Impact of onset-to-groin puncture time within three hours on functional outcomes in mechanical thrombectomy for acute large-vessel occlusion

Abstract

Introduction

Endovascular treatment for acute ischemic stroke with acute large-vessel occlusion (ALVO) has established benefits, and rapid treatment is vital for mechanical thrombectomy in ALVO. Time from onset of stroke to groin puncture (OTP) is a practical and useful clinical marker, and OTP should be shortened to obtain the maximum benefit of thrombectomy.

Objective

The aim of the present study was to assess the impact of early treatment of anterior circulation stroke within three hours after symptom onset and to evaluate the role of OTP in determining outcomes after endovascular therapy.

Methods

Consecutive patients with acute stroke due to major artery (internal carotid or middle cerebral arteries) occlusion who underwent endovascular recanalization between March 2014 and January 2017 were retrospectively evaluated. Patients were stratified by OTP into three categories: 0–≤3 h, >3–≤6 h, and >6 h. The primary outcome measure was a 90-day modified Rankin scale score of 0–2 (good outcome).

Results

Data were analyzed from 100 patients (mean age, 76.6 years; mean National Institutes of Health Stroke Scale score, 17). Groin puncture occurred within 0–≤3 h in 51 patients, >3–≤6 h in 28, and >6 h in 21. Median OTP in each group was 126 min (range, 57–168 min), 238 min (range, 186–360 min) and 728 min (range, 365–1492 min), respectively. On multivariable logistic regression analysis, category of OTP represented an independent predictor of patient outcome (adjusted odds ratio, 0.48; 95% confidence interval, 0.25–0.93; p = 0.029).

Conclusions

OTP is a prehospital and in-hospital workflow-based indicator. In this single-center study, OTP was found to independently affect functional outcomes after endovascular stroke treatment.

Introduction

Recent trials have established the clinical benefits of endovascular treatment for acute ischemic stroke patients presenting with acute large-vessel occlusion (ALVO).^1–5 These trials have confirmed the importance of rapid treatment, workflow, and efficient team-based care for intra-arterial therapy (IAT) in ALVO.^1–5 Several prior studies have indicated that the odds of good outcomes decrease by 12%–21% for every 30-minute interval of onset-to-reperfusion time (OTR).^5,6 Increasing OTR was associated with increased rates of mortality and intracerebral hemorrhage and with decreased rates of favorable and excellent outcomes.^6–9 When reperfusion was reached at three hours after stroke onset, the absolute risk difference (95% confidence interval (CI)) was 25.9% (range, 8.3%–44.4%). In the group of patients who reached Thrombolysis in Cerebral Infarction (TICI) 2b to 3 at 3 h, the likelihood of reaching a modified Rankin Scale (mRS) score of 0 to 2 was 55% (95% CI, 36%–73%). ⁸ In 2015, the Society of NeuroInterventional Surgery (SNIS) suggested several stroke process time metrics for implementation at comprehensive stroke centers. ¹⁰ SNIS recommends time from door to interpretation of computed tomography (CT) angiography <20 min, door-to-groin puncture time (DTP) initiated in <60 min, and arrival to recanalization <90 min. ¹⁰

Several target times for mechanical thrombectomy have been reported to date, including door-to-imaging time, ¹¹ OTR,^9,12 picture-to-puncture time (P2P), ¹³ DTP, ¹⁴ and imaging-to-reperfusion time. ⁷ OTR represents the sum of DTP and puncture-to-recanalization time (PTR). Achieving OTR <3 h requires performance of groin puncture within approximately 2.5 h after stroke onset. Time from onset of stroke to groin puncture (OTP) is also considered a practical and useful clinical marker in the delivery of IAT. The American Heart Association/American Stroke Association Guidelines stated that treatment can be initiated (groin puncture) within 6 h of symptom onset. ¹⁵ To ensure benefits, reperfusion to TICI 2 b/3 should be achieved as early as possible within 6 h of stroke onset. These statements mean that OTP should be shortened to obtain the maximum benefit of thrombectomy. The aim of the present study was thus to assess the impact on clinical outcomes of early treatment in patients with anterior circulation strokes within 3 h after symptom onset and to evaluate the role of OTP in determining outcomes after endovascular therapy.

