Summary of doctoral thesis in medicine: 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

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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.

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Nội dung Text: Summary of doctoral thesis in medicine: 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

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
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 Criteria Mean Standard % IV rt- Reperf- Author/ mRS of NIHSS NIHSS of ASPECT PA usion Study 0-2 score score ASPECT treatment time EXTEND- No No 71% 15 No data 100% 248 IA limitation limitation No MR CLEAN 33% ≥2 18 9 87% >260 limitation ESCAPE 53% ≥6 17 ≥6 9 76% 241 SWIFT 60% ≥8 17 ≥6 9 100% 252 PRIM REVASCAT 44% ≥6 17 ≥6 7 73% 355
7  Studies of bridging therapy that combines low dose of IV rt- PA (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
8 mortality between low dose and standard dose groups, 0% vs. 3.4% respectively, p = 1. There is similar neurological recovery rate (mRS 0-2) between low dose group and standard dose groups, 33.3% vs. 44.8%, p = 0.50), the rates of symptomatic intracerebral hemorrhage were lower in low dose groups but there is no statistic difference (low dose vs. standard dose, 0% vs. 6.9%, p =1). Based on results of this trial, authors showed when compared to standard dose treatment, low dose thrombolytic agent may have similar clinical efficacy and safety outcomes in bridging therapy. Through the above study results, there is currently not enough data on optimal dose of thrombolytic agent in bridging therapy, some evidence indicated that low doses provide similar efficacy and tend to reduce the rate of hemorrhage complications compared to standard doses. We need to expect for the results of larger and further studies to find the optimal dose of thrombolytic agent when combined with endovascular thrombectomy. CHAPTER 2. SUBJECT AND METHOD OF THE STUDY 2.1. Location of the study Emergency Department – Bach Mai Hospital, from February 2015 to July 2018. Bach Mai Radiology Center – Bach Mai Hospital. 2.2. Subject of the study 2.2.1. Criteria to select patients
9 The patients were selected to study when all the following criteria were met: - Age of patients were above 18 - The onset of stroke symptoms clearly less than 270 minutes before taking Alteplase; less than 360 minutes when thrombectomy finished. - The diagnosis of acute ischemic stroke with clear and quantitative neurological deficiencies based on the NIHSS score ≥ 6. - Images: internal carotid artery occlusion and/or the middle cerebral artery occlusion with ASPECT ≥ 6. - Patient’s family members and/or patient agree to use the preparation. 2.2.2. Patient exclusion criteria a) There are contraindications for intravenous Alteplase administration (see annex). b) Other exclusion criteria for patient underwent combined mechanical thrombectomy: - Patient has mRS score before stroke ≥ 2. - The time from using Alteplase to femoral puncture > 60 minutes. - Could not access to the femoral artery. - Patients with severe allergies to contrast medication. - Patients with end-stage chronic pathology cannot complete follow-up after treatment. - Pregnant women.
10 2.3. Method of the study 2.3.1. Method of the study According to the intervention research method, before and after comparison, there is no control group. 2.3.2. Sample size of the study We calculated the sample size for the study based on the following formula: Included: - Z1-α/2: desired reliability = 1.96 (α = 0.05). - Z1-β = 0,842 (Sample strength 80%). - P: percentage of patients with good results after treatment: P = (P1 + P2)/2. - P1: the proportion of patients with internal carotid artery occlusion, middle cerebral artery occlusion with good results at 90 days (mRS 0 - 2) if only treatment of intravenous thrombolytic according to SWIFT PRIME study, has a ratio of 35%. - P2: the percentage of patients expected to have good results when treated with Alteplase combined with artery thrombectomy, this rate is expected to be 60%. Apply to the formula, we have: n = 62. However, we estimated about 20% of patients to withdraw from the study or lose follow up tracking. Therefore, the minimum patient sample size in the study is estimated to be 75 patients.
11 Process of diagnosis and treatment of acute stroke patients (≤ 6h) Patient has onset of stroke No enough Remove from ≤ 4.5 h condition study - History, medical history - Start stroke chain - Evaluate CT, NIHSS Brain MSCT/ MRI Cerebral Remove from Hemorrhage study No cerebral hemorrhage, No enough Remove from ASPECT ≥ 6 condition study Contraindication to Remove from rtPA study (Will access Evaluate rtPA Criteria standard for 1st phase thrombectomy) - Meet rtPA Criteria - rtPA 0.6 mg/kg - MSCT occlusive vessel M1 MCA, ICA No enough Remove from the - ASPECT ≥ 6 condition study - NIHSS ≥ 6 Mechanical Thrombectomy No enough (Time from using condition Remove from the Alteplase to study thrombectomy ≤ 60 minutes) Evaluate and follow up at Emergency Department
