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Abstract
Background The DEFUSE 3 and DAWN trials have shown the benefit of thrombectomy beyond 6 hours of stroke symptom onset in carefully selected patients.
Objective To evaluate the real-world outcomes of stent retriever thrombectomy beyond 6 hours of stroke onset using combined individual patient data from the North American Solitaire Stent Retriever Acute Stroke (NASA) and Trevo Stent-Retriever Acute Stroke (TRACK) registries.
Methods Pooled analysis of individual patient data of all cases of anterior circulation acute ischemic stroke (AIS) from NASA and TRACK was performed to compare outcomes of patients presenting within the first hours 6 or beyond 6 hours of stroke symptom onset.
Results Of 830 patients with anterior circulation AIS from the NASA and TRACK registries, 32.7% (271 patients) underwent thrombectomy beyond the first 6 hours of symptom onset. The rates of good clinical outcome (modified Rankin scale score of 0–2 at 90 days), mortality, and symptomatic intracranial hemorrhage were similar: 48.1%, 20.6%, and 8.0% within 0–6 hours, 46.2%, 21.6%, and 10.9% within 6–16 hours, and 38.9%, 33.3%, and 5% within 16–24 hours (p=0.8, 0.6, and 0.5, respectively). The rates of successful recanalization (Thrombolysis in Cerebral Infarction 2b/3) were 79.4% in patients with stroke within 0–6 hours, 72.6% within 6–16 hours, and 85.0% within 16–24 hours (p=0.04).
Conclusions Real-world experience with patients with anterior circulation AIS treated with the Solitaire and Trevo thrombectomy devices beyond the first 6 hours of symptom onset proved to be equally safe and effective as for patients with symptom onset within the first 6 hours.
- stroke
- stent
- thrombectomy
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Introduction
Recent randomized clinical trials of endovascular therapy have changed the treatment guidelines of acute ischemic stroke (AIS) from anterior circulation emergent large vessel occlusion (ELVO). The DEFUSE 3 Trial (thrombectomy for stroke at 6–16 hours with selection by perfusion imaging) proved its safety and efficacy in treating AIS up to 16 hours after symptom onset, whereas the DAWN Trial (thrombectomy 6–24 hours after stroke with a mismatch between deficit and infarct) concluded treatment benefit up to 24 hours after the patient was last known to be well.1 2
Based on the results of these two trials, the American Heart Association (AHA) published updates to the 2015 AIS treatment guidelines advocating early management of AIS with mechanical thrombectomy within 6–16 hours of symptom onset as class IA and 16–24 hours as class IB recommendations.3 However, the AHA’s recommendations for thrombectomy beyond 6 hours of symptom onset are limited to patients who meet inclusion criteria from the DEFUSE 3 and DAWN trials. Compared with the results achieved in clinical trials, other studies conclude that mechanical thrombectomy for patients with ELVO has low complication rates and leads to functional recovery even when patients do not meet top tier evidence criteria from the guidelines.4 5
The purpose of our study was to evaluate the outcomes of patients treated with stent retriever thrombectomy beyond the 6 hours of stroke onset using the data from one of the largest real-world experience databases of both North American Solitaire Stent Retriever Acute Stroke (NASA) and Trevo Stent-Retriever Acute Stroke (TRACK) registries. Both were investigator-initiated, independent, US postmarketing registries evaluating the real-life clinical experience of the two FDA approved stent retriever devices (Solitaire, Medtronic, Irvine, California, USA and Trevo, Stryker Neurovascular, Fremont, California, USA) in AIS.6 7 Here, we report our analysis of the outcomes of patients with stroke onset beyond 6 hours who were treated within the combined registries database, using individual patient level data.
Methods
Institutional review board approval with waiver of patient consent for retrospective data collection was obtained from each participating institution. See below for the study investigators. The NASA and TRACK registries combined included 938 consecutive patients with AIS treated with the corresponding stent retriever (Solitaire in NASA and Trevo in TRACK) as the first approach to mechanical thrombectomy of ELVO. These registries were designed as independent investigator-initiated studies to represent real-world clinical experience of primary stent retriever mechanical thrombectomy in AIS and therefore did not specify a time-to-treatment window, clinical severity, imaging selection, or ELVO description criteria. Institutional review board approval was obtained at each participating site and clinical and radiographic data were sent to the coordinating center. Angiographic recanalization was defined using a modified Thrombolysis in Cerebral Infarction (mTICI) score.8Embolization into new territory was defined as treatment-related embolization into areas outside the target downstream territory.8Distal embolization was defined as any treatment-related embolization into the target downstream territory.8 Intracranial hemorrhage (ICH) was classified as symptomatic (sICH) if it was associated with worsening of National Institutes of Health Stroke Scale score by ≥4 points within 24 hours. Clinical outcomes were quantified using the modified Rankin Scale (mRS) score at 90 days, with good clinical outcome defined as mRS score 0–2.
