment effect size measures using a generalized linear mixed models (with binomial distribution and logit link function) including matched blocks as random effect. For comparison between MT alone and bridging therapy, we added onset-to-reperfusion time, number of patients with unknown onset time, and number of passes to achieve reperfusion as covariates into generalized linear mixed models. Detailed methodology of the statistical analysis is reported in the Supplemental Material.
Results
Among the 1872 included patients, 970 (51.8%) achieved successful reperfusion with bridging therapy, 128 (6.8%) with IVT alone, and the remaining 774 (41.4%) with MT alone. Baseline and treatment characteristics according to the treatment method (Table I in the Supplemental Material).
Comparison Between IVT Alone to Bridging Therapy Groups
Before matching, several meaningful differences (ASD>10%) were found in smoking status, anticoagulants and antiplatelets use, center of admission (with MT capability versus not), prestroke mRS, systolic and diastolic blood pressure, admission National Institutes of Health Stroke Scale score, cardioembolic cause, initial Alberta Stroke Program Early CT Score, site of occlusion, general anesthesia rate, and onset-to-puncture time. These differences were reduced after propensity score-matching with a maximum ASD of 14% for occlusion site (Table II and Figure II in the Supplemental Material). As shown in Table 1, the rates of favorable and excellent outcomes were higher in patients reperfused with IVT alone (71.9% versus 54.8% for favorable outcome; 60.9% versus 37.9% for excellent outcome). This difference did not retain significance in propensity score-matched analysis. Regarding mortality and hemorrhagic complications, no differences were found before and after propensity score-matching.
| Outcome | Before propensity score-matching | After propensity score-matching | ||||||
|---|---|---|---|---|---|---|---|---|
| IVT-reperfused group (n=128) | IVT+MT-reperfused group (n=970) | Effect size (95% CI) | P value | IVT-reperfused group (n=127) | IVT+MT-reperfused group (n=127) | Effect size (95% CI) | P value | |
| Favorable* | 92 (71.9) | 532 (54.8) | 2.08 (1.37–3.15) | <0.001 | 91 (71.7) | 81 (63.8) | 1.08 (0.93–1.25) | 0.29 |
| Excellent† | 78 (60.9) | 368 (37.9) | 2.52 (1.70–3.73) | <0.001 | 77 (60.6) | 60 (47.2) | 1.14 (0.97–1.34) | 0.098 |
| Mortality | 17 (13.3) | 134 (13.8) | 0.95 (0.56–1.65) | 0.88 | 17 (13.4) | 12 (9.4) | 1.04 (0.94–1.14) | 0.46 |
| PH | 22 (17.2) | 208 (21.4) | 0.76 (0.44–1.29) | 0.30 | 22 (17.3) | 28 (22.0) | 0.95 (0.85–1.06) | 0.36 |
| sICH | 16 (12.5) | 139 (14.3) | 0.86 (0.46–1.61) | 0.65 | 16 (12.6) | 18 (14.2) | 0.98 (0.49–1.08) | 0.75 |
Values are expressed in n (%) unless otherwise indicated.Descriptive parameters and effect sizes (odds ratio) were calculated after handling missing values for variables included in the propensity score using a multiple imputation procedure. Propensity score was calculated with all parameters presented in Table II in the Supplemental Material. IVT indicates intravenous thrombolysis; IVT+MT, bridging therapy; mRS, modified Rankin Scale; MT, mechanical thrombectomy; PH, parenchymal hematoma; and sICH, symptomatic intracranial hemorrhage.
*
Prespecified primary outcome defined as a 90-d mRS score ≤2.
†
Defined as a 90-d mRS score of 0–1, or equal to prestroke mRS score.
Comparison Between MT Alone to Bridging Therapy Groups
Before matching, several meaningful differences (SD>10%) were found in age, hypertension, anticoagulants use, center of admission, prestroke mRS, and cardioembolic cause. These differences were reduced after propensity score-matching with a maximum ASD of 11.9% for onset-to-puncture time (Table III and Figure II in the Supplemental Material). As shown in Table 2, the rates of favorable and excellent outcomes were higher in patients reperfused with bridging therapy (55.1% versus 42.5% for favorable outcome; 38.6% versus 27.4% for excellent outcome). The difference in the excellent outcome, but not in favorable outcome, remained significant in a propensity score-matched analysis adjusted for onset-to-reperfusion time, number of patients with unknown onset time, and number of passes (odds ratio, 0.70 [95% CI, 0.50–0.96]). Regarding mortality, a significantly higher rate was observed in the group reperfused with MT alone (22.4% versus 13.5%). This difference remained significant in propensity score-matched analysis (odds ratio, 1.60 [95% CI, 1.09–2.37]). Regarding hemorrhagic complications, no difference was found between both groups before and after propensity score-matching.
