Abstract
The combined technique (simultaneous use of a stent retriever and contact aspiration) is widely used for mechanical thrombectomy to treat acute large-vessel occlusions, but its clinical benefits remain unclear. We compared the efficacy and safety of different vessel-recanalization strategies on clinical outcomes across age groups. We analyzed 301 consecutive patients with internal carotid or middle cerebral artery occlusions. Between January 2017 and March 2021, 145 patients underwent single-device mechanical thrombectomy (stent retriever or contact aspiration) as the first-line strategy. Between April 2021 and December 2023, the combined technique was used as the first-line strategy in 96 patients. The modified first-pass effect (Thrombolysis in Cerebral Infarction grade ≥2b), final reperfusion outcomes, and functional outcomes were compared between strategy groups in patients <75 years and ≥75 years. In patients aged <75 years, the modified first-pass effect rate was significantly higher in the first-line combined-technique group than in the first-line single-device group (68.1% vs. 38.1%, p = 0.033), but favorable functional outcomes were similar. In patients ≥75 years, the first-line combined-technique group showed higher modified first-pass effect rates (61.3% vs. 42.7%, p = 0.03) and more frequent favorable functional outcomes than the first-line single-device group (31.3% vs. 13.4%, p = 0.0079). Thus, when performing mechanical thrombectomy for acute large-vessel occlusions, the combined technique should be used as a first-line strategy in older patients, as it is associated with more favorable functional outcomes than a first-line single-device strategy. In contrast, the favorable outcome rate in younger patients does not appear to differ by strategy.
Keywords: acute ischemic stroke, combined technique, contact aspiration, mechanical thrombectomy, stent retriever
Introduction
With the advent of endovascular techniques and devices, mechanical thrombectomy (MT) has become the standard of care for acute large-vessel occlusion (LVO) in the anterior circulation. Several devices and procedures have been used, including stent retriever (SR) thrombectomy, contact aspiration (CA) thrombectomy, and combined techniques (concomitant use of an SR and an aspiration catheter).1-4) Successful reperfusion (Thrombolysis in Cerebral Infarction [TICI] grade ≥2b) and onset-to-reperfusion time are associated with good functional outcomes.5) Zaidat et al.6) proposed the first-pass effect (defined as complete reperfusion after a single pass of the MT device without rescue treatment) as the optimal MT goal in reperfusion therapy. Additional passes may be associated with higher risks of disseminating emboli to a new territory and increasing infarct size.7) More MT attempts may also result in vascular endothelial injury and arterial stretching, leading to subarachnoid hemorrhage.8) Although the use of combined techniques (SR plus aspiration catheter) is expected to enhance the first-pass recanalization rate because of the potential synergistic effect of the techniques used―and thus improve clinical outcomes9,10)―the efficacy of the combined technique remains unclear. Recently, 2 randomized trials comparing single-device and combined-technique strategies for acute LVOs were reported. The ASTER 2 trial revealed that the combined technique provided a better recanalization rate than SR alone (TICI ≥2b, 86.2% vs. 72.3%, p < 0.01), but clinical outcomes were not better (functional independence, 38.0% vs. 41.9%, p = 0.50).11) The VECTOR trial did not show superiority of the combined SR plus CA technique over CA alone in patients with a positive susceptibility vessel sign and acute ischemic stroke with respect to achieving expanded TICI 2c-3 within 3 passes.12) Age is an important factor when assessing the effectiveness of recanalization therapy, and clinical outcomes have been reported to be poorer in older patients even with recanalization.13,14) However, MT still proves effective compared with control groups.15) Thus, we compared the safety and clinical efficacy of the combined technique with those of a single device as a first-line strategy for MT in acute ischemic stroke, with a focus on age differences.
