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Abstract
Background Mechanical thrombectomy is the standard treatment for acute ischemic stroke (AIS) with large vessel occlusion (LVO) in the anterior circulation. This trial aimed to indicate whether Skyflow, a new thrombectomy device, could achieve the same safety and efficacy as Solitaire FR in the treatment of AIS.
Methods This study was a prospective, multicenter, randomized, single blind, parallel, positive controlled, non-inferiority clinical trial. Patients with intracranial anterior circulation LVO within 8 hours from onset were included to receive thrombectomy treatment with either the Skyflow or Solitaire FR stent retriever. The primary endpoint was the rate of successful reperfusion (modified Treatment In Cerebral Infarction (mTICI) ≥2b) after the operation. The safety endpoints were the rate of symptomatic intracranial hemorrhage (sICH) and subarachnoid hemorrhage (SAH) at 24 hours after operation.
Results A total of 95 and 97 patients were involved in the Skyflow group and Solitaire FR group, respectively. A successful reperfusion (mTICI ≥2b) was finally achieved in 84 (88.4%) patients in the Skyflow group and 80 (82.5%) patients in the Solitaire FR group. Skyflow was non-inferior to Solitaire FR in regard to the primary outcome, with the criterion of a non-inferiority margin of 12.5% (p=0.0002) after being adjusted for the combined center effect and the National Institutes of Health Stroke Scale (NIHSS) score. The rate of periprocedural sICH and SAH did not differ significantly between the two groups.
Conclusion Endovascular thrombectomy with the Skyflow stent retriever was non-inferior to Solitaire FR with regard to successful reperfusion in AIS due to LVO (with a pre-specified non-inferiority margin of 12.5%).
- stroke
- thrombectomy
- stent
Data availability statement
Data are available upon reasonable request. Not applicable.
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Introduction
Stroke is one of the leading causes of human disability and death worldwide, of which acute ischemic stroke (AIS) accounts for approximately 80%.1 The key for the treatment of AIS is to recanalize occluded vessels as early as possible and save the ischemic penumbra. Owing to the development of endovascular devices, endovascular thrombectomy with or without intravenous thrombolysis has been proven effective for the treatment of AIS due to large artery occlusion (LAO), and mechanical thrombectomy using stent retriever or aspiration thrombectomy was recommended as first line treatment.2–8 To date, several stent retrievers have been approved by the China Food and Drug Administration (CFDA), while a limited number of them have been industrially manufactured in China.
Thus, to better meet people’s rapidly growing demand for thrombectomy devices in China, Skynor Corp Medical (Shanghai) developed a new endovascular thrombectomy device, namely Skyflow (figure 1). The present study aimed to assess the efficacy and safety of the device, providing the basis for product registration, listing, and application.
Description of stent composition. There are different sizes of stent retriever, including TD 320, TD420, TD430, and TD440 requiring a compatible microcatheter of 0.021 inch and TD620 and TD630 requiring a compatible microcatheter of 0.027 inch. Stent retriever with double helix structure, partial large mesh and full development design (1), pushing wire 185 cm with a variable-diameter structure coiled with platinum alloy coil in the distal part (2), introducer sheath (3), diameter of stent, 3 mm for TD 320, 4 mm for TD420, TD430, and TD440, 6 mm for TD620 and TD630 (D), and stent retriever effective length, 20 mm for TD 320, TD420, and TD620, 30 mm for TD430 and TD630, and 40 mm for TD440 (L).
Methods
Study design
This study was a prospective, multicenter, stratified randomized, single blind, parallel, positive controlled, non-inferiority clinical trial conducted in 14 stroke centers in China to compare the efficacy and safety of the Skyflow device with Solitaire FR stent retriever in the endovascular treatment of AIS patients due to LAO; the ethics committees of all those centers approved this trial. Solitaire FR or Skyflow thrombectomy stent was used for patients with intracranial anterior circulation large vessel occlusion within 8 hours from onset to compare the efficacy and safety of Skyflow over Solitaire FR. The protocol of the trial has been published previously.9
Inclusion criteria
Subjects were eligible if they met all of the following criteria: age 18–80 years; within 8 hours from stroke onset; the baseline National Institutes of Health Stroke Scale (NIHSS) score ranged from 6–30; digital subtraction angiography (DSA) suggesting internal carotid artery or middle cerebral artery segment main stem occlusion; prestroke modified Rankin Scale (mRS) ≤2; subjects or their legal guardians agreed to participate in the trial and signed the written informed consent form. Exclusion criteria were determined according to exclusion criteria of the clinical guideline which has been published previously.
