冠心病心绞痛中西医评价结局动态变化特征研究

发布时间：2018-05-02 13:24

本文选题：中医药 + 冠心病心绞痛　；参考：《中国中医科学院》2012年博士论文

【摘要】：研究思路：中医学认为“有诸内必形诸外”,主张“司外揣内”,无论是认识人体生命活动规律、疾病发生发展规律,还是评价治疗效果,都十分重视患者的“不适”症状。中医传统古籍及理论体系中虽未有疗效评价的概念,但并不缺乏预后结局与疗效评价内容的记载,而当前人们也普遍认为在中医药临床疗效中,证候的改善程度应是评价指标的内容。虽然证候已广泛应用于中医药临床疗效评价中,但是证候评价的对象在疾病结局层面的定位上目前却并不明确。我们认为分析中医评价结局——证候的动态变化特征,并比较与西医评价结局变化特征的异同,对于明确证候评价的疾病结局层面是非常重要的环节。因此本课题选择了中医药有明确治疗优势的冠心病心绞痛(心血瘀阻证)为例,选择体现中医药治疗特色的中西医评价结局指标——中医证候评分、心绞痛评分以及硝酸甘油使用量做为待分析的疗效评价指标,在对既往完成冠心病心绞痛(心血瘀阻证)中药新药临床试验项目数据进行回顾性研究的基础上,探讨冠心病心绞痛中西医评价结局——中医证候评分、硝酸甘油使用量及心绞痛评分(即西医症状评分,包括心绞痛疼痛程度、持续时间、发作频率)随时间的变化趋势,构建中医证候评分、硝酸甘油使用量与心绞痛评分的变化曲线模型,并通过小样本前瞻性序列研究进行验证,明确冠心病心绞痛中西医评价结局动态变化特征。研究目的：以中医药治疗冠心病心绞痛心血瘀阻证为例,对中西医评价结局指标随时间的变化特征进行探索性研究,构建中医证候评分、硝酸甘油使用量及心绞痛评分变化曲线模型,最终为中医药治疗冠心病心绞痛临床疗效评价提供新思路与方法,为明确证候评价的结局层面奠定基础。研究方法：本研究主要分为两部分内容：研究内容一：回顾性分析。以1190例既往中药新药治疗冠心病心绞痛(心血瘀阻证)临床试验数据为基础,所有的临床试验均为严格的随机、双盲、多中心、平行对照研究,所有受试者均明确诊断为冠心病心绞痛(稳定型劳累性心绞痛),且辨证为心血瘀阻证的患者,心功能为Ⅰ、Ⅱ、Ⅲ级。对于原有数据库进行整理及合并,将其转换为纵向数据,通过描述性统计分析、趋势分析、相关分析、线性混合效应模型广义估计方程等统计分析方法,探讨中医证候评分、硝酸甘油使用量及心绞痛评分三个变量随时间变化的趋势,构建心血瘀阻证中医证候评分、硝酸甘油使用量及心绞痛评分变化曲线模型,明确冠心病心绞痛中西医评价结局动态变化特征。研究内容二：前瞻性验证。在研究内容一中医药治疗冠心病心绞痛心血瘀阻证中西医评价结局动态变化特征研究的基础上,连续定向收集100例冠心病心绞痛(心血瘀阻证)患者,所有患者均明确诊断为冠心病心绞痛(稳定型劳累性心绞痛),且辨证为心血瘀阻证,心功能为Ⅰ、Ⅱ、Ⅲ级。对于所有纳入患者进行中医药治疗,疗程为6周,访视点为治疗前,治疗2周、治疗4周、治疗6周,评价的指标包括中医证候评分、硝酸甘油使用量及心绞痛评分,对于这三个变量进行描述性统计分析、趋势分析、相关分析、线性混合效应模型、广义估计方程等统计分析方法,验证研究内容一的结论。研究结果： (1)研究内容一：通过对于1190例中药新药治疗冠心病心绞痛(心血瘀阻证)临床试验的相关数据进行回顾性分析,我们可以看出： ①描述性统计分析：不论是单个药的数据库分析,还是合并后的数据库分析,通过描述性统计分析,结果均显示：中医证候总分、心绞痛评分、硝酸甘油每日使用总量这3个变量的平均值有随着时间点而明显减小的变化趋势,但是不同药的数据库,这三个变量下降的幅度不尽相同。 ②趋势分析：不论是单个药的数据库分析,还是合并后的数据库,将数据转换为纵向数据,结果均显示：中医证候总分、心绞痛评分、硝酸甘油每日使用总量这3个变量之间的个体差异是很明显存在的,但是对所有个体而言,都有均数随着用药时间的延长而下降,并呈线性减少的趋势。 ③相关分析：相关分析是研究变量间密切程度的一种方法,而反应两个变量间关系强弱程度和方向的的统计量称作相关系数(coefficient of correlation)。