Materials and Methods
Study population
We analyzed consecutive adult patients with acute ischemic stroke caused by anterior circulation LVO who were treated with MT at our stroke center between January 2017 and December 2023. The indications for MT were in accordance with the Japanese Guidelines for the Management of Stroke 2015, 2019, and 2021.16) Briefly, MT was indicated if patients (1) had an occlusion of a major cerebral artery of the anterior circulation―internal carotid artery (ICA) or middle cerebral artery: horizontal portion (M1) and insular portion (M2)―within 6 hrs of onset; (2) had a premorbid modified Rankin Scale (mRS) score of 0 or 1; (3) had an Alberta Stroke Program Early computed tomography (CT) Score (ASPECTS) of ≥6 on head CT or magnetic resonance imaging (MRI) diffusion-weighted imaging; (4) had a National Institute of Health Stroke Scale (NIHSS) score of ≥6; and (5) were at least 18 years of age. Additionally, MT was performed for patients admitted within 24 hrs of the last known well time if they had a mismatch between the ischemic core volume on diffusion-weighted imaging and neurological deficits or a hypoperfusion lesion on perfusion imaging. The following cases were excluded: spontaneous recanalization of occluded vessels confirmed on angiography at the initiation of the procedure, extracranial carotid artery occlusion, vessel access failure, and cases lost to follow-up within 3 months. Overall, 301 patients with acute ischemic stroke due to anterior circulation LVO (ICA, M1, and M2) were treated at our stroke center. The basic technical strategies for MT at our center depended on the study period. Between January 2017 and March 2021, a single device (SR or CA) was used as the first-line strategy (first-line single-device group). Between April 2021 and December 2023, the combined technique (concomitant use of an SR and aspiration catheter) was used as the first-line strategy (first-line combined-technique group). We included 176 patients in the first-line single-device group and 125 patients in the first-line combined-technique group. Of the 176 patients in the first-line single-device group, 10 with spontaneous clot lysis, 10 with extracranial ICA occlusion, 3 with vessel access failure, 4 lost to follow-up within 3 months, and 4 patients in whom the combined technique was first attempted based on the physician's judgment were excluded. Thus, 145 patients were subjected to angiographic evaluation and clinical follow-up. These patients were subdivided into ≥75 years old (82 cases) and <75 years old (63 cases) and included in the statistical analyses. Similarly, in the first-line combined-technique group, 7 patients with spontaneous clot lysis, 6 with extracranial ICA occlusion, and 4 lost to follow-up within 3 months were excluded. In 12 cases, an SR or CA technique was used as the first-line technique depending on the situation (such as staff constraints at night or on holidays) or based on the physician's judgment; these patients were also excluded. Finally, 96 patients were subjected to angiographic evaluation and clinical follow-up. These patients were subdivided into ≥75 years old (62 cases) and <75 years old (34 cases) and included in the statistical analyses. A flowchart of the study population is shown in Figure 1.
Fig. 1.
Flow chart of the study population.
ICA: internal carotid artery; MCA: middle cerebral artery; M1: the horizontal portion of the middle cerebral artery; M2: the insular portion of the middle cerebral artery
Data collection
The baseline characteristics included sex, age, hypertension, diabetes mellitus, hyperlipidemia, congestive heart failure, chronic renal failure, atrial fibrillation, coronary heart disease, current smoking, history of stroke, antiplatelet medication use, anticoagulant use, occluded vessels, and stroke etiology. The T2*-Clot Burden Score is a semiquantitative grading system used to evaluate the extent of intravascular thrombus on T2*-weighted or susceptibility-weighted MRI.17) In this study, the clot burden score was assessed by 2 independent senior endovascular specialists (TY and MS) in cases for which T2*-weighted or susceptibility-weighted imaging was available. For images that were difficult to interpret, the final score was determined by consensus between the 2 readers. The MRI diffusion aspect score was used to evaluate the extent of the ischemic core at presentation.18) Stroke severity was evaluated upon admission by experienced nursing staff in the emergency room, who were not involved in this study, using the NIHSS.19) Symptom onset was estimated using the last known well time. The use of tissue plasminogen activator (tPA), onset-to-door time, onset-to-tPA time, puncture-to-recanalization time, and onset-to-recanalization time were recorded. To assess MT performance, reperfusion was evaluated using the TICI grade. The modified first-pass effect (mFPE; defined as TICI ≥2b at the first pass) and the final reperfusion outcomes (defined as TICI ≥2b at the end of the procedure) were recorded.11) For functional outcomes, the mRS score at 90 days after stroke onset was evaluated, and an mRS score of 0-2 (on a scale of 0-6, with higher scores indicating greater disability) was defined as a favorable outcome and was assessed by a physician who was not involved in this study.20) For safety outcomes, serious procedure-related adverse events―including intraoperative arterial perforation due to a microcatheter, wire, or SR; embolization in a new territory (ENT) during MT; and hemorrhagic complications after the procedure―were recorded. Hemorrhagic complications included parenchymal hematoma type 2 (hematoma occupying ≥30% of the infarcted tissue, with obvious mass effect) and 3 (intracerebral hemorrhage outside the infarcted brain tissue or intracranial-extracerebral hemorrhage) of the Heidelberg classification on brain imaging (MRI or non-contrast CT) on the day following the procedure.21) Death within 90 days after stroke onset was also recorded.
Thrombectomy procedures
According to the Japanese Stroke Guidelines, patients within 4.5 hrs after stroke onset were administered intravenous recombinant tPA if eligible.22) The endovascular procedure was performed under local anesthesia and sedation. The use of a balloon-guide catheter was mandatory, and standard endovascular procedures were performed using digital subtraction angiography at our institution.
