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.
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 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: Assoc Prof PhD NGUYEN VAN CHI 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 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 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 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 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, 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 hours with intravenous thrombolytic combined with mechanical thrombectomy" in order to achieve the following two objectives: 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 hours by intravenous thrombolytic combined with mechanical thrombectomy 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 introduction pages, 43 literature review pages, 26 pages of scope of study and study method, 32 result pages, 46 discussion pages, conclusion pages and proposal page, 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 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 CHAPTER 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 first hours The rate of good neurological recovery (mRS - 1) within months (42.6% for IV rtPA compared with 26.6% for placebo (P 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 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 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) 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 87% >260 ASPECT No limitation No ≥2 18 53% ≥6 17 ≥6 76% 241 60% ≥8 17 ≥6 100% 252 REVASCAT 44% ≥6 17 ≥6 73% 355 MR CLEAN 33% ESCAPE SWIFT PRIM limitation 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 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 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 - 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 No cerebral hemorrhage, ASPECT ≥ Cerebral Hemorrhage Remove from study No enough condition Remove from study Contraindication to rtPA Remove from study (Will access standard for 1st phase thrombectomy) No enough condition Remove from the study Evaluate rtPA Criteria - Meet rtPA Criteria - rtPA 0.6 mg/kg - MSCT occlusive vessel M1 MCA, ICA - ASPECT ≥ - NIHSS ≥ Mechanical Thrombectomy (Time from Alteplase thrombectomy minutes) using to ≤ 60 Evaluate and follow up at Emergency Department No enough condition Remove from the study 12 CHAPTER 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 Age Glasgow median Heart rate (pulse/minute) Systolic blood pressure (mmHg) NIHSS median ASPECTS median Index 61.9 ± 11.8 14 (8-15) 85.7 ± 18.1 135 15.5 (8 - 24) (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 with middle cerebral artery occlusion 16/86 (18.6%) 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 25 31.25 Tandem 6.25 35 25 ICA 42 14 Middle cerebral artery 0% 16.28 15.12 9.32.333.49 38.37 15.12 General 20% 40% score score score score score score 6.25 25 6.25 35 10 18 60% 80% 100% 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 General (n=86) carotid artery artery middle cerebral (n=20) (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) hospital NIHSS score (0, 35) (0, 23) 14.5 (3, 30) (0, 35) - 24h p¶ < 0.05 < 0.05 0.030 < 0.05 NIHSS score decrease above 28 (56%) 14 (70%) (37.5%) 48 (55.81%) NIHSS score decrease 22 (44%) (30%) 10 (62.5%) 38 (44.19%) under *: Kruskal Wallis test, ¶: Wilcoxon Sign Rank test p* 0.213 0.047 < 0.05 3.2.3 Reperfusion rate after intervention according to TICI scale 0-, 1.16 3-, 52.33 1-, 1.16 2a, 6.98 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 hemorrhagic transformation Symptomatic hemorrhagic transformation General HI (8.1%) (0%) (8.1%) HI (8.1%) (0%) (8.1%) PH (7%) (0%) (7%) PH (0%) (4.7%) (4.7%) Subarachnoid hemorrhage (0%) (1.1%) (1.1%) 20 (23.2%) (5.8%) 25 (29%) Total 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 mRS - 38 (79.17%) 22 (57.89%) 60 (69.77%) mRS - 10 (20.83%) 16 (42.11%) 26 (30.23%) Chi2 p 0.03 16 3.3.2 Effect of NIHSS change to clinical outcome Table 3.5 NIHSS change affect to clinical outcome mRS - mRS - General NIHSS decrease above 43 (71.7%) (19.2%) 48 (55.8%) NIHSS decrease under 17 (28.3%) 21 (80.8%) 38 (44.2%) Total 26 (100%) 86 (100%) 60 (100%) p < 0.05 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 mRS - mRS - Chung Without hemorrhagic transformation 45 (75%) 16 (61.54%) 61 (70.93%) Asymptomatic hemorrhagic transformation 14 (23.33%) (23.08%) 20 (23.26%) Symptomatic hemorrhagic transformation (1.67%) (5.81%) (15.38%) Total 60 (100%) 26 (100%) 86 (100%) p lower upper 1 1.2054 0.3958 11.25 3.6707 0.742 1.1688 108.2797 0.036 17 3.3.4 The factors affecting to clinical outcome Table 3.7 The factors affecting to clinical outcome of patient CI p Factors OR 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 0.439 0.119 1.619 0.216 hours) Late reperfusion (after hours) 6.606 0.093 46.884 0.049 Blood glucose at hospital admission 0.898 0.651 1.238 0.511 ASPECTS ≤ 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 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 to 12* 2.134 0.370 12.315 0.397 NIHSS score 12 to 16 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 Age 1.020 0.970 1.072 0.450 Gender 1.239 0.356 4.317 0.736 18 CHAPTER DISCUSSION 4.1 General characteristic of patient in the study The average age in our study was 61.9 ± 11.8 Compared to some international studies, our patients have a lower average age, such as in MR CLEAN study of Berkhemer et al average age of intervention group was 65.8, in ESCAPE study of Goyal et al age of intervention group was 71 In our study, the median NIHSS score at hospital admission was 15.5, with the highest being 24 and the lowest being Our median NIHSS score is similar to EXTEND IA study with a NIHSS score of 15 and lower than MR CLEAN study (NIHSS 18), ESCAPE study (NIHSS 17), SWIFT PRIME study (NIHSS 17) and REVASCAT study (NIHSS 17) In the above studies, there were two studies, EXTEND IA and SWIFT PRIME, which were two studies that the intervention group took