Patients and methods

This retrospective study investigated 100 consecutive patients with acute stroke due to major artery occlusion in the anterior circulation (internal carotid and middle cerebral arteries) who underwent endovascular recanalization between March 2014 and January 2017.

A systematic approach was introduced to create a multidisciplinary collaborative effort at achieving shorter times. We are notified of en-route stroke patients by ensuring that our emergency room nurses, magnetic resonance imaging (MRI) room personnel and radiologists are available prior to admission. Our policy is first to perform MRI/magnetic resonance angiography (MRA). If MRI findings warrant recanalization therapy, the necessary preparations for intravenous tissue plasminogen activator (IV-tPA) (by stroke neurologists) and recanalization therapy (by neurosurgeons) are undertaken simultaneously. To reduce the OTP, we have prioritized patient admission to the angiography suite, and IV-tPA is administered as soon as possible. We began developing a departmental recanalization flowsheet from admission to endovascular therapy and have provided the necessary instruction so that even relatively inexperienced medical personnel can perform the necessary tests, treatments and preparations.

Patients were stratified based on treatment start time (OTP) into three categories: 0–≤3 h (category 1), >3–≤6 h (category 2) and >6 h (category 3). The primary outcome was a 90-day mRS score of 0–2 (good outcome). Specifically, the following variables were evaluated: sex, age, National Institutes of Health Stroke Scale (NIHSS) score on admission, pre-treatment Alberta Stroke Program Early CT Score–diffusion-weighted imaging (ASPECTS-DWI), ¹⁶ stroke type as determined by Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, ¹⁷ occluded vessel, and use of combined IV-tPA. The rate of effective recanalization (TICI 2 b or 3) and the percentage of patients with an mRS score of 0–2 after 90 days were also evaluated.

Statistical analysis

All statistical tests were performed using the SPSS version 22.0.0 software (IBM, Armonk, NY, USA). Analysis was performed comparing baseline characteristics between patients divided into three groups based on the OTP as follows: less than three hours, three to six hours, and more than six hours. Continuous variables are expressed as means ± standard deviation. Categorical data are expressed as numbers of patients (percentage of total). Statistical comparisons were performed using analysis of variance, followed by multiple comparisons with Bonferroni correction. In addition, univariate analysis was subsequently performed to identify potential factors associated with good clinical outcome (mRS score 0–2 at 90 days) after endovascular treatment. All variables showing values of p < 0.20 on univariate modeling were included in multivariable analysis. Odds ratios (ORs) are presented with 95% confidence intervals (CIs). All statistical tests were two sided, and values of p < 0.05 were considered significant.

Results

A total of 100 patients with a mean age of 76.6 years and a mean NIHSS score of 17 (range, 1–40) were analyzed. Of the 100 patients, OTP was 0–≤3 h in 51 patients (51%), >3–≤6 h in 28, and >6 h in 21. No significant differences were seen among these three categories as to age, sex, past history, medication, NIHSS score on admission, atrial fibrillation, DWI-ASPECTS, stroke type according to TOAST criteria, ¹⁷ location of intracranial occlusion, or final TICI grade (Table 1). Intravenous tPA was given to all eligible patients. The referral pattern to our center was as follows: Seventy patients were transferred directly to our center, 15 were transferred from a nearby primary stroke center, and 15 patients developed the requisite pathology in-hospital. The median OTP in each group was 126 min (range 57–168 min), 238 min (186–360 min) and 728 min (365–1492 min), respectively. Symptomatic hemorrhage developed in four patients (4%).

Table 1.

Demographics and clinical characteristics.