Single-device technique (SR or CA)
The balloon-guide catheter was advanced into the occluded ICA. When using an SR, a microcatheter with an inner lumen of 0.021-0.027 inches was navigated through the thrombus to the distal end of the target artery using a 0.014-inch microwire. The SR was advanced through the microcatheter and deployed across the thrombus. After 3 mins, the guide balloon was inflated, and blood was aspirated. The SR was then withdrawn. When performing CA, a 3-5 French aspiration catheter was advanced to the thrombus, coaxially over a microwire, after which manual aspiration was performed with a 30-ml syringe. When the absence of flow within the aspiration system was noted, the catheter was slowly advanced to ensure solid engagement with the thrombus. If no flow was observed through the system, the catheter was withdrawn.
Combined technique of simultaneous SR and aspiration catheter use3)
The balloon-guide catheter was advanced into the occluded ICA. A microcatheter with an inner lumen of 0.021-0.027 inches, coupled with an aspiration catheter with an outer diameter of 6-7 French was used. The microcatheter was advanced through the thrombus to the distal end of the target artery using a 0.014-inch microwire. The aspiration catheter was advanced to the proximal end of the thrombus. The SR was advanced through the microcatheter and deployed across the thrombus. The aspiration catheter was then advanced to the thrombus with suction applied until blood flow stopped. After 3 mins, the guide balloon was inflated, and blood was aspirated. Subsequently, the SR was withdrawn along with the aspiration catheter, as a single unit.
Outcome measures
To compare the efficacy outcomes in patients aged ≥75 years and those <75 years, we compared the NIHSS, ASPECTS, the percentage receiving tPA, onset-to-door time, onset-to-tPA time, puncture-to-recanalization time, onset-to-recanalization time, the percentage of mFPE, and functional outcomes (mRS 0-2 at 90 days) between the first-line single-device and the first-line combined-technique groups. For safety outcomes in patients aged ≥75 years and those <75 years, the percentage of ENT, arterial perforation, Heidelberg Classification (2+3), and all-cause mortality at 90 days were compared between the first-line single-device and the first-line combined-technique groups.
Statistical analysis
Continuous variables (age, onset-to-door time, onset-to-tPA administration time, puncture-to-recanalization time, and onset-to-recanalization time) were compared between the first-line single-device and the first-line combined-technique groups using Student's t-test. Ordinal scales (NIHSS, clot burden score, and ASPECTS) were compared using the Mann-Whiteney U test with normal approximation. Categorical variables (administration of tPA, mFPE, final reperfusion outcomes [TICI ≥2b], and favorable functional outcomes [mRS 0-2]) at 90 days were compared using Fisher's exact test. Binary logistic regression analysis was performed to examine factors associated with favorable outcomes (defined as mRS 0-2 at 90 days) in patients aged ≥75 years and those <75 years. The independent variables included NIHSS, ASPECTS, clot burden score, the use of the combined technique, onset-to-door time, puncture-to-recanalization time, onset-to-recanalization time, administration of tPA, mFPE (TICI ≥2b), final reperfusion status (TICI ≥2b), and procedure-related complications (ENT, arterial perforation, and Heidelberg Classification 2 and 3). The study period spanned 7 years, during which advancements in endovascular devices and techniques may have influenced the outcomes. The calendar year was also included as a covariate to adjust for potential period bias in the multivariable analysis. All statistical tests were two-tailed and P < 0.05 was considered statistically significant. Data were analyzed using SAS version 10.4 (SAS Institute, Cary, NC, USA).
Ethical considerations
This study was conducted in accordance with the principles of the Declaration of Helsinki, its revisions, and guidelines approved by our institution. The procedures were conducted in accordance with the “Ethical Guidelines for Medical and Health Research Involving Human Subjects (Provisional Translation as of March 2015)” and its later amendments. The ethics Committee of the Institutional Review Board of Mito Medical Center approved this study (Numbers 2023-35), and all participants provided written informed consent.
Results
Baseline characteristics
The baseline characteristics of all patients are shown in Table 1. When comparing each characteristic (sex, age, hypertension, diabetes mellitus, hyperlipidemia, congestive heart failure, chronic renal failure, atrial fibrillation, coronary heart disease, current smoking, history of stroke, antiplatelet medication, anticoagulant use, location of occluded vessels, stroke etiology, and the clot burden score) between the first-line single-device and the first-line combined-technique groups, age showed a statistically significant difference (74.0 ± 11.4 vs. 76.8 ± 8.2 years, p = 0.042).
Table 1.
