芎芍胶囊预防椎基底动脉系统支架术后再狭窄的临床研究

发布时间：2018-05-15 23:09

本文选题：芎芍胶囊 + 椎基底动脉　；参考：《中国中医科学院》2017年硕士论文

【摘要】：目的近年来随着介入治疗技术的发展、推广及应用,其创伤小、副作用少,总体治疗效果好等特点被临床认可并被广泛应用。椎基底动脉支架术后存在着的血栓形成、脑出血、支架置入术后再狭窄以及过度灌注等并发症,特别是支架置入术后再狭窄(ISR)的发生,不仅发生率高,还同样影响着脑血流动力学,从而导致缺血性脑血管病(ICVD)的发生,如短暂性脑缺血发作(TIA)、症状性脑梗死等疾病。芎芍胶囊作为血府逐瘀汤中的两味主药,具有活血化瘀的效果,经过多年的临床研究,能明显降低冠状动脉介入治疗后再狭窄的发生。依从中医“心脑同治”的原则,将芎芍胶囊运用于缺血性脑血管病-椎基底动脉支架置入术后的患者,观察其对于预防局部血管再狭窄的疗效,为治疗椎基底动脉术后再狭窄探索出新的方法途径,防止发生缺血性脑血管病。方法(1)检索、收集相关文献及报道,使用的检索工具有中国学术期刊全文数据库(CNKI)、万方数据库、中国生物医学文献数据库(Chinese Biomedical Literature Database,CBM)、电子检索 MEDLINE 数据库、EMBASE 数据库等。整理所收集数据及资料,分析椎基底动脉支架术后再狭窄的发生率、产生原理、相关因素及相关措施;中药类药物对冠状动脉支架术后再狭窄的临床研究,扩展至中药类药物对椎基底动脉支架置入术后再狭窄的预防研究。(2)制定相应的临床研究方案、方法、流程及具体实行措施,设计“芎芍胶囊临床观察表格”并应用到此次课题中,将美国国立卫生研究院卒中量表(NIHSS)及日常生活能力量表—巴氏指数(Brath指数)作为神经功能评分;同时与合作医院(首都医科大学宣武医院)积极联系及配合,共同协调完成此项临床研究。(3)选取标准:年龄在18-80岁之间、在椎基底动脉系统(包括椎动脉颅内、颅外段及基底动脉)成功接受球囊扩张和/或支架置入、术后均常规口服阿司匹林肠溶片100mgqd+氯吡格雷片75mgqd共6个月、中医辨证分型属于“血瘀证和/或气虚证”的患者,预计选取80例患者。将80例经皮椎动脉支架置入成功的缺血性脑血管病患者,通过随机数字表的方法,为西药常规治疗加安慰剂组(对照组)、西药常规加芎芍胶囊(中药组)。观察6个月后随访,有7例患者不符合录入标准(自动脱落、未规律口服抗凝及抗血小板药物、未规律口服配给药物),最后总计73例患者入选,分别为西药常规加安慰剂组(对照组)40例和西药常规加芎芍胶囊(中药组)33例。通过对血管超声检查(TCD)、经颅彩色多普勒(TCCD)、DSA等检查,了解两组支架术后再狭窄情况及程度。(4)严格按照设计要求收集资料,认真核对,保证资料的真实可靠,数据应用ACCESS进行两遍入机,进行统计分析,比较中药组与对照组椎动脉支架术后再狭窄发生情况及程度、症状性脑梗及短暂性脑缺性发作情况、高危因素对支架术后再狭窄的影响。结果(1)通过对文献搜索、整理及分析,发现以下几个特征:①围手术期的抗凝及抗血小板聚集治疗是预防椎基底动脉ISR的主要措施,常规应用抗凝及抗血小板聚集药物,6个月后改为阿司匹林长期口服,因为时间一旦超过6个月,发生ISR的原因主要是由血管内膜的过度增生所致,延长波立维的口服时间对预防ISR的意义不大。②糖尿病、病变血管成角扭曲、术后残余狭窄、长段(10mmm)的狭窄是发生椎基底动脉ISR的独立危险因素。而高血压病、高脂血症、高同型半胱氨酸症及吸烟等是ISR的高危因素。③年龄相对较小的患者更容易发生ISR,考虑是其内膜增生能力强、增生速度更快相关;另外,相对年龄较长的患者斑块钙化居多,淋巴细胞浸润少,年少的患者斑块中纤维成分及淋巴浸润更多。④有研究显示,应用自膨式支架与球囊扩张支架再狭窄发生率的差异无统计学意义。虽然自膨式支架6个月内易发生再狭窄,但其后期稳定性较球囊扩张支架更好。但仍有研究显示,径向应力大小影响着ISR的发生,如柔韧性较好的自膨式支架会增加动脉硬化斑块突入到支架管腔的风险,因其较大的径向应力可促进内膜增生导致再狭窄的发生;而球囊扩张支架恰恰相反,其相对较小的径向应力能减少再狭窄的发生。⑤从祖国传统医学的角度来看,无论支架置入术后无论有无并发症的出现,此项治疗都属于外源性创伤,作为一种治标及损伤性的手段,虽然可以解决“标实”的问题,但是“本虚”的介入治疗后依旧存在,正是这种外源性的创伤,加之支架置入术的过程是耗气伤血的过程,从而导致气虚无力推动血行,血行不畅,久而久之瘀积于脉管中,形成了术后的再狭窄,符合中医学中“血瘀证”的范畴,治疗宜活血化瘀。把中医药运用在椎基底动脉支架置入术后治疗,不但能降低患者出现消化道溃疡或者诱发出血等严重并发症,还可以减少ISR的风险,缩短患者的住院时间,提高手术的成功率。⑥在芎芍胶囊干预冠心病介入治疗后再狭窄的研究中,芎芍胶囊可明显降低血浆血管紧张素Ⅱ(AngⅡ)水平,促进平滑肌细胞(SMC)凋亡,从而抑制动脉粥样硬化(AS)的发生发展;内膜增生、病理性血管重构协同作用可造成动脉粥样硬化过程中管腔的缺失,胶原在病理性血管重构过程中起到了关键作用,芎芍胶囊可通过调节动脉粥样硬化过程中血管壁胶原的含量改善病理性血管重构和抑制内膜增生,起到预防管腔狭窄的作用,芎芍胶囊可明显增强MMP-1mRNA在损伤血管部位的表达,提示芎芍胶囊预防支架后再狭窄可能与上调MMP-1mRNA的表达,增加胶原的降解,减少胶原在血管壁的沉积有关。对冠心病介入后的临床研究也表明,芎芍胶囊可明显降低冠状动脉介入治疗后的冠脉造影随访再狭窄的发生(减少45%的再狭窄),能减少心绞痛复发并有效改善患者的血瘀状态。(2)将2012年12月到2016年6月间,在中国中医科学院西苑医院及首都医科大学宣武医院成功进行椎动脉支架置入术的患者,随机分为西药常规治疗+安慰剂(对照组)和西药常规+芎芍胶囊(中药组)。其中对照组40例,男性33例,女性7例。有高血压病史25例,糖尿病病史16例,吸烟者17例;其中置入左侧椎动脉支架23个,右侧椎动脉支架20个(40例患者安装椎动脉支架43个,其中3人为左右侧椎动脉支架各一个);西药常规加芎芍胶囊(中药组)33例,男性26例,女性7例;有高血压病史患者27例,糖尿病病史14例,吸烟者15例;置入左侧椎动脉支架17个,右侧椎动脉支架18个(33例患者安装椎动脉支架35个,其中2人为左右侧椎动脉支架各一个)。患者在一般情况、基线方面基本相似,具有可比性。(3)入选病例73例,随访6个月后,芎芍胶囊中药组的椎动脉再狭窄率为12.12%(4例/33例),对照组椎动脉狭窄率为32.5%(13例/40例),通过SPSS20.0统计软件包对所收集的数据进行整合、处理及分析,首先将所有属于计量资料的数据均用(x±S表示);其次,对全部符合纳入标准的73例临床观察项目,进行单因素分析(计量资料的比较采用t检验,计数资料的比较采用卡方检验,以P0.05为差异具有统计学意义),最后比较两组在ISR的发生率有无显著性差异,结果显示有显著性差异(P0.05),具有统计学意义。中药组与对照组相比较,其症状性脑梗及TIA的发生率无显著性差异。(4)芎芍胶囊中药组与对照组关于中医辨证论治评分显示:①治疗前粗略观察,气虚证评分明显低于血瘀证评分。②对两组组内治疗前后,分别采用配对样本t检验发现,“气虚证”评分中,治疗前后均值未见明显变化,差异无统计学意义(中药组P=0.292,对照组P=0.065,两组P0.05),说明支架置入术及术后用药,对气虚证患者影响不明显;“血瘀证”评分中,两组治疗前后均值有明显降低,其差异具有统计学意义(P0.05),说明支架置入术和/或用药,均可改善血瘀症状。③对两组组间采用独立样本t检验发现,血瘀证术后中药组与对照组均值具有差异,有统计学意义(P0.05),说明中药组在术后改善狭窄率优于对照组。结论(1)经过6个月后的疗效观察,发现血管收缩、新生内膜多度增生、血栓形成、血管重塑,最终可导致椎基底动脉支架置入术后再狭窄,其机理符合中医学“血瘀证”范畴。对中医辨证证型属于“血瘀证”的患者,芎芍胶囊不仅能降低椎动脉支架置入术后局部血管再狭窄的发生起到预防作用,还能明显改善血瘀证状态。(2)此次中医证候评分中,气虚证评分总体不高,治疗前后变化不大,考虑有以下两个原因:①行椎基底动脉支架置入术的患者,考虑其本身因血管狭窄而出现一系列症状,这与血管再狭窄的部分机理相似,符合中医学“血瘀证”范畴,造成了在病例选择上的偏向性。②考虑此次研究病例偏少。(3)对于症状性脑梗及TIA的发生无明显差异。(4)但由于时间及条件的限制,本此课题研究所选病例数偏少,在初步证实芎芍胶囊能减少椎基底动脉支架术后血管再狭窄的基础上,应进一步扩大样本量进行相关研究。