为分析中医证候评分变化与其他西医结局指标变化的特征及相关性。进行了如下分析：对每一个患者,将其中医证候总分相邻两次观察时点、用药前和用药4周后作差得到中医证候的差值分别与心绞痛评分的差值、硝酸甘油每日使用总量差值计算配对的相关系数,并计算显著性水平。统计结果显示：无论是用药前与用药后4周,用药前与用药后2周以及用药后2周与用药后4周相关系数均有显著意义,说明中医证候总分变化与心绞痛评分变化、中医证候总分变化与硝酸甘油每日使用总量变化之间都存在着正相关关系,但相关系数不是很高。 ④线性混合效应模型分析：在此模型分析中因变量为中医证候总分、心绞痛评分以及硝酸甘油每日使用总量,这三个指标是一个在用药前、用药后2周和用药后4周三个时间点重复测量3次的指标。设定重复测量指标变量为用药后时间点(TIME)。因此相应的影响因素有两个：不同药种类数据库(Database)、用药后时间点(TIME),将其作为定性变量(因素)纳入模型,统计分析结果显示：对于中医证候总分、心绞痛评分以及硝酸甘油每日使用总量这三个指标而言,用药后时间点和药种类数据库的系数都通过了显著性检验,说明这两个指标对个体中医证候总分、心绞痛评分以及硝酸甘油每日使用总量都有影响,并且随着用药时间的延长,中医证候总分、心绞痛评分以及硝酸甘油每日使用总量呈现明显的下降趋势。 ⑤广义估计方程(GEE)分析：广义估计方程(generalized estimating equations, GEE)是在广义线性模型(generalized linear model, GLM)的基础上发展而来,专门用来分析纵向数据,其优点在于可区分群体效应和个体内部的各个变量随时间变化趋势,因此,通过GEE模型,分析中医证候评分、硝酸甘油使用量及心绞痛评分的动态变化特征。分析结果显示：观察时间点和药种类数据库对中医证候总分、心绞痛评分以及硝酸甘油每日使用总量有影响,并且相对于用药后4周的患者而言,随着用药时间的延长,各个患者的中医证候总分、心绞痛评分以及硝酸甘油每日使用总量都有下降趋势。 (2)研究内容二：通过连续定向收集102例冠心病心绞痛(心血瘀阻证)患者进行分析,结果表明： ①描述性统计分析：中医证候总分、心绞痛评分的平均值有随着用药时间延长而明显减小的变化趋势,但从用药4周后到药6周后的时间段中平均值的减小趋势趋缓。 ②趋势分析：对所有个体而言,中医证候总分、心绞痛评分都有均数随着用药时间的延长而下降,并呈线性减少的趋势,但是随着用药时间的延长,下降的趋势减缓,而硝酸甘油每日使用总量仅在用药前至用药2周后呈现出下降的趋势。 ③相关分析：中医证候总分变化与心绞痛评分变化之间存在正相关关系,但相关系数不是很高。中医证候总分变化与硝酸甘油每日使用总量变化之间不存在相关关系。 ④线性混合效应模型分析：对于中医证候总分、心绞痛评分而言,用药后时间点系数通过了显著性检验,说明这指标对中医证候总分、心绞痛评分有影响,并且随着用药时间的延长有下降的趋势；对于硝酸甘油每日使用总量而言,用药后时间点系数通过了显著性检验,说明这指标对硝酸甘油每日使用总量有影响,但用药2周后至用药6周后硝酸甘油每日使用总量变化不大。 ⑤广义估计方程(GEE)分析：对于中医证候总分、心绞痛评分而言,用药时间对其有影响,随着用药时间的延长中医证候总分、心绞痛评分有下降的趋势；用药后时间点对硝酸甘油每日使用总量有影响,但用药2周后至用药6周后硝酸甘油每日使用总量变化不大。结论：通过以中医药治疗冠心病心绞痛(心血瘀阻证)为例,分析中医结局评价指标——中医证候评分,西医结局评价指标——心绞痛评分、硝酸甘油使用量的动态变化特征可以看出： (1)用药时间及干预措施效应是冠心病心绞痛中西医评价结局动态变化的影响因素。 (2)冠心病心绞痛中西医评价结局都有随着时间延长而呈减少的趋势,其中,中医证候总分、心绞痛评分在用药前至用药2周后变化最大,而从用药4周到用药6周后减小趋势趋缓。 (3)治疗6周后,中医证候总分、心绞痛评分仍在下降,提示评价中医药治疗冠心病心绞痛的疗效,6周的治疗周期仍显不足。
[Abstract]:Research thinking :