For this study, patients who underwent anterior circulation intervention for AIS were selected. Patients with posterior circulation AIS were excluded because strokes such as these were not represented in the DAWN or DEFUSE 3 trials.
Statistical analysis
Statistical analyses were performed using JMP V.13 (SAS institute, Cary, North Carolina, USA). χ2 and Fisher exact or χ2 tests were used for categorical variables and the Student’s t-test/F-test for continuous variables. For all statistical analyses, p<0.05 was considered statistically significant.
Results
Of 830 patients with anterior circulation AIS in the combined NASA and TRACK registries, mechanical thrombectomy with the Solitaire and Trevo stent retrievers was performed in 32.7% (271) patients presenting with symptom onset beyond the first 6 hours. Demographic, clinical, and procedural characteristics of the entire combined NASA and TRACK cohorts were divided into the following categories based on the time of onset of stroke symptoms or time last known well in patients with unwitnessed/wake-up stroke: 0–6, 6–16, 16–24, and >24 hours (table 1). Most patients who were treated within the ‘late’ (beyond first 6 hours) time window presented within 6–16 hours of stroke onset (248/271 patient, 91.5%). There was a similar distribution of age and cerebrovascular risk factors in patients arriving within the first 6 hours and beyond 6 hours of stroke symptom onset (table 1). Both groups of patients had similar approaches to thrombectomy using the Solitaire and Trevo devices, including the use of a balloon-guide catheter, use of continuous aspiration, or general anesthesia (p=0.12, 0.15, and 0.52, respectively; table 2).
Demographics, clinical characteristics, and treatment details of the TRACK Registry
Treatment details, angiographic and clinical outcomes
Radiographic recanalization outcome data were available for all 830 patients (table 2). The rates of successful (TICI 2b/3) recanalization were different depending on time from symptom onset: 79.4% in the 0–6 hour group, 72.6% in the 6–16 hour group, 85% in the 16–24 hour group and 33.3% in patients with symptom onset >24 hours, p=0.04. The rates of distal embolization or embolization of new territories were similar among those groups (p=0.57 and 0.33, respectively). Clinical follow-up data at 90 days were available for 715/830 (86%) patients.
Good clinical outcome (mRS=0–2) was similar among the groups: 48.1% in the 0–6 hours group, 46.2% in the 6–16 group, 38.9% in the 16–24 group and 33.3% in the >24 hour group, p=0.8. There was also no difference in rates of sICH or mortality (p=0.5 and 0.6, respectively).
Discussion
The majority of patients with AIS present to the emergency department with time of symptom onset beyond the first 6 hours. Tong et al used the admission data of 413 147 patients between 2003 and 2009 from the Get With The Guidelines–Stroke (GWTG-Stroke) programme and found that only 36% of patients presented within the first 8 hours of symptom onset.9 This study, however, was not designed to specifically examine the arrival times of patients with AIS due to ELVO. In another study, Mokin et al, using single-center data of patients with AIS between 2014 and 2015 found that ELVO was present in 23% of such patients.10 Specifically, in patients with occlusion of the internal carotid artery or middle cerebral artery M1 segment, 34% arrived at the hospital beyond the first 6 hours from symptom onset, including wake-up strokes.
Recently, DAWN and DEFUSE 3 studies provided evidence in support of thrombectomy in patients with anterior circulation ELVO within 6–24 and 6–16 hours.1 2 Both trials relied on a very rigorous selection process. Case inclusion in DAWN encompassed age-stratified estimates of the volume of the ischemic core, and penumbral regions were used as part of the case selection process in DEFUSE 3. In contrast, other than documentation of ELVO, enrollment in TRACK and NASA registries did not mandate any single specific imaging modality. Therefore, TRACK and NASA are representative of real-world experience with thrombectomy in patients with AIS from ELVO and wake-up strokes at early (0–6 hours) and late (>6 hours) time windows. Our analysis suggests that even without the use of specific strict selection criteria, primary stent retriever thrombectomy with Solitaire or Trevo is equally effective in patients with anterior circulation AIS with symptom onset >6 hours. The goal of our analysis was not to identify the clinical or radiographic factors predictive of clinical outcomes in patients treated with thrombectomy at a late time window, but rather to interpret out findings as evidence in support of stent retriever thrombectomy in the presence of multiple variables and selection protocols rather than relying on the DAWN and DEFUSE 3 criteria alone.