Comparison of background characteristics between the first-line single-device and the first-line combined-technique groups in all cases
| First-line single-device January 2017-March 2021 145 cases |
First-line combined-technique April 2021-December 2023 96 cases |
P value | |
|---|---|---|---|
| Age, years | 74.0±11.4 | 76.8±8.2 | 0.042 |
| Women | 57 (39.3%) | 39 (40.6%) | 0.89 |
| Systolic blood pressure, mmHg | 150.1±22.3 | 154.2±24.1 | 0.52 |
| Hypertension | 86 (59.3) | 60 (62.5) | 0.69 |
| Diabetes Mellitus | 38 (26.2) | 19 (19.8) | 0.28 |
| Hyperlipidemia | 34 (23.4) | 27 (28.1) | 0.45 |
| Congestive heart failure | 12 (8.3) | 14 (14.6) | 0.14 |
| Chronic kidney disease | 7 (4.8) | 2 (2.1) | 0.32 |
| Atrial fibrillation | 50 (34.5) | 37 (38.5) | 0.58 |
| Coronary heart disease | 13 (9.0) | 10 (10.4) | 0.82 |
| Smoking | 29 (20.0) | 20 (20.8) | 0.87 |
| Previous stroke | 20 (13.8) | 19 (19.8) | 0.28 |
| Previous antipletelet medications | 25 (17.2) | 19 (19.8) | 0.61 |
| Previous anticoagulant medications | 24 (16.6) | 19 (19.8) | 0.6 |
| Occlusion site | 0.59 | ||
| Internal carotid artery | 50 (34.5) | 36 (37.5) | |
| M1-middle cerebral artery | 63 (43.4) | 44 (45.8) | |
| M2-middle cerebral artery | 32 (22.1) | 16 (24.2) | |
| Cardioembolic | 59 (40.7) | 44 (45.8) | 0.51 |
| Other or unknown | 86 (59.3) | 52 (54.2) | |
| Clot burden score (median IQR) (n=193) | 8 (6-9) | 7 (6-9) | 1.00 |
IQR, interquartile range
Endovascular procedures
Details of the techniques used in the first-line single-device group are shown in Table S1. Of the 145 cases in the first-line single-device group, the SR alone was used in 102 cases, while CA alone was used in 8 cases, based on the surgeon's judgment. In 26 cases in which a single device (SR or CA) was used as a first-line technique, the combined technique was ultimately required as rescue procedure after recanalization was not achieved despite multiple attempts. Nine patients whose condition was complicated by an arterial stenotic lesion required percutaneous transluminal angioplasty (PTA) with or without intracranial stenting as a rescue procedure. In contrast, of the 96 cases (88.9%) treated with the combined technique as the first-line strategy, 2 cases needed PTA, with or without intracranial stenting, as a rescue procedure.
Devices
The devices used in the first-line single-device group during the study period between January 2017 and March 2021 were as follows: SRs included Solitaire 2 (Medtronic, Irvine, CA, USA) and Trevo (Stryker Corp., Kalamazoo, MI, USA). The following aspiration catheters were used either as a first-line approach (8 cases) or as part of a rescue combined technique (26 cases): Penumbra MAX series and ACE 68 (Penumbra, Inc., Alameda, CA, USA). Conversely, the devices used in the first-line combined technique during the study period between April 2021 and December 2023 were as follows: SRs included Solitaire 2, Trevo, and Embotrap (Cerenovus/Johnson & Johnson, Miami, FL, USA), while aspiration catheters included CAT 6/7 (Stryker Corp., Kalamazoo, MI, USA), Sofia Flow 6/7 (Terumo Neuro/MicroVention, Aliso Viejo, USA), and React 68/71 (Medtronic, Irvine, CA, USA).
Efficacy outcomes
Table 2 shows the efficacy outcomes of patients <75 years of age between the first-line single-device and first-line combined-technique groups. Age, NIHSS, ASPECTS, clot burden score, percentage of tPA use, onset-to-door time, onset-to-tPA time, puncture-to-recanalization time, and onset-to-recanalization time were not significantly different between the 2 groups. The percentage of the mFPE was higher in the first-line combined-technique group than in the first-line single-device group (68.1% vs. 38.1%, p = 0.033), while the percentage of final successful reperfusion tended to be higher in the first-line combined-technique group than in the first-line single-device group (94.1% vs. 84.1%, p = 0.20) but did not reach statistical significance. Regarding functional outcomes (mRS 0-2 at 90 days), no statistically significant difference was observed between the first-line single-device and the first-line combined-technique groups (58.8% vs. 54.0%, p = 0.67). Binary logistic regression analysis for participants <75 years of age revealed that only NIHSS (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.73-0.96; p = 0.011) was associated with favorable functional outcomes, whereas calendar year (OR, 0.68; 95% CI 0.30-1.57; p = 0.37), ASPECTS (OR, 1.36; 95% CI, 0.99-1.88; p = 0.056), clot burden score (OR, 1.23; 95% CI, 0.84-1.79; p = 0.29), tPA use (OR, 1.33; 95% CI, 0.28-6.21; p = 0.72), first-line combined-technique strategy (OR, 3.31; 95% CI, 0.21-52.6; p = 0.40), onset-to-door time (OR, 0.99; 95% CI, 0.96-1.02; p = 0.74), puncture-recanalization time (OR, 0.96; 95% CI, 0.91-1.02; p = 0.26), onset-to-recanalization time (OR, 1.00; 95% CI, 0.981.03; p = 0.79), mFPE (OR, 1.27; 95% CI, 0.31-5.15; p = 0.73), final successful reperfusion (TICI ≥2b; OR, 4.92; 95% CI, 0.44-55.8; p = 0.20), and procedure-related complications (OR, 0.059; 95% CI, 0.0010-1.48; p = 0.98) were not.
