Endovascular Therapy for Acute Ischemic Stroke: Reducing Door-to-puncture Time

DOI: 10.5797/jnet.oa.2016-0140 Endovascular Therapy for Acute Ischemic Stroke: Reducing Door-to-puncture Time Yoichi Morofuji, 1,2 Nobutaka Horie, 1,2 Yohei Tateishi, 2,3 Minoru Morikawa, 4 Eisaku Sadakata, 1,2 Tsuyoshi Izumo, 1,2 Akira Tsujino, 2,3 and Takayuki Matsuo 1,2 Objective: Reducing the time to recanalization is important for the treatment of acute ischemic stroke. We changed the treatment protocol to reduce the door-to-puncture time (DTP). In this study, we evaluated the effects of this protocol change on the treatment of ischemic stroke. Methods: Consecutive 633 patients with acute ischemic stroke were analyzed. We divided the patients into pre-protocol change and post-protocol change (359 pre-protocol changes and 274 post-protocol changes). The percentage of patients with endovascular therapy, DTP, and outcome were retrospectively compared. Results: After the protocol change, the percentage of patients with endovascular therapy in acute ischemic stroke increased (14.9 vs. 9.4%, p = 0.03), and DTP was significantly reduced (78 vs. 108 minutes, p = 0.003). No difference was observed in the outcome 90 days after the onset. Conclusion: In patients with acute ischemic stroke suspected to have major artery occlusion, DTP could be shortened by 30 minutes by informing neurointerventionalists before MRI and deciding to perform endovascular treatment and starting the setup angiography suite during MRI. It is considered vital for all members of the staff involved in stroke management to recognize the importance of early recanalization and organize a system for cooperation. Keywords acute ischemic stroke, door-to-puncture time, endovascular therapy Introduction Acute major artery occlusion of the brain leads to permanent tissue injury in the absence of early recanalization. Acute ischemic stroke within 4.5 hours after the onset 1 Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan 2 Stroke Center, Nagasaki University Hospital, Nagasaki, Nagasaki, Japan 3 Department of Neurology and Strokology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan 4 Department of Radiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan Received: December 29, 2016; Accepted: August 12, 2017 Corresponding author: Yoichi Morofuji. Department of Neurosurgery, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, Nagasaki 852-8501, Japan Email: yoichi51@hotmail.com This work is licensed under a Creative Commons Attribution-NonCommercial- NoDerivatives International License. 2017 The Japanese Society for Neuroendovascular Therapy is an indication for intravenous thrombolysis with tissue plasminogen activator (tpa), the recanalization rate of the proximal part of the major artery of the brain is reportedly low. 1) Recently, however, with improvements in endovascular devices, percutaneous intracranial thrombectomy devices such as the Penumbra system (Penumbra, Alabama, CA, USA), Solitaire FR (Covidien, Irvine, CA, USA), and Trevo ProVue Retriever (Stryker Neurovascular, Fremont, CA, USA) have been developed, and recanalization of thrombosed proximal parts of major arteries of the brain has become possible. In clinical studies including the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke (MR CLEAN), Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial (EXTEND-IA), Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE), Solitaire With the Intention For Thrombectomy as PRIMary Endovascular Treatment (SWIFT PRIME), and Thrombectomy within 8 hours after symptom onset in ischemic stroke (REVASCAT), the therapeutic outcome has been 1

Morofuji Y, et al. a. Pre (Jan 2012 Dec 2013) Stroke Hotline arrival to ED Imaging MRI in ED Transfer to suite Groin Puncture RT/NS alert Clinical tpa decision NI alert tpa start/failed EVT decision Setup Suite b. Post (Jan 2014 May 2015) Stroke Hotline RT/NS alert arrival to ED Clinical NI alert Imaging MRI tpa/evt decision Setup suite in ED tpa start Transfer to suite Groin Puncture Time saved Fig. 1 Comparison of EVT processes. ED: emergency department; EVT: endovascular therapy; NI: neurointerventionalist; NS: nurse; tpa: tissue plasminogen activator; RT: radiological technician reported to be more favorable by the addition of thrombectomy to intravenous thrombolysis with tpa than by tpa alone, and this combination has also become a standard therapy in Japan. 2 6) In the above clinical studies, there have been schemes to shorten the time from the onset to recanalization, and the importance of reducing the onset-to-reperfusion time (OTR) and door-topuncture time (DTP) has been indicated in not only intravenous thrombolysis with tpa but also thrombectomy therapy. 