key: cord-0718456-h7quhf21
authors: Kalousek, Vladimir; Yoo, Albert J.; Sheth, Sunil A.; Janardhan, Vikram; Mamic, Josip; Janardhan, Vallabh
title: Cyclical aspiration using a novel mechanical thrombectomy device is associated with a high TICI 3 first pass effect in large‐vessel strokes
date: 2021-06-08
journal: J Neuroimaging
DOI: 10.1111/jon.12889
sha: 2f74519a0d842a325a065316caafdfc7545db126
doc_id: 718456
cord_uid: h7quhf21

BACKGROUND AND PURPOSE: Complete reperfusion (TICI 3) after the first thrombectomy attempt or first pass effect (FPE) is associated with best clinical outcomes in large‐vessel occlusion (LVO) acute ischemic stroke. While endovascular therapy techniques have improved substantially, FPE remains low (24–30%), and new methods to improve reperfusion efficiency are needed. METHODS: In a prospective observational cohort study, 40 consecutive patients underwent cyclical aspiration thrombectomy using CLEAR(TM) Aspiration System (Insera Therapeutics Inc., Dallas, TX). Primary outcome included FPE with complete/near‐complete reperfusion (TICI 2c/3 FPE). Secondary outcomes included early neurological improvement measured by the National Institute of Health Stroke Scale (NIHSS), safety outcomes, and functional outcomes using modified Rankin Scale (mRS). Outcomes were compared against published historical controls. RESULTS: Among 38 patients who met criteria for LVO, median age was 75 (range 31–96). FPE was high (TICI 3: 26/38 [68%], TICI 2c/3: 29/38 [76%]). Among anterior circulation strokes, core lab‐adjudicated FPE remained high (TICI 3: 17/29 [59%], TICI 2c/3: 20/29 [69%]), with excellent final successful revascularization results (Final TICI 3: 24/29 [83%], Final TICI 2c/3: 27/29 [93%]). FPE in the CLEAR‐1 cohort was significantly higher compared to FPE using existing devices (meta‐analysis) from historical controls (TICI 2c/3: 76% vs. 28%, p = 0.0001). High rates of early neurological improvement were observed (delta NIHSS≥4: 35/38 [92.1%]; delta NIHSS≥10: 27/38 [71%]). Similarly, high rates of good functional outcomes (mRS 0–2: 32/38 [84%]) and low mortality (2/38 [5%]) were observed. CONCLUSION: Cyclical aspiration using the CLEAR(TM) Aspiration System is safe, effective, and achieved a high TICI 3 FPE for large‐vessel strokes.

Large-vessel strokes have a poor natural history with a high mortality (41.9%) and low rate of good functional outcomes defined by the modified Rankin Scale (mRS) of 0-2 (mRS 0-2 [20.7%] ). 1 Vessel reopening with complete distal territory reperfusion (TICI 3) in the first thrombectomy attempt, also known as the first pass effect (FPE), has become the top-line metric for a successful thrombectomy in patients with large-vessel strokes. 2 TICI 3 FPE is associated with the lowest mortality (mRS 6 [16.3%] ) and the highest rates of functional independence (mRS 0-2 [61.3%]). 2 9 ). More recently, it has been suggested that near-complete reperfusion (TICI 2c) is associated with comparable good outcomes as TICI 3 Stroke Thrombectomy and Aneurysm Registry (STAR) registry. 10 A recent meta-analysis has shown that FPE inclusive of near-complete reperfusion (TICI 2c/3) is also low at 28% with existing mechanical thrombectomy devices. 11 There is clearly an unmet need for a novel mechanical thrombectomy device to improve the relatively low rate of TICI 2c/3 FPE seen with current retrievable stents or continuous uniform aspiration systems, [4] [5] [6] [7] [8] [9] and thereby help achieve better outcomes in patients with large-vessel strokes.

Preclinical results with a novel mechanical thrombectomy device that can generate cyclical aspiration, the CLEAR TM Aspiration System (Insera Therapeutics Inc., Dallas, TX), have shown an improved safety profile, 12 and demonstrated that complete clot ingestion with cyclical aspiration also increases first pass recanalization and reduces distal embolization. 13 There is a need to understand how these preclinical results translate from the bench to the bedside. The authors aim to describe the clinical safety and efficacy profile for cyclical aspiration, using the CLEAR TM Aspiration System, and its impact on TICI 2c and 3 FPE.