Characteristics	All	Category 1 (0–3 h)	Category 2 (3–6 h)	Category 3 (6 h)	p value
Number of cases	100	51	28	21
Patient and stroke risk factors
Age (years), (range)	76.6	74.6 (39–94)	80.5 (38–93)	76.2 (55–90)	0.091
Female gender, n (%)	44	24 (47.0%)	13 (46.4%)	7 (33.3%)	0.549
Hypertension, n (%)	46	18 (35.3%)	15 (53.6%)	13 (61.9%)	0.077
Diabetes mellitus, n (%)	18	9 (17.6%)	5 (17.9)	4 (19.0%)	0.990
Dyslipidemia, n (%)	19	7 (13.7%)	8 (28.6)	4 (19.0%)	0.280
Antiplatelet use	27	16 (31.3%)	8 (28.6%)	3 (14.3%)	0.331
Anticoagulant use	20	9 (17.6%)	5 (17.9%)	6 (28.6%)	0.551
NIHSS upon admission
Mean (range)	17 (1–40)	18 (0–40)	17 (5–29)	15 (1–34)	0.800
Atrial fibrillation, n (%)	56	26 (51.0%)	18 (64.3%)	12 (57.1%)	0.527
DWI-ASPECTS, mean (range)	7 (1–10)	7(1–11)	7 (1–9)	7 (2–10)	0.801
Symptomatic ICH	4	2 (3.9%)	2 (7.1%)	1 (4.8%)	0.824
TOAST criteria, n (%)
Cardiac emboli	87	45 (88.2%)	24 (85.7%)	18 (85.7%)	0.934
Large artery	11	4 (7.8%)	4 (14.3%)	3 (14.3%)	0.597
Other determined	2	2 (3.9%)	0	0	0.383
Location of intracranial occlusion, n (%)
ICA	15	7 (13.7%)	3 (10.7%)	5 (23.8%)	0.527
ICA-T	19	11 (21.6%)	6 (21.4%)	2 (9.5%)
MCA M1	43	18 (35.3%)	13 (46.4%)	12 (57.1%)
MCA M2	23	15 (29.4%)	6 (21.4%)	2 (9.5%)
TICI grade at final DSA, n (%)
TICI 2b	40	21 (41.2%)	12 (42.9%)	7 (33.3%)	0.779
TICI 3	40	23 (45.1%)	9 (32.1%)	8 (38.1%)	0.529
TICI 2b/3	80	44 (86.3%)	21 (75.0%)	15 (71.4%)	0.271

NIHSS: National Institutes of Health Stroke Scale; DWI: diffusion-weighted imaging; ASPECTS: Alberta Stroke Program Early CT Score; ICH: intracerebral hemorrhage; TOAST: the Trial of Org 10172 in Acute Stroke Treatment; ICA: internal carotid artery; MCA: middle cerebral artery; TICI: Thrombolysis in Cerebral Ischemia; DSA: digital subtraction angiography.

Variables associated with good patient outcome at 90 days were identified on univariate testing (Table 2). Good outcome was associated with age (70.0 years vs. 80.3 years, p < 0.001), lower initial NIHSS score (15.4 vs. 19.2, p = 0.0021) and TICI reperfusion grade (TICI 2 b/3: 91.7% vs. 73.4%, p = 0.021). Female sex (33.3% vs. 50.0%, p = 0.105) and atrial fibrillation (44.4% vs. 62.5%, p = 0.081) also showed trends toward associations with good outcomes. No differences in symptomatic intracranial hemorrhage were found. On multivariable logistic regression analysis adjusted for age (per 10 years), sex, reperfusion success, NIHSS score, atrial fibrillation, and category of OTP (Table 3), OTP category was an independent predictor of patient outcome (adjusted OR, 0.48; 95% CI, 0.25–0.93; p = 0.029). This analysis confirmed that the OR of mRS score 0–2 for each 10-year increase in age was 0.40 (95% CI, 0.24–0.67; p = 0.001), and the OR of mRS score 0–2 for each one-point increase in NIHSS was 0.91 (95% CI, 0.85–0.97; p = 0.007).

Table 2.

Comparison of patients who achieved good outcomes versus poor outcomes at 90 days following endovascular treatment.

