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MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY DAO VIET PHUONG RESEARCH ON TREATMENT OF PROXIMAL ARTERIAL OCCLUSION OF THE ANTERIOR CEREBRAL CIRCULATION SYSTEM WITHIN THE FIRST 6 HOURS WITH INTRAVENOUS THROMBOLYTIC COMBINED WITH MECHANICAL THROMBECTOMY Major : Emergency and Clinical Toxicology Code number : 62720122 SUMMARY OF MEDICAL DOCTORAL THESIS HANOI - 2019 THE WORK HAS BEEN COMPLETED AT HANOI MEDICAL UNIVERSITY Academic Supervisor: 1. Assoc. Prof. PhD. NGUYEN VAN CHI 2. Assoc. Prof. PhD VU DANG LUU Opponent 1: Assoc. Prof. PhD. Mai Xuan Hien Opponent 2: Assoc. Prof. PhD. Le Thi Viet Hoa Opponent 3: Assoc. Prof. PhD. Nguyen Van Lieu The thesis has been defended at University-level Thesis Evaluation Council held in Hanoi Medical University At hour , date month year 2019. This thesis may be found at: - National Library - Library of Hanoi Medical University LIST OF ANNOUNCED RESEARCHS OF AUTHOR RELATED TO THE THESIS 1. Dao Viet Phuong, Nguyen Van Chi (2016), “Combine therapy of intravenous thrombolytic with mechanical arterial thrombectomy in acute ischemic stroke”. Vietnam Medicine Journal, 449 (02) 2/2016, p. 81-85. 2. Dao Viet Phuong, Nguyen Van Chi, Vu Dang Luu (2019), “Factors affecting treatment results for acute ischemic stroke due to proximal arterial occlusion”. Vietnam Medicine Journal, 476 (01&02) 3/2019, p. 156-160. 3. Dao Viet Phuong, Nguyen Van Chi, Vu Dang Luu (2019), “Combined therapy low-dose thrombolysis with mechanical thrombectomy in patient with acute ischemic stroke”. Vietnam Medicine Journal, 480 (01&02) 7/2019, p. 199-203. 1 INTRODUCTION Stroke due to proximal arterial occlusion of the anterior cerebral circulation system has a very high mortality and disability rate, possibly up to 60-80% in patients with simple internal carotid artery occlusion or in combination with the middle cerebral artery. Therefore, revascularization treatment in the acute phase is the most important treatment to reduce mortality and sequelae. Revascularization after acute ischemic stroke is associated with improved clinical outcomes as well as reduced mortality. A meta-analysis of 53 studies in more than 2000 patients showed a close association between the rate of cerebral revascularization and the improvement in clinical outcome after three months compared to the non-revascularization group (odds ratio OR 4.43, 95% confidence interval CI 3.32 - 5.91). Currently, most hospitals could perform treatment technique using intravenous thrombolytic agents for stroke patients with anterior cerebral circulation occlusion in the window 4.5 hours after the onset of symptoms, however the effect has not been significant in these patients, for example revascularization with carotid artery occlusion below 10%, occlusion of the middle cerebral artery in the middle of M1 is 30%, occlusion of M2 is 42% ... Therefore, it is necessary to have more treatment methods for cerebral revascularization even though the patients have been used with thrombolytic agents. Therefore, endovascular intervention to take away thrombosis is very important, for patients who have not yet been revascularized. Another problem is that in Western countries, using the standard dose of thrombolytic agents is combined with thrombectomy. In Vietnam, especially in Bach Mai hospital, using low dose of thrombolytic agents 0.6 mg/kg is becoming regular protocol, so how to access this combination? How is the effective of method? That are the questions need to be studied. On the other hand, 2 this combination treatment used to be performed only when treatment using intravenous thrombolytic agent failed, thus delaying the cerebral re-vascular process, so the combination intravenous thrombolytic agent with endovascular intervention will help to revascularize faster and more effectively. Therefore, we conducted the study "Research on treatment of proximal arterial occlusion of the anterior cerebral circulation system within the first 6 hours with intravenous thrombolytic combined with mechanical thrombectomy" in order to achieve the following two objectives: 1. Evaluate the results and some complications of treatment for acute ischemic stroke due to proximal arterial occlusion of the anterior cerebral circulation in the first 6 hours by intravenous thrombolytic combined with mechanical thrombectomy. 