Traditional Chinese medicine and theoretical system do not lack the concept of curative effect evaluation , but it is generally believed that the improvement degree of syndrome should be the content of the evaluation index . Although the syndrome has been widely used in the evaluation of clinical curative effect of traditional Chinese medicine , it is not clear that the object of syndrome evaluation is not clear at the position of disease outcome .

Based on a retrospective study of the clinical trial project data of traditional Chinese medicine ( TCM ) with definite therapeutic benefit , this paper discusses the trend of TCM syndrome score , angina pectoris and angina pectoris score ( including angina pain degree , duration and frequency of attack ) as an example .

Purpose of study :

Taking Chinese medicine as an example for treating angina pectoris with coronary heart disease and angina pectoris , exploratory research is carried out on the change characteristics of the outcome index of traditional Chinese medicine and western medicine with time , so as to construct the model of TCM syndrome score , the dosage of nitroglycerine and the change curve of angina pectoris score , and finally provide a new idea and method for the evaluation of clinical curative effect of traditional Chinese medicine for treating coronary heart disease and angina pectoris .

Study method :

This study is mainly divided into two parts :

A retrospective analysis was made on the clinical trial data of patients with coronary heart disease and angina pectoris ( heart and blood stasis syndrome ) . All the clinical trials were strictly random , double - blind , multi - center and parallel - controlled study . All the subjects were diagnosed as coronary heart disease angina pectoris ( stable type fatigue angina pectoris ) . All the subjects were diagnosed as coronary heart disease angina pectoris ( stable type fatigue angina pectoris ) .

In this study , 100 patients with coronary heart disease and angina pectoris ( heart and blood stasis syndrome ) were randomly divided into two groups : coronary heart disease and angina pectoris ( stable type of angina pectoris ) . All patients were diagnosed as coronary heart disease and angina pectoris ( stable type of angina pectoris ) . The treatment course was 6 weeks . The indexes of evaluation included syndrome score of TCM , usage of glycerin and angina pectoris , and the results were analyzed by descriptive statistics , trend analysis , correlation analysis , linear mixed effect model and generalized estimation equation .

Results of the study :

( 1 ) Content I : Through a retrospective analysis of the data related to clinical trials in patients with coronary heart disease and angina pectoris ( heart and blood stasis syndrome ) , we can see that :

Descriptive statistics analysis : Whether the database analysis of single medicine or the database analysis after merging , through descriptive statistics analysis , the results show that the average value of the three variables of TCM syndrome total score , angina pectoris score and the total daily use of Nitroglycerin has the obvious decrease trend with time point , but the database of different drugs , these three variables are different in magnitude .