12 CHAPTER 3. RESULTS The study was conducted on 86 patients with acute ischemic stroke due to proximal arterial occlusion of anterior cerebral circulation, which met the criteria of selection, did not violate any of the criteria for exclusion and admission at the Emergency Department - Bach Mai Hospital. The results as below: 3.1. General characteristic Table 3.1. Clinical characteristic Clinical characteristic Index Age 61.9 ± 11.8 Glasgow median 14 (8-15) Heart rate (pulse/minute) 85.7 ± 18.1 Systolic blood pressure (mmHg) 135 NIHSS median 15.5 (8 - 24) ASPECTS median 8 (6 - 10) Blood Glucose (mmol/L) 7.54 ± 2.69 Platelet (G/L) 233.2 ± 6.8 INR 1.01 ± 0.15 Internal carotid artery occlusion 20/86 (23.3%) Combined internal carotid artery occlusion 16/86 (18.6%) with middle cerebral artery occlusion M1 middle cerebral artery occlusion 50/86 (58.1%) Atrial fibrillation 24/86 (27.9%)
13 3.2. Assessment of the results of IV rt-PA therapy combined with thrombectomy 3.2.1. Clinical outcome according to mRS scale distribution at 90 days. General 15.12 38.37 16.28 15.12 9.32.333.49 Tandem 6.25 31.25 25 6.25 25 6.25 0 ICA 25 35 5 35 0 Middle cerebral artery 14 42 18 10 8 2 6 0% 20% 40% 60% 80% 100% 0 score 1 score 2 score 3 score 4 score 5 score 6 score Chart 3.1. Distribution of modified Rankin score Comment: The rate of clinical recovery was good, calculated according to the modified Rankin score of 0-2 at 90 days was 69.8% (60 patients out of 86 patients). Mortality rate (corresponding to mRS = 6) at 90 days, accounting for 3.49%. 3.2.2. Change NIHSS score
14 Table 3.2. Evolution of NIHSS scores in 24 hours Middle Internal carotid Internal cerebral artery and carotid artery General (n=86) artery middle cerebral (n=20) p* (n=50) artery (n=16) Median Median (min, Median (min, Median (min, (min, max) max) max) max) NIHSS score – admitted to 15 (8, 23) 16 (10, 22) 18.5 (11, 24) 15.5 (8, 24) 0.213 hospital NIHSS score 7 (0, 35) 6 (0, 23) 14.5 (3, 30) 7 (0, 35) 0.047 - 24h p¶ < 0.05 < 0.05 0.030 < 0.05 NIHSS score decrease above 8 28 (56%) 14 (70%) 6 (37.5%) 48 (55.81%) < 0.05 NIHSS score decrease under 8 22 (44%) 6 (30%) 10 (62.5%) 38 (44.19%) *: Kruskal Wallis test, ¶: Wilcoxon Sign Rank test 3.2.3. Reperfusion rate after intervention according to TICI scale 1-, 1.16 0-, 1.16 2a, 6.98 3-, 52.33 2b, 38.37 Chart 3.2. Reperfusion grade according to TICI score
15 3.2.4. The rate of hemorrhagic transformation Table 3.3. The rate of hemorrhagic transformation Asymptomatic Symptomatic hemorrhagic hemorrhagic General transformation transformation HI 1 7 (8.1%) 0 (0%) 7 (8.1%) HI 2 7 (8.1%) 0 (0%) 7 (8.1%) PH 1 6 (7%) 0 (0%) 6 (7%) PH 2 0 (0%) 4 (4.7%) 4 (4.7%) Subarachnoid 0 (0%) 1 (1.1%) 1 (1.1%) hemorrhage Total 20 (23.2%) 5 (5.8%) 25 (29%) Fisher 3.3. The factors affecting clinical outcomes and treatment procedure 3.3.1. Classification of clinical outcomes according to NIHSS score at hospitalization Table 3.4. mRS 0-2 classification (90 days) according to NIHSS score NIHSS ≤ 16 NIHSS > 16 General p mRS 0 - 2 38 (79.17%) 22 (57.89%) 60 (69.77%) 0.03 mRS 3 - 6 10 (20.83%) 16 (42.11%) 26 (30.23%) Chi2
16 3.3.2. Effect of NIHSS change to clinical outcome Table 3.5. NIHSS change affect to clinical outcome mRS 0 - 2 mRS 3 - 6 General p NIHSS decrease above 8 43 (71.7%) 5 (19.2%) 48 (55.8%) < 0.05 NIHSS decrease under 8 17 (28.3%) 21 (80.8%) 38 (44.2%) Total 60 (100%) 26 (100%) 86 (100%) Chi2 test 3.3.3. Effect of bleeding complication to clinical outcome Table 3.6. Bleeding complication affect to clinical outcome Clinical outcome after 90 days CI (95%) OR p mRS 0 - 2 mRS 3 - 6 Chung lower upper Without 16 61 hemorrhagic 45 (75%) 1 1 1 (61.54%) (70.93%) transformation Asymptomatic 14 6 20 hemorrhagic 1.2054 0.3958 3.6707 0.742 (23.33%) (23.08%) (23.26%) transformation Symptomatic 4 hemorrhagic 1 (1.67%) 5 (5.81%) 11.25 1.1688 108.2797 0.036 (15.38%) transformation Total 60 (100%) 26 (100%) 86 (100%)
17 3.3.4. The factors affecting to clinical outcome Table 3.7. The factors affecting to clinical outcome of patient CI Factors OR p lower upper Middle cerebral - - - - artery* Internal carotid Occlusion 1.500 0.351 6.412 0.584 artery location Internal carotid artery & middle 0.504 0.103 2.461 0.397 cerebral artery Early hospital admission (under 2 0.439 0.119 1.619 0.216 hours) Late reperfusion (after 4 hours) 6.606 0.093 46.884 0.049 Blood glucose at hospital admission 0.898 0.651 1.238 0.511 ASPECTS ≤ 7 1.161 0.690 1.953 0.574 Non hemorrhage* - - - - Asymptomatic 1.442 0.356 5.852 0.608 Hemorrhage hemorrhage Symptomatic 574.40 33.611 1.967 0.015 hemorrhage 7 Under 30 minutes* - - - - Intervention 30 to 60 minutes 0.526 0.092 3.025 0.472 time Above 60 minutes 1.473 0.171 12.654 0.724 6 to 12* - - - - NIHSS score 12 to 16 2.134 0.370 12.315 0.397 at hospital 16 to 20 7.901 1.243 50.232 0.028 admission 149.16 15.092 1.527 0.020 20 to 24 1 Age 1.020 0.970 1.072 0.450 Gender 1.239 0.356 4.317 0.736