2. Comment on some factors affecting the effectiveness of treatment and the treatment protocol used in the study. Organization of the study: Thesis includes 155 pages with 3 introduction pages, 43 literature review pages, 26 pages of scope of study and study method, 32 result pages, 46 discussion pages, 3 conclusion pages and 1 proposal page, 1 limitation page. Reference: 167 documents. New contributions of the thesis: The thesis has shown good results both in clinical and medical image of the combination treatment of intravenous thrombolytic agent dose of 0.6 mg/kg with endovascular intervention in the first 6 hours in patients with acute ischemic stroke due to proximal arterial occlusion of the anterior cerebral vessels. The thesis also points out some complications, factors effecting outcome and aligns emergency procedure and treatment procedure by above combination methods. 3 CHAPTER 1. LITERATURE REVIEW 1.1. Cerebral revascularization method 1.1.1. IV rtPA In the 1990s, the National Institute of Stroke and Neurology (NINDS) conducted a randomized clinical trial comparing IV rtPA and placebo, including 624 patients with ischemic stroke for 3 first hours. The rate of good neurological recovery (mRS 0 - 1) within 3 months (42.6% for IV rtPA compared with 26.6% for placebo (P <0.01); NNT 6. The risk of symptomatic intracerebral hemorrhage of IV rtPA has increased (6.4% for IV rtPA compared with 0.6% for placebo, p < 0.001), the benefit of thrombolytic therapy is higher than the risk. Therefore, the US Food and Drug Administration (FDA) has approved IV rtPA for treatment of patients with acute ischemic stroke in the first 3 hours. A follow-up clinical trial conducted in Europe on 821 stroke patients within the first 3 to 4.5 hours, age under 80, also showed benefits of IV rtPA, however its efficacy is lower (mRS 0-1: 52.4% for IV rtPA compared with 45.2% for placebo, p = 0.04; NNTB, 14). The results of these studies confirmed IV rtPA is the standard treatment for stroke patients in the first 4.5 hours.  Background of low-dose intravenous Alteplase 0.6 mg/kg in patients with acute ischemic stroke: In Japan with the initial trial J-ACT (Japan Alteplase Clinical) 103 patients who were diagnosed with acute cerebral infarction within the first 3 hours were treated with intravenous Alteplase at a dose of 0.6 mg/kg. The results showed that 36.9% of patients had a good level of recovery (mRS score 0-1), while symptomatic 4 intracerebral hemorrhage was 5.8%. Since this study, the Ministry of Health of Japan has approved the use of Alteplase at a dose of 0.6 mg/kg to treat patients with acute ischemic stroke within the first 3 hours. The J-ACT II trial, with 58 patients with acute ischemic stroke within the first 3 hours of middle cerebral artery occlusion being treated with intravenous Alteplase, resulted in: revascularization is 69% and good clinical recovery after three months is 46.6%; especially, there is no patient with symptomatic intracerebral hemorrhage complication. 1.1.2. Endovascular Intervention Endovascular intervention for acute ischemic stroke patients has been known since the 1980s. Since then, endovascular interventions for patients with acute ischemic stroke have made significant progress, from the use of arterial thrombolytic agents to first generation arterial thrombectomy devices (Merci, Penumbra ...) and recently second generation mechanical thrombectomy devices (Solitaire, Trevo). Based on whether or not it is combined with IV rtPA, at the time of intervention after IV rtPA treatment, it is divided into three groups:  Primary endovascular intervention Primary intravascular intervention (first-line vascular intervention) is a stroke patient with proximal arterial occlusion who is treated immediately by endovascular intervention without combining intravenous thrombolytic treatment. In routine practice, 5 endovascular intervention is usually conducted in stroke patients in windows 4.5 - 6 hours, patients with contraindications to intravenous thrombolytic agents such as underpass surgery recently, using anticoagulants with INR > 1.7 ...  