	90-Day outcomes
Characteristics	Good (mRS 0–2)	Poor (mRS 3–6)	p value
Number of cases	36	64
Patient and stroke risk factors
Age (years), mean ± SD	70.0 ± 13.0	80.3 ± 8.5	<0.001
Female gender, n (%)	12 (33.3%)	32 (50.0%)	0.105
Hypertension, n (%)	15 (41.7%)	31 (48.4%)	0.514
Diabetes mellitus, n (%)	6 (16.7%)	12 (18.8%)	0.794
Dyslipidemia, n (%)	8 (22.2%)	11 (17.2%)	0.541
Atrial fibrillation, n (%)	16 (44.4%)	40 (62.5%)	0.081
Antithrombotic agents
Antiplatelet use	8 (22.2%)	19 (29.7%)	0.415
Anticoagulant use	6 (16.7%)	14 (21.9%)	0.528
Clinical assessment
NIHSS upon admission, mean ± SD	15.4 ± 9.6	19.2 ± 6.6	0.021
IV-tPA given	16 (44.4%)	29 (45.3%)	0.933
Radiographic
ASPECTS > 7, n (%) a	16 (45.7%)	23 (39.0%)	0.523
Symptomatic ICH	2 (5.6%)	3 (4.7%)	0.849
TICI grade at final DSA
TICI 2b/3	33 (91.7%)	47 (73.4%)	0.021

^aSix patients with pacemakers were excluded.

mRS: modified Rankin Scale; SD: standard deviation; NIHSS: National Institutes of Health Stroke Scale; IV: intravenous; tPA: tissue plasminogen activator; ASPECTS: Alberta Stroke Program Early CT Score; TICI: Thrombolysis in Cerebral Ischemia; DSA: digital subtraction angiography.

Table 3.

Multivariable logistic regressions of variables associated with good outcome after endovascular treatment for acute ischemic stroke.

Variables	OR (95% CI)	p value
Age (every 10 years)	0.40 (0.24–0.67)	0.001
Female	2.32 (0.78–6.87)	0.129
Baseline NIHSS score	0.91 (0.85–0.97)	0.007
Atrial fibrillation	1.14 (0.39–3.34)	0.82
Category of OTP	0.48 (0.25–0.93)	0.029
TICI 2b/3 at final DSA	2.76 (0.64–11.89)	0.173

CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale; OR: odds ratio; OTP: onset-to-groin puncture time; TICI: Thrombolysis in Cerebral Ischemia; DSA: digital subtraction angiography.

Discussion

In this single-center study, the independent effect of OTP on functional outcome after endovascular stroke treatment was confirmed; as OTP time decreased, fewer patients showed poor outcomes. To the best of our knowledge, the efficacy of OTP has been demonstrated in only a small number of reports. ¹⁸ In this study, we considered the importance of OTP with the effect of endovascular procedure time subtracted. Of several time goals in mechanical thrombectomy, OTP does not include endovascular procedural time; that is, this value is not dependent on the endovascular technique, device, or patient condition (type of aortic arch, vessel tortuosity, etc.). Given that OTP, as the time to the start of treatment, represents an important factor in improving outcomes, a prehospital and in-hospital approach is required to achieve shorter times.

The most commonly studied time metric is OTR.^5,9 Time saved at every stage, including reaching the hospital, initial patient evaluation, transfer to imaging, imaging time, imaging post-processing and interpretation, and, finally, initiation of treatment and achievement of revascularization, carries potential to improve clinical outcomes. ¹⁶ OTR includes OTP and PTR. Use of stent retrievers leads to shortened OTR, and mainly PTR has seen marked decreases. However, PTR is partially the result of the skills of the interventionists, devices used, and patient conditions (type of aortic arch, course of the artery, stiffness of thrombus, etc.). On the other hand, OTP depends on prehospital and in-hospital workflow. OTP is an in-hospital workflow-based indicator, which means that improvement of workflow can directly shorten OTP in every institute. Efficient recanalization cannot be achieved in all ALVO cases. We want to emphasize OTP as a practical and useful clinical marker that can be applied in every ALVO case. In this study, we considered the importance of OTP with the effect of endovascular procedure time subtracted. Lodi et al. reported that primary stent retriever thrombectomy within three hours without IV thrombolysis in acute ischemic stroke from larger vessel occlusion with a high NIHSS score (≥10) is associated with efficient recanalization in all cases and good outcomes. ¹⁹ These findings showed that early initiation of endovascular therapy resulted in early recanalization, which might have been reflected in good functional outcome. ¹⁹ Three hours after stroke onset can be one of the important time indices in endovascular thrombectomy. In-hospital workflow should be designed so as to deliver patients with ALVO with an OTP <3 h to the angiography suite for the start of treatment.