A real-world observational study was performed with retrospective analysis of a prospectively maintained registry at the local institution, the Cyclical, Luminal, Evacuation, Aspiration and Retrieval (CLEAR) registry. The prospective cohort in the CLEAR registry includes a consecutive series of patients who met the broad principles of patient selection criteria in the local institution and underwent cyclical aspiration thrombectomy in the stroke interventional lab at the local institution (University Hospital Center 'Sestre Milosrdnice' , Zagreb, Croatia). Thrombectomy was performed using cyclical aspiration after Conformité Européenne (CE Mark) approval was obtained for the CLEAR TM Aspiration System (Insera Therapeutics Inc.) in the European Union (EU). Approval was also obtained from the local institutional leadership/institutional review board. Informed consent prior to each thrombectomy procedure was obtained as required by the local institutional guidelines.

In this analysis (CLEAR-1 cohort), a consecutive series of patients with large-vessel strokes who met the broad principles of patient selection criteria in the local institution and underwent thrombectomy using cyclical aspiration were included. There were no patient selection criteria imposed and thrombectomy was performed as per the local insti- The initial 20 patients (n = 20/40, 50.0%) in this cohort were treated in the pre-Corona Virus Disease 2019 (COVID-19) era wherein protocols similar to published consensus criteria for developing and maintaining a stroke interventional lab were followed. 14 The second half of this cohort (n = 20/40, 50.0%) in this cohort were treated during the COVID-19 era wherein additional preparedness similar to several multisociety consensus recommendations were implemented. [15] [16] [17] Demographics, initial stroke severity, and stroke systems of care Information on baseline demographics, NIHSS, IV r-tPA use prior to thrombectomy (which was permitted as per local institutional protocol), large-vessel stroke presentation direct to comprehensive stroke center (CSC) or via transfer to CSC, time from stroke onset (in witnessed strokes) or time from last seen well (in unwitnessed strokes) to skin puncture (groin or radial) in the early time window (defined as <6 h from TLSW, and/or endovascular treatment <8 h from stroke onset or TLSW) or extended time window (defined as outside the early time window and within 24 h from TLSW), and wake up stroke or not were obtained from the prospectively collected registry.

Cyclical aspiration was performed, using the CLEAR TM Aspiration System (Insera Therapeutics Inc.) after CE Mark approval in the EU, on a consecutive series of large-vessel stroke patients who met the patient selection criteria in the local institution during this CLEAR-1 cohort period (n = 38). Further enrollment in this cohort was limited due to the December 2020 earthquake that affected Zagreb, Croatia, as well as the COVID-related restrictions. CLEAR TM is a digital smart vacuum aspiration system that can generate continuous uniform aspiration as well as cyclical or pulsatile or intermittent suction pattern, with a Standard commercially available aspiration catheters, medium and large-bore aspiration catheters, balloon guide catheters, and guide catheters, with inner diameters (ID) ranging from 0.032" (0.81 mm) to 0.088" (2.24 mm), and outer diameters (OD) ranging from 3F to 9F (1.0-3.0 mm) that have CE Mark approval in the EU were used for access to the clot and were appropriately chosen by the treating physician based on each target vessel diameter.

In nearly half the patients (n = 17/38, 45%), there was good catheter access to the proximal face of the clot using standard techniques including direct "snaking" without microcatheter and microwire support, or catheterizing with a microwire and microcatheter and then tunneling the aspiration catheter over the microcatheter and microwire for support. Cyclical aspiration was directly performed. This is referred to as the PACE (Proximal Aspiration using Cyclical followed by Corking Embolectomy) technique. 12, 13 In the rest of the patients (n = 21/38, 55%), there was difficulty in advancing the large-bore aspiration catheter. This was related to excessive vessel tortuosity especially in the older population, for example, in several octogenarians and nonagenarians. This is not uncom-mon for current large-bore aspiration catheters, with reported rates of nearly 25-40% of patients, having difficult catheter access. 18 In these patients, to avoid catheter herniation and improve catheter delivery to the clot, the active portion of a stent retriever is anchored distal to the clot and the retriever wire is used as a support to track and advance the large-bore aspiration catheter to the proximal face of the clot ("grappling hook" technique). 18 Cyclical aspiration is then performed. This is also referred to as the ReWiSed (Retriever Wire Supported) PACE technique.