Table 2.
Efficacy outcomes in patients <75 years of age between the first-line single-device and first-line combined-technique groups
| First-line single device 63 cases |
First-line combined technique 34 cases |
P value | |
|---|---|---|---|
| Age, years (mean ± SD) | 67.8±9.2 | 68.2±6.5 | 0.68 |
| NIHSS (median IQR) | 19 (12-24.5) | 18 (13-22) | 0.82 |
| ASPECTS (median IQR) | 7 (5-8) | 6 (4.25-8) | 0.28 |
| Clot burden score (median IQR) (n=71) | 8 (5.75-9.25) | 7 (5-8) | 0.63 |
| Use of tPA | 25 (39.7%) | 16 (47.1%) | 0.84 |
| Onset to door time, min | 226.1±215.8 | 137.4±124.5 | 0.03 |
| Onset to tPA time, min (n=32) | 218.4±135.7 | 160.5±65.2 | 0.12 |
| Onset to puncture time, min | 268.0±213.6 | 198.8±121.1 | 0.08 |
| Puncture to recanalization time, min | 49.7±37.4 | 49.8±28.6 | 0.99 |
| Onset to recanalization time, min | 317.7±223.9 | 248.5±121.7 | 0.09 |
| Modified first pass effect (TICI≥2b at the first pass) | 24 (38.1%) | 21 (68.1%) | 0.033 |
| Successful reperfusion at the end of procedure (TICI≥2b) | 53 (84.1%) | 32 (94.1%) | 0.2 |
| Functional outcomes (mRS 0-2 at 90 days) | 34 (54.0%) | 20 (58.8%) | 0.67 |
ASPECTS, Alberta Stroke Program Early CT Score; NIHSS, National Institute of Health Stroke Scale; tPA, tissue plasminogen activator; TICI, Thrombolysis in Cerebral Infarction; SD, standard deviation; IQR, interquartile range; mRS, modified Rankin Scale
Table 3 shows the efficacy outcomes of patients ≥75 years of age between the first-line single-device and first-line combined-technique groups. Age, NIHSS, ASPECTS, clot burden score, and tPA use were not significantly different between the groups. Onset-to-door time, onset-to-tPA administration time, puncture-to-recanalization time, and onset-to-recanalization time also did not differ significantly. The mFPE in the first-line combined-technique group was statistically significantly higher than that in the first-line single-device group (61.3% vs. 42.7%, p = 0.03), while final successful reperfusion tended to be higher in the first-line combined-technique group than in the first-line single-device group (83.9% vs. 74.4%, p = 0.22) but did not reach statistical significance. The first-line combined-technique group also had statistically significantly more favorable functional outcomes than the first-line single-device group (31.3% vs. 13.4%, p = 0.0079). Binary logistic regression analysis for participants ≥75 years of age revealed that NIHSS (OR, 0.88; 95% CI, 0.79-0.98; p = 0.021), ASPECTS (OR, 1.53; 95% CI, 1.07-2.20; p = 0.019), combined-technique first strategy (OR, 9.03; 95% CI, 1.06-76.7; p = 0.043), mFPE (OR, 5.53; 95% CI, 1.28-23.9; p = 0.022), and procedure-related complications (OR, 0.083; 95% CI, 0.0084-0.81; p = 0.033) were associated with favorable functional outcomes, whereas the calendar year (OR, 0.75; 95% CI, 0.45-1.24; p = 0.27), clot burden score (OR, 0.93; 95% CI, 0.65-1.33; p = 0.72), tPA use (OR, 1.12; 95% CI, 0.35-3.54; p = 0.84), onset-to-door time (OR, 1.00; 95% CI, 0.99-1.01; p = 0.82), puncture-recanalization time (OR, 1.00; 95% CI, 0.97-1.03; p = 0.96), onset-to-recanalization time (OR, 1.00; 95% CI;, 0.99-1.01; p = 0.86), and final successful reperfusion outcomes (OR, 1.42; 95% CI, 0.21-9.60; p = 0.71) were not.
Table 3.
