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

rculation 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/ Study mRS 0-2 Criteria of NIHSS score Mean NIHSS score Standard of ASPECT ASPECT % IV rt- PA treatment Reperf- usion time EXTEND- IA 71% No limitation 15 No limitation No data 100% 248 MR CLEAN 33% ≥ 2 18 No limitation 9 87% >260 ESCAPE 53% ≥ 6 17 ≥ 6 9 76% 241 SWIFT PRIM 60% ≥ 8 17 ≥ 6 9 100% 252 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 ≤ 4.5 h No enough condition Remove from study - History, medical history - Start stroke chain - Evaluate CT, NIHSS Brain MSCT/ MRI Cerebral Hemorrhage Remove from study No cerebral hemorrhage, ASPECT ≥ 6 No enough condition Remove from study Evaluate rtPA Criteria Contraindication to rtPA Remove from study (Will access standard for 1st phase thrombectomy) - Meet rtPA Criteria - rtPA 0.6 mg/kg - MSCT occlusive vessel M1 MCA, ICA - ASPECT ≥ 6 - NIHSS ≥ 6 No enough condition Remove from the study Mechanical Thrombectomy (Time from using Alteplase to thrombectomy ≤ 60 minutes) No enough condition Remove from the study 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 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. 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 0% 20% 40% 60% 80% 100% Middle cerebral artery ICA Tandem General 14 25 6.25 15.12 42 35 31.25 38.37 18 5 25 16.28 10 35 6.25 15.12 8 0 25 9.3 2 6.25 2.33 6 0 3.49 0 score 1 score 2 score 3 score 4 score 5 score 6 score 14 Table 3.2. Evolution of NIHSS scores in 24 hours Middle cerebral artery (n=50) Internal carotid artery (n=20) Internal carotid artery and middle cerebral artery (n=16) General (n=86) p* Median (min, max) Median (min, max) Median (min, max) Median (min, max) NIHSS score – admitted to hospital 15 (8, 23) 16 (10, 22) 18.5 (11, 24) 15.5 (8, 24) 0.213 NIHSS score - 24h 7 (0, 35) 6 (0, 23) 14.5 (3, 30) 7 (0, 35) 0.047 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 Chart 3.2. Reperfusion grade according to TICI score 0-, 1.16 1-, 1.16 2a, 6.98 2b, 38.37 3-, 52.33 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 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 hemorrhage 0 (0%) 1 (1.1%) 1 (1.1%) 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 OR CI (95%) p mRS 0 - 2 mRS 3 - 6 Chung lower upper Without hemorrhagic transformation 45 (75%) 16 (61.54%) 61 (70.93%) 1 1 1 Asymptomatic hemorrhagic transformation 14 (23.33%) 6 (23.08%) 20 (23.26%) 1.2054 0.3958 3.6707 0.742 Symptomatic hemorrhagic transformation 1 (1.67%) 4 (15.38%) 5 (5.81%) 11.25 1.1688 108.2797 0.036 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 Factors OR CI p lower upper Occlusion location Middle cerebral artery* - - - - Internal carotid artery 1.500 0.351 6.412 0.584 Internal carotid artery & middle cerebral artery 0.504 0.103 2.461 0.397 Early hospital admission (under 2 hours) 0.439 0.119 1.619 0.216 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 Hemorrhage Non hemorrhage* - - - - Asymptomatic hemorrhage 1.442 0.356 5.852 0.608 Symptomatic hemorrhage 33.611 1.967 574.40 7 0.015 Intervention time Under 30 minutes* - - - - 30 to 60 minutes 0.526 0.092 3.025 0.472 Above 60 minutes 1.473 0.171 12.654 0.724 NIHSS score at hospital admission 6 to 12* - - - - 12 to 16 2.134 0.370 12.315 0.397 16 to 20 7.901 1.243 50.232 0.028 20 to 24 15.092 1.527 149.16 1 0.020 Age 1.020 0.970 1.072 0.450 Gender 1.239 0.356 4.317 0.736 18 CHAPTER 4. 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 8. 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 8 points in 48 patients, accounted for 55.8%. NIHSS score decrease about 8 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 3 was 52%, TICI 2b: 39%, only 8 patients (9%) achieved the reperfusion rate TICI 0-2a, of which 1 patient (1.2%) TICI 0, 1 patient (1.2%) TICI 1, 6 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 3 studies that showed the benefit of vascular intervention compared with standard medical treatment, however, the intervention group of 3 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 1 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 5 patients, accounting for 5.8%. In these 5 patients, there were 4 patients with hemorrhagic transformation PH 2 and 1 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 3 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 be