[Abstract]:Objective in recent years, with the development, popularization and application of interventional therapy, its characteristics of small trauma, less side effects and better overall therapeutic effect have been clinically recognized and widely used. There are complications such as thrombosis, cerebral hemorrhage, restenosis and overperfusion after stenting of vertebrobasilar artery, especially stent implantation. The incidence of post restenosis (ISR) is not only high, but also affects cerebral hemodynamics, which leads to the occurrence of ischemic cerebrovascular disease (ICVD), such as transient ischemic attack (TIA) and symptomatic cerebral infarction. Xiong Shao capsule, as the two main drug in Xuefu Zhuyu Decoction, has the effect of activating blood and removing stasis, after years of clinical research. It can obviously reduce the occurrence of restenosis after coronary artery interventional therapy. According to the principle of "heart and brain therapy", Xiong Shao capsule is applied to patients with ischemic cerebrovascular disease - vertebrobasilar artery stenting, and the effect on prevention of local restenosis is observed, and a new approach is explored for restenosis after the operation of vertebral basilar artery. Methods to prevent ischemic cerebrovascular disease. Method (1) retrieval, collection of related literature and reports, the retrieval tools used are Chinese academic journal full text database (CNKI), Wanfang database, Chinese biomedical literature database (Chinese Biomedical Literature Database, CBM), electronic retrieval MEDLINE database, EMBASE database Collect data and data, analyze the incidence of restenosis after stenting of vertebrobasilar artery, principle, related factors and related measures; the clinical study of restenosis after coronary stent implantation by traditional Chinese medicine drugs is extended to the prevention and study of restenosis after the brace of vertebrobasilar artery stenting. (2) formulate corresponding The clinical study scheme, method, process and specific implementation measures were used to design "Xiong Shao capsule clinical observation form" and apply the National Institutes of Health Stroke Scale (NIHSS) and the daily living capacity scale - the barson index (Brath index) as the neurological function score; and the cooperative hospital (Capital Medical University Declaration) (3) select the standard: age 18-80 years old, the vertebral basilar artery system (including the vertebral artery intracranial, the extracranial segment and basilar artery) successfully accepted balloon dilatation and / or stent implantation, and the routine oral administration of Aspirin Enteric-coated Tablets 100mgqd+ clopidogrel 75mgqd after the operation. 6 months, TCM syndrome differentiation type belongs to the patients with "blood stasis syndrome and / or qi deficiency syndrome", and 80 patients are expected to be selected. 80 cases of percutaneous vertebral artery stents are placed in the patients with successful ischemic cerebrovascular disease. By the method of random numbers, the routine treatment of Western Medicine plus placebo group (control group), western medicine routine plus Xiong Shao capsule (Chinese medicine group). 