The present study found an OTP similar (mean, 284 min) to several previous reports.^8,18,20 A cohort study of 202 patients reported a median OTP of 238 min (range, 72–714 min). ²⁰ Among 500 patients (58% male; median age, 67 years), median OTP was 260 min (interquartile range (IQR), 210–311 min). ⁸ A meta-analysis of five prospective, randomized, controlled trials reported that OTP ranged from 200 to 269 min. ¹⁸ Median OTP showed significant (p = 0.0077) inverse associations with better functional outcomes. Analyses of these data suggested that delays of even 50 min in treatment initiation may have meaningful negative consequences on functional outcomes. ¹⁸

Given that time to treatment is an important factor in improving outcomes, a systematic approach is required to create a multidisciplinary collaborative effort at achieving shorter times. In the analysis of workflow from the Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) study, patients who initially arrived at a referring facility had longer OTP compared with patients who presented directly to the endovascular-capable center (275 vs. 179.5 min; p < 0.001). ²¹ DTP can be shortened significantly using a standardized multidisciplinary approach. ²² To reduce inefficiencies in workflow that prolong the delivery of treatment and subsequent reperfusion, the Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) trial used an active quality improvement process that provided site guidance on rapid image acquisition and interpretation, quick transfer to the angiography suite, and rapid endovascular techniques. This quality-improvement process contributed to the trial achieving highly efficient workflow metrics. ⁷ Importantly, this approach is likely to prove broadly effective across institutions. ²³ Delays in P2P times for interhospital transfers reduce the probability of good outcomes for treated patients. ¹³ P2P could be influenced by numerous variables, including the availability and speed of access to a scanner, type of imaging modality used, efficiency of the picture archival and retrieval system, workflow for IV-tPA administration, method of activation of the neurointerventional team, and so on. ²⁴ Hospital experience and the need for streamlined protocols is important for achieving lower P2P times. ¹³ In a recent retrospective analysis, higher-volume endovascular stroke centers showed faster treatment times, better reperfusion rates, and improved clinical outcomes. ²⁵ A workflow that offers IV-tPA administration in parallel with rapid activation of the neurointerventional team and transfer to the angiography suite has the potential to reduce P2P. In recent reports, early triage and transportation of the patient directly to the CT/MR suite or even to the neuroangiography suite, completely bypassing the emergency department, has been considered much more important.²⁶

Several limitations to the present study must be considered. This was a retrospective study at a single stroke center. Second, the patient group was relatively small. Third, the methods of acute thrombectomy included use of stent retrievers, aspiration catheters, carotid artery stenting, etc. Fourth, we did not perform any analysis including infarct or penumbra size. As DWI-ASPECTS was previously correlated with DWI lesion volume²⁷, we used DWI-ASPECTS as a substitute. More accurate analysis would be achieved using infarct or penumbra volume. Finally, the focus was on OTP, although stroke onset time is often inaccurate, including either the precise time of symptom onset or the earliest time at which a witness (e.g., family member) found the patient displaying stroke symptoms, possibly a considerable time after onset. In the latter cases, stroke may actually have occurred during sleep, and in other cases the witness was unable to recall the precise time of onset. ⁷ Stroke symptom onset to imaging or reperfusion time is probably a less accurate measure of stroke physiology than imaging. ⁷

Nevertheless, the results of this study are very appropriate in demonstrating the importance of shortening OTP to achieve good functional results after acute thrombectomy. Endovascular thrombectomy has the potential to achieve more benefits in the ultra-early stage with experience and dedication to reduction of treatment delays. With the importance of early initiation of endovascular therapy resulting in early recanalization, we strongly recommend that patients who can undergo groin puncture in less than three hours be treated in a highly efficient manner based on hospital workflow metrics.

Conclusion

In this single-center study, OTP was found to have an independent effect on functional outcomes after endovascular stroke treatment. Reducing stroke onset to groin puncture time is key, and OTP is an effective target time that efficient workflow can shorten in every institute. Further studies of large numbers of patients are needed to confirm the present findings.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with response to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Clinical Research Fund of the Tokyo Metropolitan Government (H290502003).