Efficacy outcomes in patients of ≥75 years of age between the first-line single-device and first-line combined-technique groups
| First-line single device 82 cases |
First-line combined technique 62 cases |
P value | |
|---|---|---|---|
| Age, years (mean ± SD) | 81.7±5.0 | 82.0±5.4 | 0.76 |
| NIHSS (median IQR) | 19 (14-25) | 18 (15-21) | 0.84 |
| ASPECTS (median IQR) | 7 (5.5-8) | 7 (6-9) | 0.87 |
| Clot burden score (median IQR) (n=122) | 8 (6-8) | 8 (6-9.25) | 0.59 |
| Use of tPA | 42 (52.5%) | 25 (40.3%) | 0.24 |
| Onset to door time, min | 189.1±191.6 | 181.9±185.6 | 0.71 |
| Onset to tPA time, min (n=67) | 228.8±90.1 | 225.5±95.2 | 0.82 |
| Onset to puncture time, min | 243.1±185.8 | 235.5±179.2 | 0.8 |
| Puncture to recanalization time, min | 52.6±29.3 | 55.6±28.8 | 0.54 |
| Onset to recanalizationtime, min | 293.6±183.2 | 292.5±183.2 | 0.97 |
| Modified first pass effect (TICI≥2b at the first pass) | 35 (42.7%) | 38 (61.3%) | 0.03 |
| Successful reperfusion at the end of procedure (TICI ≥ 2b) | 61 (74.4%) | 52 (83.9%) | 0.22 |
| Functional outcomes (mRS 0-2 at 90 days) | 11 (13.4%) | 20 (31.3%) | 0.0079 |
ASPECTS, Alberta Stroke Program Early CT Score; NIHSS, National Institute of Health Stroke Scale; tPA, tissue plasminogen activator; TICI, Thrombolysis in Cerebral Infarction; SD, standard deviation; IQR, interquartile range; mRS, modified Rankin Scale
The horizontal bar graph represents the distribution of functional outcomes (mRS) at 90 days for all ages, those <75 years of age, and those ≥75 years of age (Figure S1). The proportion of mRS 0-2 was statistically significantly higher in the first-line combined-treatment group than in the first-line single-device group for all ages combined and for patients ≥75 years. However, among those <75 years, no statistically significant difference was observed between the first-line combined-technique and the first-line single-device groups.
Safety outcomes
Table 4 shows the comparison of procedure-related serious adverse events―including ENT, arterial perforation, and hemorrhagic complications of Heidelberg Bleeding Classification grades 2-3―and all-cause mortality at 90 days between the first-line single-device and the first-line combined-technique groups. In patients <75 years of age, the rate of procedure-related serious adverse events was higher in the first-line single-device group than in the first-line combined-technique group (27.0% vs. 23.5%, p = 0.81) but did not reach statistical significance. The rate of ENT was also higher in the first-line single-device group than in the first-line combined-technique group, but without statistical significance (7.9% vs. 0%, p = 0.16). In patients ≥75 years of age, the rate of procedure-related serious adverse events was significantly higher in the first-line single-device group than in the first-line combined-technique group (25.6% vs. 9.7%, p = 0.018). In particular, the rate of ENT was significantly higher in the first-line single-device group than in the first-line combined-technique group (9.8% vs. 0%, p = 0.010), while the rates of arterial perforation, Heidelberg Bleeding Classification grades 2-3, and all-cause mortality at 90 days did not differ between the 2 groups.
Table 4.
Safety outcomes in patients of <75 years and ≥75 years of age between the first-line single-device and first-line combined-technique groups
| Participant characteristics | Participants <75 years of age | Participants ≥75 years of age | ||||
|---|---|---|---|---|---|---|
| First-line single-device 63 cases |
First-line combined-technique 34 cases |
P value | First-line single-device 82 cases |
First-line combined-technique 62 cases |
P value | |
| Procedure-related complications | 17 (27.0%) | 8 (23.5%) | 0.81 | 21 (25.6%) | 6 (9.7%) | 0.018 |
| Embolization in a new territory | 5 (7.9%) | 0 (0%) | 0.16 | 8 (9.8%) | 0 (0%) | 0.01 |
| Arterial perforation | 1 (1.6%) | 1 (2.9%) | 1 | 1 (1.2%) | 2 (3.2%) | 0.58 |
| Heidelberg classification (2+3c) | 11 (17.5%) | 7 (20.6%) | 0.79 | 12 (14.6%) | 8 (12.9%) | 0.62 |
| All-cause mortality at 90 days | 2 (3.2%) | 3 (8.9%) | 0.34 | 15 (18.3%) | 5 (8.1%) | 0.09 |
Discussion
Previous studies comparing the combined technique and the single-device technique (SR or CA) failed to demonstrate superiority of the clinical effect of the combined technique over the single-device technique on acute LVO.11,12) These studies examined the clinical effect of the combined technique without differentiating age groups. In general, vascular conditions such as atherosclerotic changes and ischemic tolerance differ depending on age. As age increases, catheter manipulation time increases due to the tortuosity of blood vessels, and in the event of ischemia, ischemic tolerance is considered lower than in younger people.23,24) Thus, the present study evaluated clinical effects of the combined technique with a focus on age differences (population <75 years old and ≥75 years old).