2 6) We changed our therapeutic protocol for patients with acute ischemic stroke due to major artery occlusion of the brain to reduce DTP in January 2014. In this study, we evaluated the effects of this protocol change on the treatment of acute ischemic stroke at our hospital. Subjects and Methods The subjects were 633 patients transported to our hospital between January 2012 and May 2015 within 24 hours after they were last confirmed to be well. We conventionally used MRI for screening of patients suspected to have acute ischemic stroke but changed the treatment protocol for patients with major artery occlusion of the brain in January 2014. Before the protocol change, we evaluated the indication for intravenous thrombolysis with tpa by MRI, assessed the effectiveness of intravenous thrombolysis with tpa, and, in some patients, performed CT before endovascular treatment. After the protocol change, we abandoned these processes and referred patients suspected to have major artery occlusion to neurointerventionalists before MRI. If occlusion of a major artery of the brain was revealed by MRI, the new protocol prescribed implementation of intravenous thrombolysis with tpa with the decision to perform endovascular therapy, initiation of setup of the angiography suite, and implementation of endovascular treatment while continuing intravenous thrombolysis with tpa. The workflows before and after the protocol change are compared (Fig. 1). In this study, the effects of this protocol change on the treatment for acute ischemic stroke at our hospital were evaluated retrospectively. The items were the patient background, percentage of patients who underwent endovascular treatment, door-to-image time (DTI), door-to-needle time (DTN), OTR, DTP in endovascularly treated patients, endovascular device used, rate of Thrombolysis in Cerebral Infarction (TICI) 2b/3, presence or absence of symptomatic intracranial hemorrhage after treatment, and modified Rankin scale (mrs) score 90 days after the onset. If the time of onset is unclear as in wake-up stroke, endovascular treatment was performed by evaluating the indication based on images including T2-weighted fluid-attenuated inversion recovery (FLAIR), so we selected patients within 24 hours after they were last confirmed to be well as the subjects. In patients with unknown time of onset, OTR was evaluated by assuming the time when they were last confirmed to be well as the time of onset. Statistical analyses were carried out using GraphPad PRISM ver.5 (GraphPad Software, Inc., La Jolla, CA, USA). Age, National Institute of Health Stroke Scale (NIHSS) scores, and DTP were analyzed by the t-test, and other variables including the percentage of endovascularly treated patients were analyzed using Fisher s exact test, at the p <0.05 level of significance. 2

Reducing Time to Endovascular Therapy Table 1 Summary of the results characteristics Pre (n = 29) Jan 2012 Dec 2013 Post (n = 36) Jan 2014 May 2015 p value Age, median (IQR) 72 (66 83) 77 (68 83) 0.367 Male sex, no. (%) 18 (62) 16 (44.4) 0.14 Baseline NIHSS, median (IQR) 15 (11 20) 15 (9 20) 0.881 Prestroke mrs 0 2 no. (%) 29 (100) 32 (88.9) 0.122 DWI-ASPECTS 7 (6 9) 7 (6 9) 0.533 Combined IV tpa, no. (%) 11 (37.9) 15 (41.6) 0.803 Site of vessel occlusion, no. (%) ICA 6 (20.6) 9 (25) 0.772 MCA 18 (62) 19 (52.7) 0.614 Posterior circulation 5 (17.2) 8 (22.2) 0.758 Door to image time (min), median (IQR) 28 (22 35) 23 (16 31) 0.09 Door to needle time (min), median (IQR) 57 (51 57) 48 (43 55) 0.003 Door to puncture time (min), median (IQR) 108 (89 131) 78 (70 94) 0.003 IV tpa (+) 104 (91 150) 73 (69 95) 0.044 IV tpa (-) 108 (88 129) 83 (73 93) 0.039 Onset to revascularization time (min), median (IQR) 305 (251 381) 268 (227 380) 0.065 Endovascular techniques IA UK 11 0 Angioplasty 6 3 MERCI 2 0 Penumbra system 10 11 Stent retriever 0 22 TICI 2b + 3, no. (%) 11 (37.9) 26 (72.2) 0.011 mrs 0 2 at 90 days, no. (%) 18 (62) 18 (50) 0.452 Death at 90 days, no. (%) 2 (6.9) 2 (5.5) 0.879 DWI-ASPECTS: diffusion-weighted imaging-the Alberta Stroke Program Early Computed Tomography Score; IA UK: intraarterial urokinase injection; ICA: internal carotid artery; IQR: interquartile range; IV tpa: intravenous tissue plasminogen activator; MERCI: Mechanical Embolus Removal in Cerebral Ischemia; MCA: middle cerebral artery; mrs: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale; TICI: thrombolysis in cerebral infarction Results Thrombectomy procedures were performed in 34 (9.4%) of the 359 patients with acute ischemic stroke transported to our hospital within 24 hours after the onset before the protocol change (January 2012 December 2013) but in 41 (14.9%) of the 274 patients after the protocol change (January 2014 May 2015), showing