Random grouping
The enrolled subjects were randomly assigned into the experimental group or control group (1:1) using an interactive web-based response system. When grouping the patients, stratification was performed to control key indicators by the clinical trial center and the baseline NIHSS score (divided by NIHSS score ≤17 points or >17 points). The time points of randomization were the end of cerebrovascular DSA and before thrombectomy.
Treatment
Intravenous thrombolysis was conducted according to the guideline for patients meeting the indications for intravenous thrombolysis. For all the enrolled patients, stent retriever thrombectomy was the first-line approach. In the present trial, the Skyflow device was used in the experimental group and Solitaire FR in the control group. General or local anesthesia could be undertaken based on the patient’s clinical condition and heparin was administered selectively. Stent retriever thrombectomy could be performed repeatedly and generally no less than three times before rescue therapy. The researcher evaluated whether to perform the aspiration thrombectomy, balloon dilatation, stent implantation or other rescue treatment based on the subject’s clinical condition. In case of performing rescue treatment, it was essential to carry out DSA and to re-evaluate modified Treatment In Cerebral Infarction (mTICI) scores.
Trial outcomes
The primary endpoint was the rate of successful reperfusion (mTICI ≥2b) of target vessels, and mTICI ≥2b was defined as a successful reperfusion. If other rescue treatments were performed after thrombectomy, the classification of mTICI was based on DSA images after adjuvant therapy. The modified first pass effect (FPE) was defined as achieving a successful reperfusion (mTICI ≥2b) with a single thrombectomy device pass. Two experienced neurointerventional reviewers from the independent core laboratory adjudicated the angiograms and assessed the mTICI scores. Any discrepancies were resolved through a consensus discussion with a third reviewer.
The secondary efficacy endpoints were the time from artery puncture to successful reperfusion (mTICI ≥2b), NIHSS scores at 24 hours (18–36 hours) and at 7±2 days after the operation, mRS scores and the rate of patients with 0–2 scores 90±14 days after the operation, and the success rate of instrument operation.
The safety endpoints were the rates of symptomatic intracranial hemorrhage (sICH) and subarachnoid hemorrhage (SAH) at 24 hours post-operation, 90-day all-cause mortality, incidence of adverse events (AEs), serious adverse events (SAEs), and device defects.
Statistical analysis
The statistical analysis was performed based on full analysis set. Continuous variables was presented as mean±SD, and categorical variables were expressed as either counts or percentages. Continuous calibration χ2 tests or Fisher’s exact tests were used for comparison of enumeration data between groups. Group t-test was used for comparison of normally distributed measurement data between groups, and Wilcoxon rank sum test for non-normally distributed measurement data. For the primary outcome—the successful reperfusion (mTICI ≥2b) rate of blood vessels—the Cochran-Mantel-Haenszel (CMH) χ2 analysis with adjusted center effect will be used for comparison between groups. In addition to the successful reperfusion rate, the difference of the success rate between the experimental group and the control group and the 95% confidence interval with the lower boundary greater than −12.5% was also estimated. According to results previously reported in the literature, a clinically relevant non-inferiority margin of 12.5% was chosen as the acceptable difference between groups simultaneously. All data were statistically analyzed using the SAS 9.4 software, and a two-sided p<0.05 was considered statistically significant.