Rescue therapy Patients with ischemic stroke due to proximal arterial occlusion within 4.5 hours were treated with IV rt-PA. Neurologist are ready when the patient does not respond to IV rt-PA. After 60 minutes of IV rt-PA, the patient was reassessed. If the NIHSS score above 8 or the patient still has serious neurological defects, then it is considered a failure of IV rt-PA. At this time, endovascular thrombectomy is carried out immediately.  Combine therapy Patients with ischemic stroke due to proximal arterial occlusion within 4.5 hours is treated with IV rt-PA. Endovascular thrombectomy will be combined when intervention room is ready. In contrast to rescue therapy, in combined therapy, patients do not need to wait 60 minutes to re-evaluate whether there is a response to treatment of IV rt-PA or not, and IV rt-PA continue to be delivered during endovascular thrombectomy. With the objective "time is brain", while IV rt-PA in the first 4.5 hours is considered a standard treatment, for patients with proximal arterial occlusion, endovascular thrombectomy is also recommended early to shorten time to revascularize. Therefore, in most stroke centers, the procedure for treating ischemic stroke patients with proximal arterial occlusion is combine therapy (IV rt-PA as soon as possible, immediately afterwards conduct integrated endovascular thrombectomy as soon as the intervention room is ready). 6 Currently in clinical practice at Bach Mai Hospital as well as the guidelines of the American Heart Association/American Stroke Association (AHA/ASA), the European Stroke Organization (ESO) is all ischemic stroke patients with proximal arterial occlusion are treated with combine therapy (endovascular thrombectomy is performed immediately after IV rt-PA). 1.1.3. Studies about endovascular thrombectomy Based on the successful results of the following studies, the authors aligned on the efficacy of IV rt-PA in combination with mechanical thrombectomy in ischemic stroke patients with proximal arterial occlusion, as well as combine therapy is recommended that increases the rate of revascularization and shortening the time from stroke to revascularization. Studies combined IV rt-PA dose 0.9 mg/kg with mechanical thrombectomy Author/ mRS Study 0-2 Criteria Mean Standard of NIHSS NIHSS EXTENDIA 71% score No limitation score 15 of % IV rt- ReperfASPECT PA usion treatment time No data 100% 248 9 87% >260 ASPECT No limitation No ≥2 18 53% ≥6 17 ≥6 9 76% 241 60% ≥8 17 ≥6 9 100% 252 REVASCAT 44% ≥6 17 ≥6 7 73% 355 MR CLEAN 33% ESCAPE SWIFT PRIM limitation 7  Studies of bridging therapy that combines low dose of IV rtPA (0.6 mg/kg) with mechanical thrombectomy Until now, there are very few studies announcing results of combined treatment between low-dose IV rt-PA (0.6 mg/kg) with mechanical thrombectomy. In particular, there is no randomized double-blind studies compared the efficacy between low dose and standard doses when combined with endovascular thrombectomy. Kim et al. conducted the trial compare efficacy of low dose and standard dose when combination with endovascular thrombectomy in bridging therapy. The trial was conducted in 12 centers of South Korea, the total number of patients was 361, but only 33 standard-dose patients and 34 low-dose patients were treated by bridging therapy with endovascular thrombectomy. The rate of reperfusion between 2 groups was not different, this rate in the standard dose group and low dose group was 76% and 85% respectively, p = 0.324. There were no differences in neurological recovery outcomes (mRS 0-1) between standard and low dose groups, respectively 39% and 21%, odds ratio OR 2.39, 95% confidence interval CI 0.73 - 7.78, p = 0.149. The study did not show the difference in neurological recovery outcomes between standard and low doses when using bridging therapy. Lin et al. compare clinical outcomes of low dose and standard dose in bridging therapy, trial was conducted in Taiwan from 2015 to 2017, included 42 patients, of which 13 patients used low doses and 29 patients used standard doses. There is no difference in rate of