6 cases are observed. After month follow-up, 7 cases were not conformed to the standard of entry (auto fall off, irregular oral anticoagulant and antiplatelet drugs, irregular oral dispensing), and finally total of 73 patients were selected, 40 cases of Western medicine routine plus placebo group (control group) and 33 cases of Western medicine routine plus Xiong Shao capsule (Chinese medicine group). Through the TCD, the blood vessel ultrasound examination was carried out. Cranial color Doppler (TCCD), DSA and other examinations to understand the situation and degree of restenosis after two groups of stents. (4) collect data strictly according to the design requirements, carefully check the data, ensure the true and reliable data. The data are applied to the machine for two times, the statistical analysis is carried out, and the occurrence and process of restenosis after the vertebral artery stenting of the Chinese medicine group and the control group are compared and the process is compared. Degree, symptomatic cerebral infarction and transient ischemic attack, and the effect of high risk factors on post stent restenosis. Results (1) through literature search, sorting and analysis, the following characteristics are found: (1) anticoagulant and antiplatelet therapy in the perioperative period are the main measures to prevent ISR of vertebrobasilar artery. Anticoagulant and antiplatelet therapy are routinely applied. The drug was changed to aspirin for a long time after 6 months. As the time passed for more than 6 months, the cause of ISR was mainly caused by excessive hyperplasia of the intima of blood vessels. Prolonging the oral time of brili was not significant for preventing ISR. 2. Diabetes, the vascular distortion of the lesion, the postoperative remnant stenosis, and the stenosis of the long segment (10mmm) were vertebral ISR independent risk factors of basilar artery. Hypertension, hyperlipidemia, Hyperhomocysteine, and smoking are the high risk factors for ISR. (3) ISR is more likely to occur in patients with relatively younger age. There is no statistically significant difference in the incidence of restenosis between self expanding stents and balloon dilatation stents. Although self expanding stents are prone to restenosis in 6 months, the later stability is better than that of balloon dilatation stents. However, there are still studies showing that the diameter of the stent is better than that of balloon dilatation. The size of the stress affects the occurrence of ISR, such as a better flexible self expanding stent, which increases the risk of atherosclerotic plaques penetrating into the stent, because its larger radial stress can promote intimal hyperplasia to cause restenosis, and the balloon dilatation stent is the opposite, and its relatively small radial stress can reduce the occurrence of restenosis. From the point of view of traditional medicine of the motherland, no matter whether or not the stent implantation has complications, this treatment belongs to exogenous trauma. As a standard and damaging means, although it can solve the problem of "the standard", "this deficiency" still exists after the intervention treatment. It is this kind of exogenous trauma, plus branch. The process of stent implantation is the process