Results
From May 2018 to September 2019, a total of 201 patients from 14 Chinese medical centers were included in the randomization; nine patients who did not receive Skyflow or Solitaire FR treatment after randomization were excluded from the analysis. Finally, 95 patients in the Skyflow group and 97 patients in the Solitaire FR group were involved. The patients’ median age was 65 years (IQR 24–87), and the median NIHSS score was 16 (IQR 6–30). There were 110 males patients (57.29%). A significantly higher proportion of men was found in the Skyflow group compared with the Solitaire FR group (65.3% vs 49.5%, p=0.0267). Other baseline characteristics such as age, history of hypertension, history of diabetes mellitus, hyperlipidemia, atrial fibrillation, history of coronary heart disease, history of smoking, history of stroke, baseline NIHSS score at baseline, the Alberta Stroke Program Early CT Score (ASPECTS), the site of occlusion, and the collateral circulation score were not significantly different between the two groups (table 1).
Baseline characteristics
There were 23 patients in the Skyflow group and 22 patients in the Solitaire FR group who received intravenous thrombolysis before thrombus thrombectomy; there were 38 (40.0%) in the Skyflow group and 44 (45.4%) patients in the Solitaire FR group who underwent local anesthesia, and other patients underwent general anesthesia. A total of 106 stents in the Skyflow group and 102 stents in the Solitaire FR group were used, in which 11 patients in the Skyflow group and five patients in the Solitaire FR group used two stent retrievers. The median number of passes was 2 (IQR 1–3) in the two groups, and 32 patients received more than three passes in both groups. The success rate of instrument operation was 100% in the Skyflow group and 99% in the Solitaire FR group. An intermediate catheter was used in 77 (77.0%) and 80 (80.0%) patients in the two groups, respectively. The rate of modified FPE was 32.32% in the Skyflow group and 30.92% in the Solitaire FR group (p=0.877). In addition, 15 and 16 patients received adjuvant therapy after stent retrieval in the Skyflow and Solitaire FR groups, respectively, in which balloon dilatation was used in 13 and 12, and seven and 14 patients received stent implantation in the Skyflow and Solitaire FR groups, respectively. Successful reperfusion (mTICI >2b) was finally achieved in 84 (88.4%) patients in the Skyflow group and 80 (82.5%) patients in the Solitaire FR group, without significant difference (p=0.634). With the criterion of a non-inferiority margin of 12.5%, CMH χ2 test adjusted for combined center effect and NIHSS score (≤17 points, >17 points) was used based on full analysis set to analyze the p value that was 0.0002. The mean time from successful puncture to reperfusion (77.15 min vs 72.44 min) was much the same in both groups (table 2). The median NIHSS score at 24 hours after surgery was 14 in the Skyflow group and 14.5 in the Solitaire FR group (p=0.790). After 7 days of follow-up, the median NIHSS scores were 10.00 and 10.00 in the two groups (p=0.922). After 90 days of follow-up, the proportions of mRS ≤2 in the two groups were 46 (48.4%) and 40 (41.2%) in the Skyflow and Solitaire FR groups, respectively (p=0.711), without difference (table 3).
Procedural details
Clinical efficacy and safety endpoints
Primary safety endpoint
The incidence rates of sICH were 7.4% (n=7) and 6.2% (n=6) in the Skyflow and Solitaire FR groups (p=0.744), respectively; the incidence rates of SAH were 7.4% (n=7) and 8.2% (n=8) in the Skyflow and Solitaire FR groups (p=0.820), respectively; and 90-day all-cause mortality rates at 90-day follow-up were 17.9% (n=17) and 24.7% (n=24) in the Skyflow and Solitaire FR groups (p=0.246), respectively. The incidence rates of AEs and SAEs were 98.9% and 36.8% in the Skyflow group, and 95.9% and 37.1% in the Solitaire FR group, respectively. The incidence deficiencies of device was 0.0% (n=0) and 1.0% (n=1) in the Skyflow and Solitaire FR groups (p=0.490), respectively. One stent in the Solitaire FR group was not successfully placed due to obstacles in delivery.
Discussion
The results of the present trial showed that a high final recanalization rate (mTICI ≥2b) of 88% could be achieved using the Skyflow device that was non-inferior to the US FDA approved Solitaire FR device in the mechanical recanalization of LVO. The results of follow-up revealed that the clinical prognosis was comparable between the two groups. Safety indicators, such as sICH and 90-day all-cause mortality, were not significantly different between the two groups, indicating that the Skyflow device has a comparable surgical safety with the Solitaire FR stent. Several studies have concentrated on the clinical application of the Solitaire FR stent. A successful recanalization rate of 90% was achieved in a previous study on mechanical thrombectomy,3 which was close to the rate achieved in the current study. In a previous meta-analysis on the clinical application of the Solitaire FR stent as the main device, the overall success reperfusion rate in the HERMES study was 86%.10 An outstanding recanalization rate was attained in the experimental group in the present trial, and there was a consistency between the clinical outcomes of this trial and those reported previously.