Procedural information regarding angiographic outcomes at the end of the procedure, the number of passes required, complete clot ingestion (wherein the clot is completely inside the catheter, tubing, or canister) or partial clot ingestion (wherein the clot is corked, partially inside the catheter and partially exposed outside the catheter), emboli to distal territory or emboli to new territory, any device-related adverse events or intraprocedural complications, and whether clots were aspirated in a single piece or multiple pieces were obtained.

For early ischemic changes, the ASPECTS was measured on noncontrast-enhanced CT head scans. (eTICI) 20 scores were measured on DSA. The mTICI score is essentially similar to the eTICI score except that mTICI 2b (50-89% partial reperfusion) is further classified as eTICI 2b-50 (50-66% partial reperfusion) and eTICI 2b-67 (67-89% partial reperfusion). 19, 20 The CT and angiographic images were adjudicated locally at treating facility. Baseline and procedural characteristics among the large-vessel stroke patients with FPE having complete reperfusion (TICI 3) or near-complete reperfusion (TICI 2c) compared to the non-FPE cohort are shown in Table 1 .

Baseline and procedural characteristics of the CLEAR-1 first pass effect cohort

Characteristic

Age ( Note: SD indicates standard deviation; IQR indicates interquartile range; n indicates sample size; CI indicates confidence interval; PACE technique indicates proximal aspiration using cyclical followed by corking embolectomy when there is good catheter access to the clot; ReWiSed PACE indicates retriever wire supported PACE when there is difficult catheter access to the proximal face of clot. A stent retriever is anchored distal to the clot and the retriever wire is used to track the aspiration catheter to the proximal face of the clot, cyclical aspiration is then performed; FPE indicates first pass effect; TICI indicates Thrombolysis in Cerebral Ischemia Score. 19, 20 *Statistically significant (p-value ≤0.05) using the Fisher Exact P test.

For recanalization, the Arterial Occlusive Lesion (AOL) scale was used to measure the degree of recanalization at the target arterial lesion. 19 Baseline and final angiographic images were core-lab adjudicated based on the degree of luminal opening (none, partial, or complete) with further qualification based on the presence (grades 2 or 3)

or absence (grades 0 or 1) of any downstream flow. 19 To compare angiographic outcomes of the CLEAR-1 cohort with those of recent registries or trials of current retrievable stents or continuous uniform aspiration systems in anterior circulation strokes, 3, 21, 22 an angiographic analysis of all the anterior circulation strokes (n = 29/38, 76.3%) in the CLEAR-1 cohort was performed by an independent core lab. Blinded core lab-adjudication was done using the mTICI, 19 and the eTICI scores in patients with anterior circulation occlusions, consistent with prior studies. 20

In this analysis, the primary outcome is the "first pass effect"

(FPE) which includes angiographic outcomes of complete (TICI 3), near-complete (TICI 2c), or partial vessel reopening (TICI 2b, also called modified FPE) in the first operative thrombectomy attempt. 2 The secondary outcomes include (1) and were not included in this analysis.

Full demographics of the CLEAR-1 cohort are provided in 

The rate of core lab-adjudicated FPE remained high for anterior cir- Figure 1B . A coded system can help graphically better visualize mTICI or eTICI outcome distributions. 28 Figure 2A shows a similar coded system or tool to better visualize revascularization rates. 28 Figure 2B shows the reperfusion rates in this CLEAR-1 cohort relative to the ease or difficulty in accessing the proximal face of the clot compared to the recent meta-analysis of existing devices. In nearly half the patients (n = 21/38, 55%), the stent part of a stent retriever is anchored distal to the clot and the retriever wire is used as a support to track and advance the large-bore aspiration catheter to the proximal face of the clot, like a "grappling hook." 18 

Early neurological improvement was mild (NIHSS ≥4 improvement or an improvement to a score of 0 or 1) in 92.1% (35/ (Figures 4D and 5 ).