Regarding efficacy outcomes, among patients <75 years of age, the first-line combined-technique group had a significantly higher proportion of patients achieving the mFPE and showed a trend toward a higher rate of final successful reperfusion (TICI ≥2b). Additionally, the onset-to-reperfusion time tended to be shorter in the first-line combined-technique group compared to the first-line single-device group. However, no significant difference in favorable functional outcomes (mRS 0-2 at 90 days) was observed between the groups. Multivariate analysis revealed that only NIHSS score on admission was significantly associated with favorable outcomes. Neither the use of the combined technique nor achievement of mFPE was independently associated with favorable outcomes in this age group. Conversely, in patients ≥75 years of age, the first-line combined-technique group demonstrated higher rates of both mFPE and favorable functional outcomes compared to the first-line single-device group. Multiple regression analysis further identified the combined technique as a first-line strategy and mFPE as independent predictors of favorable outcomes. These findings suggest that the clinical benefits of employing the combined technique and achieving mFPE were more pronounced in older patients. In this older cohort, the first-line combined-technique group also showed a trend toward a higher rate of final successful reperfusion (TICI ≥2b) and had a significantly lower incidence of procedure-related adverse events compared to the first-line single-device group. These factors may have contributed to the superior clinical outcomes observed with the combined technique in older patients. Previous studies have reported that clot characteristics, such as susceptibility vessel sign positivity and clot burden score, are associated with clinical outcomes after recanalization therapy.17,25) In the present study, the clot burden score could not be assessed in all cases, and even when it was evaluable, the imaging sequences were not standardized―being based either on susceptibility vessel imaging or T2*-weighted gradient-echo imaging―and should be regarded as a supplementary finding. Pretreatment MRI demonstrated comparable clot burden scores between the first-line single-device and the first-line combined-technique groups, and multivariate analysis revealed no significant association between the clot burden score and clinical outcomes. Differences in procedural complexity between the single-device and the combined techniques may have influenced the clinical outcomes. However, because the puncture-to-recanalization time (procedure duration) was comparable between the 2 groups, this explanation may not be applicable. Accordingly, the lack of disparity in clinical outcomes between 2 endovascular strategies in younger patients may be explained, at least in part, by greater tolerance to ischemia and superior neuroplasticity in younger patients, which may facilitate recovery even in the presence of stroke-related deficits.26,27)
Regarding safety outcomes, among patients ≥75 years of age, the first-line single-device group had higher rates of procedure-related complications, with a particularly higher rate of ENT than the first-line combined-technique group (25.6% vs. 9.7%, p = 0.018, and 9.8% vs. 0%, p = 0.010, respectively). Although similar trends were observed among patients <75 years old, they were not statistically significant. Previously published articles reported that infarcts in a new territory were observed in approximately 10% of patients who underwent endovascular thrombectomy for acute ischemic stroke and that these were associated with poor outcomes.26,27) The concomitant use of an SR and a distal access (aspiration) catheter lowered the risk of infarcts in a new territory.28) In older patients, the guiding catheter could not always be advanced sufficiently into the distal portion of the ICA and sometimes had to be placed in the common carotid artery because of arterial elongation. However, when using the combined technique, aspiration catheters can be advanced to reach the thrombus or the nearest portion of the occluded vessel. The synergistic effect of using an SR for entangling and an aspiration catheter for suctioning the thrombus could help prevent distal emboli. Multivariate analysis also showed that procedure-related complications were negatively associated with functional outcomes. Thus, to achieve favorable outcomes from recanalization therapy in older patients, prevention of procedure-related complications (especially ENT) is crucial. Among hemorrhagic complications, the first-line combined-technique group had slightly higher rates of arterial perforation in both younger and older patients, although this difference was not statistically significant. A possible mechanism is that the use of an aspiration catheter may facilitate more direct transmission of force from the microcatheter or microwire to the vessel wall.29) While soft thrombi may allow relatively easy passage of the microcatheter or microwire, harder thrombi often require greater manipulation. In such cases, the application of excessive force may increase the risk of vessel perforation, warranting careful attention by the operator. In the event of an arterial perforation, depending on the severity of the hemorrhage, embolization of the perforated vessel using liquid embolic materials or coils, which poses a risk of irreversible cerebral infarction, may be necessary. Other hemorrhagic complications, including parenchymal hematoma type 2 and subarachnoid hemorrhage type 3c, according to the Heidelberg classification, were similar in both treatment groups among both younger and older patients.