a significant increase in the percentage of patients who underwent endovascular treatment (p = 0.03). By excluding those who did not undergo MRI at our hospital before endovascular treatment, 29 patients before the protocol change and 36 after the protocol change were compared. The results are summarized in Table 1. No significant difference was noted in the age, male/female ratio, NIHSS score on arrival, percentage of patients who received intravenous thrombolysis with tpa, and occluded vessels between before and after the protocol change. In no patient, endovascular treatment was cancelled due to complete recanalization during the preparation for endovascular treatment after the initiation of intravenous thrombolysis with tpa. Median DTP, which was the primary item of this study, was 108 and 78 minutes before and after the protocol change, respectively, showing shortening of 30 minutes (p = 0.003). When the patients were divided into those who received and those who did not receive intravenous thrombolysis with tpa, it was shortened by 31 and 25 minutes, respectively. DTI and DTN were shortened by 5 and 9 minutes, respectively. The rate of TICI 2b/3 recanalization was 37.9% before the protocol change but increased to 72.2% after the protocol change, but no significant difference was noted in the percentage of patients with a good outcome (mrs 0-2) 90 days after the onset. Discussion In this study, we changed the treatment protocol for patients with acute ischemic stroke suspected to be due to occlusion of a major artery to contacting neurointerventionalists before MRI, deciding to perform endovascular treatment during MRI, and starting the setup of the angiography suite. In addition, we decided to perform endovascular treatment before judgment of the effectiveness of intravenous thrombolysis with tpa. This change made it possible to promptly initiate endovascular treatment also in patients undergoing intravenous thrombolysis with tpa, reduced 3

Morofuji Y, et al. DTP by about 30 minutes, and increased the percentage of endovascularly treated patients. In treating acute ischemic stroke, it is important to shorten the time from the onset to reperfusion (ORT). In five recently reported clinical studies, also, the management policy was to confirm occlusion of major arteries and to shorten ORT, and favorable results were obtained. 2 6) Based on these results, the guidelines for endovascular treatment for acute ischemic stroke by the American Heart Association (AHA)/American Stroke Association (ASA) were revised. For patients with an indication for thrombectomy, the guidelines recommend intravenous thrombolysis with tpa and, if the occluded vessel is the internal carotid artery or M1 of the middle cerebral artery, endovascular treatment using a stent retriever is strongly recommended for lesions within 6 hours after the onset (Class I, Level of Evidence A). 7) Prior to this study, we attempted to shorten the time from onset to intravenous thrombolysis with tpa (DTN) 8) specifically by 1) introducing the stroke hotline, 2) speeding neurologic and simplifying examinations on the arrival at the emergency room, 3) preparing a stroke MRI protocol, and 4) nurse-initiated intravenous thrombolysis with tpa. By introducing the stroke hotline, it became possible to consider the possibility of intravenous thrombolysis with tpa/endovascular treatment at the point when the stroke physician is contacted or examines the patient and to request support to the endovascular treatment team. According to a report from abroad, where the care system differs from Japan, early consultation with the endovascular treatment team resulted in shortening of DTP by a median of 36 minutes. 9) They sought to shorten the time by simultaneously performing the body weight measurement, blood collection, securing of the intravenous route, and examination by a stroke doctor and emergency nurses after the arrival of the patient at the emergency department before MRI and postponing examinations including Electrocardiogram (ECG) and chest radiography. A study of intravenous thrombolysis with tpa reported that DTP could be shortened by 6 and 13 minutes by omitting ECG and chest radiography, respectively. 