There were no symptomatic intracerebral hemorrhages observed.

There were also no device-related serious adverse events in the More recently, it has been suggested that near-complete reperfusion (TICI 2c) is associated with comparable good outcomes as TICI 3 (STAR registry 10 ). A recent meta-analysis has shown that FPE inclusive of near-complete reperfusion (TICI 2c/3) is also low at 28% with existing mechanical thrombectomy devices. 11 The present CLEAR-1 findings suggest that TICI 3 FPE and TICI 2c/3 FPE can be dramatically improved using cyclical aspiration. 

Comparing revascularization rates relative to location and catheter access to clot. A novel coded system or tool to help better visualize reperfusion rates with respect to one or multiple operative attempts or passes is shown, wherein broadly green signifies complete (TICI 3, 100%) or near-complete (TICI 2c, 90-99%) reperfusion, yellow (TICI 2b-50 and 2b-67, 50-89%) and orange (TICI 2a, 1-49%) signify partial reperfusion, and red signifies trickle of flow (TICI 1, <1%) or no (TICI 0, 0%) reperfusion. n indicates sample size. CLEAR indicates this Cyclical, Luminal, Evacuation, Aspiration, and Retrieval cohort. The complete (dark green) or near complete (parrot green) first pass effect (TICI 2c/3 FPE) is high in the CLEAR-1 cohort and its subgroups based on location and catheter access to clot. HERMES indicates a pooled analysis of seven (7) endovascular stroke trials, Highly Effective Reperfusion Evaluation in Multiple Endovascular Stroke trials; 20 NASA indicates North American Solitaire Stent retriever Acute stroke registry; 2 ARISE II indicates Analysis of Revascularization in Ischemic Stroke with EmboTrap study. 6 (B) Comparing first pass effect with cyclical aspiration relative to the ease or difficulty in catheter access to the proximal face of the clot. A recent meta-analysis comprising 16,870 patients has shown that with existing thrombectomy devices, the complete or near-complete first pass effect is low (TICI 2c/3 FPE: 28%). 11 19, 20 In the CLEAR-1 cohort, among patients with difficult catheter access to the clot, the active component of a stent retriever is anchored distal to the clot and the retriever wire is used to track the large-bore aspiration catheter to the proximal face of the clot, like a "grappling hook." 18 Cyclical aspiration is then performed, also known as ReWiSed PACE technique, 29 with a high first pass effect (approximately two-fold higher). 11 Among patients with ease of catheter access to the clot, cyclical aspiration is directly performed, also known as PACE technique, 12,13 with a much higher first pass effect (3.4-fold higher than the recent meta-analysis) 11 The reduced rate of first pass success in patients with difficult catheter access to the clot may be related to the retriever wire and/or the microcatheter, which remain in place during cyclical aspiration. This wire and/or the microcatheter can decrease the luminal inner diameter of the large-bore aspiration catheter and limit the aspiration force.

In addition, the active component of the stent retriever might cause vessel wall injury 12, 30, 31 or clot fragmentation, 13 The results in the anterior circulation subgroup were confirmed by core lab-adjudication. Importantly, cyclical aspiration was performed using standard commercially available aspiration catheters that have CE mark approval in the EU, allowing for direct comparison with using propensity score matching with an LVO cohort of best medical therapy (control group) will be invaluable in the future.

The clinical implications of the findings in the CLEAR-1 cohort are highly relevant to the unmet need in improving access to stroke thrombectomy worldwide. The ability to activate and have direct control of cyclical vacuum aspiration remotely via an iPad app during stroke thrombectomy 37 could pave the way for robotic or remote stroke thrombectomy in the future.

Cyclical aspiration using the CLEAR TM Aspiration System is safe and effective, and achieves an exceedingly high rate of TICI 3 FPE for largevessel strokes compared to stent retrievers and aspiration using continuous uniform aspiration.

Dr. Vallabh Janardhan reports grants from National Science Foun- 

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First pass effect: a new measure for stroke thrombectomy devices

Endovascular mechanical thrombectomy for acute ischemic stroke: a new standard of care

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Cyclical aspiration using a novel mechanical thrombectomy device is associated with a high TICI 3 first pass effect in large-vessel strokes