In patients <75 years of age, the average onset-to-door time and onset-to-recanalization time in the combined-technique group tended to be shorter than that in the first-line single-device group, without statistical significance. In Ibaraki Prefecture, located in the suburbs of Tokyo, Japan, the centralization of stroke centers performing MT for acute ischemic stroke has been introduced since April 2021. Patients with acute ischemic stroke and suspected LVO are transported directly to a stroke center capable of endovascular thrombectomy based on the emergent LVO screening, a prehospital tool that allows paramedics to identify LVO appropriately.30) This period almost coincided with when our hospital adopted combination techniques as the first choice of treatment for acute ischemic stroke. This system likely contributed to shortening onset-to-door time and onset-to-recanalization time in the first-line combined-technique group. However, the shortening of these intervals did not affect clinical outcomes in younger patients. This may be because the non-significant reduction in treatment time might not significantly influence clinical outcomes in younger patients, who generally have a greater ability to recover from stroke sequelae, as discussed earlier.13,23,24) Conversely, onset-to-door time and onset-to-recanalization time in patients ≥75 years of age were not significantly different between the first-line single-device and first-line combined-technique groups. If these intervals in patients ≥75 years of age could be further reduced through an emergent LVO screening-based emergency transport system, clinical outcomes would be expected to improve. The procedure time (puncture-to-recanalization time) in patients ≥75 years of age was longer than in those <75 years old, likely because vessel tortuosity affects procedure duration.31) Procedure time was similar between the first-line single-device and first-line combined-technique groups across all ages. Although the combined technique is relatively complex and time-consuming compared with the single-device approach, it achieved higher first-pass recanalization rates. The additional time required for the more complex setup is likely offset by fewer device passes. Therefore, these higher rates of recanalization at the first pass led to lower rates of serious procedure-related complications, which is important for obtaining favorable functional outcomes in older patients.
Limitations
This study has some limitations. First, this was a retrospective study that compared single-device and combined-technique use as first-line strategies for acute ischemic stroke. As age is an important source of bias related to the clinical outcomes after MT in these patients, we subdivided the study population into 2 groups to reduce the bias of age: patients <75 years and ≥75 years of age. This approach could clarify the differences in the effects of single-device and combined techniques by age.
Second, this study was a single-center clinical study with a relatively small number of cases. The advantages are that the procedures and strategies in the study were relatively uniform, with a small number of physicians performing standardized endovascular procedures under a standardized management system for recanalization therapy for acute LVO. Furthermore, we excluded cases in which combined technique was first attempted in the first-line single-device group to evaluate the effectiveness of the single-device technique, and vice versa to evaluate the effectiveness of the combined technique. Among the 145 cases in the single-device group, only 8 cases involved the use of CA as the first-line approach. Therefore, the present study was not a pure comparison of a single type of device (either SR or CA) with a combined technique (SR plus CA), as conducted in the ASTER or VECTOR trials.11,12) Rather, it compared single-device approaches (including both SRs and CA) with combined techniques, which may better reflect real-world clinical practice.
Third, although this study included a consecutive series of cases, it compared 2 distinct time periods, raising the potential for period bias. Temporal changes in operator experience and institutional workflows related to recanalization therapy may have influenced treatment outcomes. Moreover, due to advancements in endovascular treatment technologies and devices, slight differences existed in the types of devices used between the 2 periods. MT using a stent retriever was introduced at our institution in July 2014. In April 2017, our institution was staffed with 3 board-certified neuroendovascular specialists accredited by the Japanese Society for Neuroendovascular Therapy (TY, MS, and KN), and the current institutional framework for recanalization therapy was established. Accordingly, this study focused on cases treated after April 2017, when treatment techniques and procedures had been standardized. In addition, although the aspiration catheters used in the latter period were of larger caliber, no major differences in the types of SRs employed were observed throughout the study period. Further, in the statistical analysis, potential confounding factors were appropriately adjusted through multivariable analysis. Therefore, we consider that the variations in devices and techniques were not substantial enough to significantly affect the study outcomes. However, to overcome these limitations and draw conclusive evidence, a larger, multicenter prospective study is warranted.
Conclusions
For all patients with acute ischemic stroke due to LVO in the anterior circulation, rates of the mFPE and final effective reperfusion were higher when using the combined technique as the first-line strategy than when using a single device as the first-line strategy. Among older patients, using the combined technique (simultaneous use of an SR and CA) as the first-line strategy was more effective in achieving favorable functional outcomes at 90 days after onset than using a single device as the first-line strategy. Thus, in older patients with acute ischemic LVO, the combined technique should be employed as the first-line strategy. However, among younger patients, favorable functional outcomes at 90 days after stroke onset did not differ significantly between the 2 MT strategies.
Conflicts of Interest Disclosure
All authors have no conflict of interest.
Data Availability
The datasets and analytical results of this study are available from the corresponding author upon reasonable request.
Supplementary Material
The horizontal bar graph represents the distribution of functional outcomes (mRS) at 90 days for all ages, participants of <75 years of age, and participants of ≥75 years of age
mRS: modified Rankin Scale; NS: not significant.
Acknowledgments
The authors would like to thank Editage (https://www.editage.jp/) for the English-language editing.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
The horizontal bar graph represents the distribution of functional outcomes (mRS) at 90 days for all ages, participants of <75 years of age, and participants of ≥75 years of age
mRS: modified Rankin Scale; NS: not significant.
Data Availability Statement
The datasets and analytical results of this study are available from the corresponding author upon reasonable request.