10) According to the stroke, MRI protocol of our hospital, DWI, 3D time-of-flight MRA, FLAIR, T2 star-weighted MR angiography (SWAN), and 3D arterial spin labeling (ASL) perfusion imaging are performed in this order, and the total time of imaging studies is about 20 minutes. Since only radiology technicians who can comply with this protocol are allowed to be on duty, the system ensures that imaging examinations can be performed without delay even during the night and on holidays. In this study, shortening of not only DTP but also DTI and DTN was observed, and this is considered to be based on our efforts established and developed at our hospital to shorten DTN in intravenous thrombolysis with tpa. The nurses, radiology technicians, laboratory technicians, and office workers as well as doctors have sufficient understanding of the importance of early recanalization in treating acute ischemic stroke, and their cooperation is also considered to have contributed to shortening of DTP in thrombectomy therapy. Moreover, in this study, the percentage of endovascularly treated patients in all acute ischemic stroke patients increased from 9.4% to 14.9% after the protocol change by deciding to perform endovascular treatment early after arrival. This may be explained by the early involvement of neurointerventionalists in addition to the improvement in the hospital system and awareness of the staff. Furthermore, a high recanalization rate (TICI 2b/3: 72.2%) was obtained after the protocol change, but this is not considered to be a result of the protocol change because stent retrievers became available at our hospital after the protocol change. However, while patients who underwent endovascular treatment increased, DTP was shortened, and the recanalization rate improved, no significant difference was observed in the percentage of patients with a good outcome after 90 days between the two groups. This may have been a result of a high recanalization rate due to the advent of the stent retriever and consequent widening of the range of its application. After the protocol change, we aggressively performed endovascular treatment even in recurrent ischemic stroke patients originally with neurologic deficits, such as paresis and patients with cancer, who included 4 in whom the baseline mrs score was 3-4. This resulted in satisfactory recanalization rate but poor outcome after 90 days in some patients. Our study has several limitations. It was a single-center retrospective study involving a small number of patients. In addition, the available thrombectomy devices changed during the study period. As new intracranial thrombectomy devices are expected to appear, the importance of establishing a hospital care system and preparing a treatment protocol to shorten OTR and increase patients with a favorable outcome is considered to increase further. Conclusion In patients with acute ischemic stroke suspected major artery occlusion, DTP could be reduced by 30 minutes by 4

Reducing Time to Endovascular Therapy contacting neurointerventionalists before MRI and deciding to perform endovascular treatment and starting the setup angiography suite early during MRI. It is important that all members of the staff involved in stroke management to recognize the importance of recanalization therapy for acute ischemic stroke and to cooperate systematically. Acknowledgments The authors express their sincere gratitude to the nurses of the neurosurgery and neurology departments, radiology technicians, and laboratory technicians of the emergency medical center and stroke care unit, and all members of the hospital staff for their generous cooperation in conducting this study. Disclosure Statement Neither the first author nor any of the co-authors have any conflicts of interest. References 1) Saqqur M, Uchino K, Demchuk AM, et al: Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke 2007; 38: 948 954. 2) Berkhemer OA, Fransen PS, Beumer D, et al: A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372: 11 20. 3) Campbell BC, Mitchell PJ, Kleinig TJ, et al: Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372: 1009 1018. 4) Goyal M, Demchuk AM, Menon BK, et al: Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372: 1019 1030. 5) Saver JL, Goyal M, Bonafe A, et al: Stent-retriever thrombectomy after intravenous t-pa vs. t-pa alone in stroke. N Engl J Med 2015; 372: 2285 2295. 6) Jovin TG, Chamorro A, Cobo E, et al: Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015; 372: 2296 2306. 7) Powers WJ, Derdeyn CP, Biller J, et al: 2015 American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015; 46: 3020 3035. 8) Tateishi Y, Kanamoto T, Nakaoka K, et al: A stroke code and cooperation between doctors and nurses could reduce door-to-needle time for acute ischemic stroke. Jpn J Stroke 2017 March 01. doi.org/10.3995/jstroke.10493 [Epub ahead of print] (in Japanese) 9) Mehta BP, Leslie-Mazwi TM, Chandra RV, et al: Reducing door-to-puncture times for intra-arterial stroke therapy: a pilot quality improvement project. J Am Heart Assoc 2014; 3: e000963. 10) Schrock JW, Lum M: Drill down analysis of door-to-needle time of acute ischemic stroke patients treated with intravenous tissue plasminogen activator. Am J Emerg Med 2014; 32: 1330 1333. 5