We excluded patients with posterior circulation LVO from our analysis as both DAWN and DEFUSE 3 included only anterior circulation strokes. A randomized trial of endovascular therapy of basilar artery occlusion versus medical management alone within 0–6 hours, the Basilar Artery International Cooperation Study (BASICS), is approaching completion.11 It will be more appropriate to compare real-world data of posterior circulation ELVO thrombectomy from TRACK and NASA with the BASICS trial, once the results of that trial are available.
Our study has several limitations. Data in both NASA and TRACK included a mixed group of retrospectively and prospectively followed patients. Both registries included consecutive patients treated with stent retrievers as the first approach to thrombectomy. However, those patients in whom alternative treatment strategies, such as direct aspiration including the ADAPT technique, were used were excluded from our analysis, introducing selection bias. While TRACK relied on the use of a core imaging laboratory, the NASA registry did not have a core imaging laboratory to adjudicate radiographic outcomes of thrombectomy. Information on the severity of the Alberta Stroke Program Early CT Score (ASPECTS) or volumetric analysis of perfusion data on baseline imaging were not available to describe specific imaging criteria used for patient selection, which are critical components when determining eligibility for thrombectomy at a late time window. However, the use of physiological imaging was not mandatory and was not routine in clinical practice at the time of NASA and TRACK completion. Also, the perfusion software used in DAWN AND DEFUSE 3 had not been approved at the time of the registry completion. Only a small number of patients (n=20) were treated with thrombectomy within 16–24 hours, limiting our ability to perform rigorous statistical analysis. Surprisingly, this group showed the highest rate of successful recanalization with TICI 2b/3 in 85%. This may be explained by the smaller number of patients with internal carotid artery occlusion in this group of patients (5% vs 23% and 19% in patients treated with thrombectomy within the first 6 and 6–16 hours, respectively).
Conclusion
In real-life experience with patients who presented with anterior circulation AIS, using the Solitaire and Trevo thrombectomy devices beyond the first 6 hours of symptom onset proved to be equally safe and effective as compared with patients with symptom onset within the first 6 hours, despite an abundance of uncontrolled variables. Similar rates of functional independence at 90 days as in the randomized highly selective clinical trials were observed.
Footnotes
Contributors MM and OOZ: study concept and design; wrote the manuscript. OOZ: statistical analysis. All authors participated in data collection and analysis, edited the manuscript, and approved the final version.
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 JDE: honoraria from Medtronic, Stryker Neurovascular, and Penumbra. MM: consultant for Cerebrotech, speaker for Penumbra, Canon Medical. RGN, OOZ: consultant/advisory board member for Styker Neurovascular, Covidien.
Patient consent Not required.
Ethics approval Institutional review board at each participating site.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data are presented in this paper.
Collaborators The NASA investigators: Osama O. Zaidat, Alicia C. Castonguay, Italo Linfante; Rishi Gupta, Coleman O. Martin, William E. Holloway, Nils Mueller-Kronast, Joey D. English,; Guilherme Dabus, MD; Tim W. Malisch, Franklin A. Marden, Hormozd Bozorgchami, Andrew Xavier, Ansaar T. Rai, Michael T. Froehler, Aamir Badruddin, Thanh N. Nguyen, M. Asif Taqi, Michael G. Abraham, Albert J. Yoo, Vallabh Janardhan, Hashem Shaltoni, Roberta Novakovic, Alex Abou-Chebl, Peng R. Chen, Gavin W. Britz, Chung-Huan J. Sun, Vibhav Bansal, Ritesh Kaushal, Ashish Nanda, Raul G. Nogueira. The TRACK registry local investigators: Osama O Zaidat, Alicia C Castonguay, Raul G Nogueira, Diogo C Haussen, Joey D English, Sudhakar R Satti, Jennifer Chen, Hamed Farid, Candace Borders, Erol Veznedaroglu, Mandy J Binning, Ajit Puri, Nirav A Vora, Ron F Budzik, Guilherme Dabus, Italo Linfante, Vallabh Janardhan, Amer Alshekhlee, Michael G Abraham, Randall Edgell, Muhammad Asif Taqi, Ramy El Khoury, Maxim Mokin, Aniel Q Majjhoo, Mouhammed R Kabbani, Michael T Froehler, Ira Finch, Sameer A Ansari, Roberta Novakovic, Thanh N Nguyen.