of blood consumption and blood consumption, which leads to Qi deficiency to push blood, blood flow is not smooth, blood stasis is not smooth, and the blood stasis is accumulated in the pulse tube for a long time. It forms the restenosis after the operation. It is in line with the category of "blood stasis syndrome" in traditional Chinese medicine. The treatment should be used to activate blood and dissipate blood stasis. There are severe complications such as peptic ulcer or induced bleeding, which can also reduce the risk of ISR, shorten the time of hospitalization and improve the success rate of the operation. (SMC) apoptosis, thus inhibiting the occurrence and development of atherosclerosis (AS); intimal hyperplasia and pathological vascular remodeling synergy can cause the absence of the lumen in the process of atherosclerosis. Collagen plays a key role in the process of pathological vascular remodeling. Xiong Shao capsule can be used to regulate the content of collagen in the vascular wall during the process of atherosclerosis. The effect of improving pathological vascular remodeling and inhibiting intimal hyperplasia plays a role in preventing the stenosis of the lumen. Xiong Shao capsule can obviously enhance the expression of MMP-1mRNA in the injured part of blood vessel. It suggests that Xiong Shao capsule may increase the expression of MMP-1mRNA, increase the degradation of collagen and reduce the deposition of collagen in the vascular wall. The clinical study after the intervention showed that Xiong Shao capsule could obviously reduce the incidence of restenosis after coronary artery angiography after coronary intervention (45% reduction of restenosis), reduce the recurrence of angina and effectively improve the blood stasis of the patients. (2) from December 2012 to June 2016, in Xiyuan Hospital of Chinese Academy of Chinese medicine and the capital medicine The patients in Xuanwu Hospital of the University of science and universities were successfully treated with vertebral artery stenting, which were randomly divided into western medicine conventional therapy + placebo (control group) and Western medicine routine + Xiong Shao capsule (Chinese medicine group), of which 40 cases in the control group, 33 men, 7 women, 25 cases of hypertension, 16 diabetic history and 17 smokers, which were placed in the left vertebral artery stents 23. There were 20 stents on the right vertebral artery (40 cases with 43 vertebral artery stents, of which 3 were the left and right vertebral artery stents); the western medicine routine plus Xiong Shao capsule (Chinese medicine group) 33 cases, male 26 cases, 7 women, 27 patients with hypertension history, 14 cases of diabetes, 15 smokers, 17 left vertebral artery stents and right vertebral artery. There were 18 stents (33 patients with 35 vertebral artery stents, of which 2 were one of the left and right vertebral arteries). In general, the baseline was similar and comparable. (3) 73 cases were selected. After 6 months of follow-up, the restenosis rate of Xiong Shao capsule Chinese medicine group was 12.12% (4 cases /33 cases), and the control group's vertebral artery stenosis rate was 32. 