mechanical thrombectomy with the ratio of 100% previous treatment of thrombolytic In our study, there were 24 patients (27.9%) with atrial fibrillation on the electrocardiogram, this result is similar to the results of MR CLEAN study with atrial fibrillation was 28.3%, less than SWIFT PRIME study was 39%, ESCAPE study was 37% Our results may be because we probably ignore patients with paroxysmal atrial fibrillation To overcome this, 24-hour, 72-hour, or even longer electrocardiographic Holter may be useful in detecting patients with paroxysmal atrial fibrillation 19 4.2 Result and some complications of combined treatment of IV thrombolytic alteplase with mechanical arterial thrombectomy Clinical outcome according to mRS scale distribution at 90 days In the 86 patients studied, 60 patients with a modified Rankin score on the 90th day were 0-2, accounting for 69.8% Our results are higher than the rate of clinical recovery based on a modified Rankin scale of 0-2 at 90 days of intervention group of Nguyen Hoang Ngoc et al was 58.7%, Nguyen Quang Anh was 66.7%, MR CLEAN study was 33%, ESCAPE study was 53%, SWIFT PRIME study was 60%, REVASCA was 44% and equivalent to EXTEND IA was 71% The following reasons suggest that the clinical recovery rate in our study is as high as the EXTEND IA study, and higher than other studies: (1) short intervention & reperfusion time, (2) NIHSS score at hospital admission, (3) ASPECT score, (4) rate of thrombolytic treatment, (5) degree of reperfusion after intervention Change of NIHSS score after 24 hours At 24 hours: the median NIHSS score was 7, the highest 35, the lowest 0, and the 24-hour NIHSS score is significantly lower than the NIHSS score at hospital admission with p < 0.05 Our result is equivalent to the result of the ESCAPE study when median 24-hour NIHSS score was 7, and lower than the MR CLEAN study was 13 The rate of early neurological recovery in our study, with the criterion is that NIHSS score decrease about points in 48 patients, accounted for 55.8% NIHSS score decrease about points used to 20 evaluate early neurological improvement in recent vascular intervention studies, this ratio in the EXTEND IA study was 80% In our study, improving the 24-hour NIHSS score used is a criterion for evaluating short-term results The above results show that combination treatment of low dose thrombolytic with vascular intervention improved 24-hour NIHSS scores compared to hospital admission, this difference was statistically significant Evaluation of cerebral reperfusion degree according to TICI scale Results of the reperfusion rate in our study with a successful reperfusion rate of TICI 2b-3 reached 91%, of which the rate of TICI was 52%, TICI 2b: 39%, only patients (9%) achieved the reperfusion rate TICI 0-2a, of which patient (1.2%) TICI 0, patient (1.2%) TICI 1, patients (6.9%) TICI 2a Our results were also higher than the MR CLEAN study 58%, the ESCAPE study was 72%, the REVASCAT study was 66%, these were the studies that showed the benefit of vascular intervention compared with standard medical treatment, however, the intervention group of studies had only rate of using thrombolytic was 70-80% Our results were equivalent to the reperfusion rate in the SWIFT PRIME study was 88% and EXTEND IA study was 94% A point of interest in this intervention group with high reperfusion rate, besides using 2nd generation thrombectomy, 100% patients were used intravenous thrombolytic before intervention, similar to combination treatment of thrombolytic and thrombectomy in our study Especially, the combination of thrombolytic with a dose of 0.6 mg/kg 21 with endovascular intervention, gives the rate of reperfusion equivalent to the published studies using a thrombolytic dose of 0.9 mg/kg combine with endovascular intervention Rate of hemorrhagic transformation and symptomatic hemorrhagic transformation Of the 86 patients studied, 25 patients had hemorrhagic transformation of different types according to ECASS III classification, accounting for 29% Our results were higher than the results of the Revascat study when the rate of hemorrhagic transformation was 21.4% Our higher rates can be explained because after 24 hours we used cranial MRI to assess injury of patients, that could increase the incidence of hemorrhagic transformation complications, especially HI form was hemorrhagic transformation that it was more difficult to detect on CT than on MRI Our results were similar to those of Arimura when using MRI to assess hemorrhagic transformation complications in 157 vascular intervention patients, the rate of hemorrhagic transformation accounted for 36.3%, however the rate of symptomatic hemorrhagic transformation in this study only accounted for 4.5% Notably in our results, symptomatic hemorrhagic transformation rates occurred in patients, accounting for 5.8% In these patients, there were patients with hemorrhagic transformation PH and patient with subarachnoid hemorrhage Our rate of symptomatic hemorrhagic transformation is lower than MR CLEAN study, which was 7.7%, but higher than the results of the ESCAPE study of 3.6% REVASCAT study was 2% These were 22 studies that combined thrombolytic 0.9 mg/kg with cerebral vascular intervention This result shows that thrombolytic dose of 0.9 mg/kg or 0.6 mg/kg before undergoing thrombectomy did not show the difference in symptomatic hemorrhagic transformation rate 4.3 Factors affecting the clinical outcome and treatment procedure in the study Evaluate clinical outcome according to NIHSS score at hospital admission NIHSS score when hospitalized evaluates a patient's stroke level, contributes to prognosis in stroke diagnosis and treatment Adams et al analyzed the results of the TOAST study, including 1281 ischemic stroke patients, who were assessed on the NIHSS score at hospital admission, showing that NIHSS score ≥ 16 was related to the high ratio of mortality and disability The results of our study were similar to those of Adams et al., when we divided 86 patients into groups, group had NIHSS score of