The mechanical design of the Skyflow and Solitaire FR devices is similar to a certain extent. Compared with the other stent retrievers,11–13 the Skyflow has exhibited the following advantages. (1) The device was designed with a dual helical structure, excellent flexibility and adhesiveness, and a high rate of thrombus removal, avoiding excessive stimulation of the intracranial vessels. (2) The stent was designed with large mesh, and the wall thickness was greater than the width of the rod, thus, the thrombus could be embedded and removed effectively. (3) Multiple radiopaque markers design assists clinicians to determine the position and length of the stent and its unfolding shape, improving the success rate of the surgery. (4) The pushing wire of the thrombectomy device was made of nickel-titanium material, and the distal end was designed as a variable-diameter structure with a platinum alloy coil, improving the pushability and visualization of the product. (5) The device has different models and specifications, which can meet the requirements of occluded vessels with different diameters. Before clinical studies, the stents had been validated in animal experiments for highly effective recanalization effects in animal occlusion models. All these features provide the theoretical basis for the safety and efficacy of the test product.
The FPE is an important index to evaluate the effects of thrombectomy equipment, indicating immediate achievement of reperfusion on a single device pass, which could improve patients’ clinical outcomes. In our study, the modified FPE in the present study was 32.32% in the Skyflow group and 30.92% in the Solitaire FR group, and there is no difference between the two devices. For patients who failed with stent retrieval, angioplasty with or without stent placement is an effective rescue treatment. In our study, of the patients who received balloon dilatation and/or stent placement, the proportion of the treatment that was succesful was comparable to a previous study using the Trevo retriever,14 while it was lower than that reported previously by Chinese scholars.15 This may be related to the fact that the possibility of extracranial arterial occlusion was not considered in the current trial.
Perioperative SAH was reported as an important index of safety, which may caused by vessel perforation or endothelial damage of arterioles. Theoretically, a smaller stent may reduce the incidence of SAH-associated complications, while in our study, in the Skyflow group, although 13 patients received a smaller size stent for thrombectomy, the incidence of SAH was approximately the same as that recorded in the Solitaire FR group; it was also comparable to that of the Trevo stent retriever in a previous study, although the rate of SAH was more common with the first generation thrombectomy device, Merci retriever.14
The present trial contains a number of limitations. First, this was a multicenter study; however, there was a large variation in the number of enrolled cases among the different centers, in which seven centers only recruited fewer than 10 patients. Second, although we followed a 1:1 randomization for enrollment, some of the baseline data were biased, such as gender. Finally, the use of stent models was not uniform between the two groups, with more use of stent model types in the Skyflow group, particularly the 4–30 stent type, which was not used in the Solitaire FR group.
Conclusions
The present trial showed that endovascular thrombectomy with the Skyflow device was non-inferior with regard to successful reperfusion to the Solitaire FR stent for AIS patients (with a pre-specified non-inferiority margin of 12.5%).
Supplemental material
Data availability statement
Data are available upon reasonable request. Not applicable.
Ethics statements
Patient consent for publication
Ethics approval
The study was approved by the Ethics Committee of Henan Province (2017-034-01) and all the participants gave informed consent before taking part.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors TFZ, TXL, LFZ, ZSL, QL, XL, ZXZ and YKH designed the study. HTG, YML, JZL, LPW, GXN, HZL, CMW, YDZ, HYQ, JFH, SCW, JPG, XLC and TFZ conducted the trial and collected information. WXB and SL participated in the imaging evaluation. TFZ drafted the manuscript. All authors critically reviewed the manuscript and approved the final version. TXL acted as guarantor responsible for the overall content.
Funding Supported by grant of Technological Research Project of Henan Province (182102310162).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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