5% (13 cases of /40 cases), the collected data were integrated, processed and analyzed through the SPSS20.0 statistical package. First, all the data belonging to the measured data were used (x + S). Secondly, the single factor analysis was carried out for all the 73 clinical observation items which were in conformity with the inclusion criteria. The comparison of the data was compared with t test and the comparison of counting data. With chi square test, P0.05 was statistically significant). At last, there was no significant difference in the incidence of ISR between the two groups. The results showed significant difference (P0.05). There was no significant difference in the incidence of symptomatic cerebral infarction and TIA between the Chinese medicine group and the control group. (4) Xiong Shao capsule Chinese medicine group and the control group. The score of TCM syndrome differentiation and treatment showed: (1) rough observation before treatment, the score of qi deficiency syndrome was significantly lower than that of blood stasis syndrome. (2) before and after treatment in the two groups, the paired sample t test showed that there was no significant change in the mean value of "Qi deficiency syndrome" before and after treatment (P=0.292, P=0.065 of the control group, and two groups of P). 0.05) the effect of stent implantation and postoperative medication on Qi deficiency syndrome was not obvious; in the "blood stasis syndrome" score, the mean value of the two groups before and after treatment was significantly reduced, and the difference was statistically significant (P0.05), indicating that the stent implantation and / or drug use could improve the blood stasis symptoms. (3) the blood stasis syndrome was found by independent sample t test among the two groups. The mean difference between the traditional Chinese medicine group and the control group was statistically significant (P0.05), indicating that the improvement of the stenosis rate in the Chinese medicine group was better than that of the control group. Conclusion (1) after the observation of the curative effect after 6 months, the vasoconstriction, neointimal hyperplasia, thrombosis and blood vessel restenosis can eventually lead to restenosis after the stenting of vertebral basilar artery. The mechanism conforms to the category of blood stasis syndrome of traditional Chinese medicine. Xiong Shao capsule can not only reduce the occurrence of local vascular restenosis after the stent implantation, but also obviously improve the state of blood stasis syndrome. (2) the score of qi deficiency syndrome is generally not high, and the treatment of qi deficiency syndrome is not high, and the treatment of qi deficiency syndrome is not high. There are two reasons for the following reasons: (1) a series of symptoms in the patients with vertebral basilar artery stent implantation, considering their own vascular stenosis, are similar to the mechanism of vascular restenosis, which conforms to the category of "blood stasis syndrome" in traditional Chinese medicine and causes the bias in the selection of cases. Less. (3) there is no significant difference in the occurrence of symptomatic cerebral infarction and TIA. (4) but due to the limitation of time and conditions, the number of cases selected in this study is less than that of the selected cases. On the basis of the preliminary confirmation that Xiong Shao capsule can reduce the restenosis after the stenting of vertebrobasilar artery, the sample should be further expanded to do the related research.

【学位授予单位】：中国中医科学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R743

【参考文献】