| Outcome | Before propensity score-matching | After propensity score-matching | ||||||
|---|---|---|---|---|---|---|---|---|
| MT-reperfused group (n=774) | IVT+MT-reperfused group (n=970) | Effect size (95% CI) | P value | MT-reperfused group (n=537) | IVT+MT-reperfused group (n=537) | Effect size (95% CI) | P value | |
| Favorable* | 329 (42.5) | 534 (55.1) | 0.60 (0.49–0.74) | <0.001 | 252 (46.9) | 285 (53.1) | 0.77 (0.57–1.07) | 0.12 |
| Excellent† | 212 (27.4) | 374 (38.6) | 0.60 (0.48–0.74) | <0.001 | 158 (29.4) | 198 (36.9) | 0.70 (0.50–0.96) | 0.026 |
| Mortality | 173 (22.4) | 131 (13.5) | 1.84 (1.43–2.37) | <0.001 | 113 (21) | 77 (14.3) | 1.60 (1.09–2.37) | 0.017 |
| PH | 132 (17.1) | 194 (20.0) | 0.82 (0.63–1.08) | 0.16 | 90 (16.8) | 112 (20.9) | 0.74 (0.51–1.05) | 0.09 |
| sICH | 75 (9.7) | 121 (12.5) | 0.75 (0.52–1.09) | 0.13 | 52 (9.7) | 71 (13.2) | 0.68 (0.42–1.09) | 0.10 |
Values are expressed in n (%) unless otherwise indicated. Descriptive parameters and effect sizes (odds ratio) were calculated after handling missing values for variables included in the propensity score using a multiple imputation procedure. Propensity score was calculated with all parameters presented in Table III in the Supplemental Material. Effect sizes (95% CI) after propensity score-matching were obtained after adjustment on onset-to-reperfusion time, number of patients with unknown onset time, and number of passes. IVT indicates intravenous thrombolysis; IVT+MT, bridging therapy; mRS, modified Rankin Scale; MT, mechanical thrombectomy; PH, parenchymal hematoma; and sICH, symptomatic intracranial hemorrhage.
*
Prespecified primary outcome defined as a 90-d mRS score ≤2.
†
Defined as a 90-d mRS score of 0–1, or equal to prestroke mRS score.
Discussion
This observational study of patients with anterior circulation LVO strokes did not find any significant difference in favorable outcome after successful reperfusion with different therapeutic strategies. However, bridging therapy compared with MT alone was significantly associated with a higher likelihood for excellent outcome and lower mortality.
Strength of our study is the fact that it focused only on patients with angiographic proven successful reperfusion. This may explain some differences between this study and recent results from literature.
First, we observed a low incidence (6.8%) of early LVO reperfusion after IVT alone in patients referred for MT, compared with the reported rate of 20%.2 Notably, most of our patients were treated following a drip-and-ship paradigm, leaving time for IVT to lyse the clot. Patients reperfused with IVT alone had a higher rate of functional independence; however, the difference did not retain significance after adjustment for potential confounders. Therefore, this study suggests that LVO patients may benefit from early reperfusion with IVT before planned MT, especially those transferred from remote centers.
Second, patients reperfused with bridging therapy had better clinical outcome compared with those with MT alone, consistent with a previous study.3 Recent results from DIRECT-MT and DEVT trials suggested noninferiority of MT alone compared with bridging therapy,4,5 SKIP trial failed to demonstrate similar findings.6 These trials included only patients admitted directly to MT capable centers. In contrast, our study also included patients managed following the drip-and-ship paradigm reflecting real-world experience and explaining the higher onset-to-puncture time. In the DIRECT-MT trial, successful reperfusion was observed more frequently in patients who received IVT, with no increase in time from onset to MT procedure. Moreover, experimental studies have demonstrated that IVT could act on downstream microvascular thrombosis and promote microvascular permeability, which eventually improve cerebral blood flow and prevent infarct extension.7 Therefore, we think that IVT could promote reperfusion, which goes beyond simple recanalization of the arterial trunk, in stroke patients with LVO, which could have contributed to the higher rate of excellent outcome observed with the bridging therapy.
The main limitation of this study is its observational nonrandomized design as the differences in baseline and treatment characteristics of the groups may have influenced patients’ outcomes, especially for those treated with MT alone.
Our real-world data study suggests that IVT should be administrated to stroke patients with LVO before MT as it could promote excellent clinical outcome without safety concerns.
Article Information
Supplemental Materials
Expanded Materials and Methods
Supplemental Tables I–III
Supplemental Figures I–II
Supplemental Appendix
RECORD guideline checklist
Footnote
Nonstandard Abbreviations and Acronyms
- ASD
- absolute standardized difference
- IVT
- intravenous thrombolysis
- LVO
- large vessel occlusion
- mRS
- modified Rankin Scale
- MT
- mechanical thrombectomy
Supplemental Material
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References
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© 2021 American Heart Association, Inc.
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History
Received: 16 September 2020
Revision received: 1 July 2021
Accepted: 28 July 2021
Published online: 3 November 2021
Published in print: January 2022
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Disclosures
Disclosures Dr Lapergue received grants from Stryker Neurovascular, Penumbra, Microvention outside the present study. The other authors report no conflicts.
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