( 2 ) Trend analysis : Whether a single drug database analysis or a consolidated database was used to convert the data into longitudinal data , the data were converted into longitudinal data . The results showed that the individual difference between the three variables of the total score of TCM syndrome , angina pectoris and the total daily use of Nitroglycerin was obvious , but for all individuals , the average number decreased with the extension of the time of administration , and decreased linearly .

( 3 ) Correlation analysis : Correlation analysis is a method to study the degree of closeness among variables , and the statistical quantity of the degree and direction of the relationship between the two variables is called coefficient of correlation . In order to analyze the characteristics and correlation between the change of TCM syndrome score and other western medicine outcome indexes , the difference of TCM syndrome score and angina pectoris score were calculated before and after 4 weeks . The statistical results showed that there was positive correlation between the change of TCM syndrome score and angina pectoris score , the change of total score of TCM syndrome and the change of total daily use of Nitroglycerin , but the correlation coefficient was not very high .

( 4 ) Linear mixed effect model analysis : In the analysis of this model , the factors are the total score of TCM syndrome , angina pectoris score and the total daily use of Nitroglycerin . The three indexes are the following three indexes : different medicine category database ( Database ) , time point ( TIME ) after administration , as the qualitative variable ( factor ) , and the statistical analysis result shows that the two indexes have significant influence on the total score of TCM syndrome , angina pectoris and total daily use of Nitroglycerin .

Generalized estimating equation ( GEE ) analysis : Generalized estimating equation ( GEE ) is developed on the basis of generalized linear model ( GLM ) . It is specially used to analyze longitudinal data . It has the advantages of distinguishing between group effect and variation trend of individual variables in individual .

( 2 ) Content II : 102 patients with coronary heart disease and angina pectoris ( heart and blood stasis syndrome ) were collected by continuous orientation analysis . The results showed that :

( 1 ) Descriptive statistics analysis : The mean value of TCM syndrome score and angina pectoris score decreased significantly with the time of medication , but the trend of decrease of mean value in the time period from 4 weeks to 6 weeks after medication was slow .

( 2 ) Trend analysis : For all individuals , the average score of TCM syndrome and angina pectoris score decreased with the extension of the time of administration and decreased linearly . However , with the prolongation of the time of administration , the trend of decline was slow , while the daily use amount of Nitroglycerin showed a downward trend only after 2 weeks before medication .

( 3 ) Correlation analysis : There is a positive correlation between the change of TCM syndrome differentiation and the change of angina pectoris score , but the correlation coefficient is not very high . There is no correlation between the total variation of TCM syndrome and the change of total daily use of Nitroglycerin .

( 4 ) Linear mixed effect model analysis : For the total score of TCM syndrome and angina pectoris , the time point coefficient after medication passed a significant test , indicating that the index had an influence on the total score of TCM syndrome and angina pectoris score , and decreased with the extension of medication time .
For the total daily use of Nitroglycerin , the time point coefficient after administration passed a significant test indicating that this indicator had an impact on the total daily use of Nitroglycerin , but the total daily use of Nitroglycerin was not large after 2 weeks of administration to 6 weeks after administration .

( 5 ) Analysis of the generalized estimation equation ( GEE ) : For the total score of TCM syndrome and angina pectoris , the time of medication had an effect on it . With the prolongation of the time of administration , the symptoms of angina pectoris were decreased .
The total daily use of Nitroglycerin was affected by the time point after administration , but the total daily use of Nitroglycerin was not large after 2 weeks of administration to 6 weeks after administration .

Conclusion :

By taking traditional Chinese medicine for treating coronary heart disease and angina pectoris ( heart and blood stasis syndrome ) as an example , the dynamic characteristics of TCM outcome evaluation index , TCM syndrome score , western medicine outcome evaluation index and angina pectoris score and the usage of Nitroglycerin were analyzed .

( 1 ) The effect of medication time and intervention was the influencing factor of the dynamic changes of the outcome of the evaluation of the patients with coronary heart disease and angina pectoris .

( 2 ) The outcome of the evaluation of angina pectoris and the traditional Chinese medicine and western medicine were decreased with time . Among them , the total score of TCM syndrome and angina pectoris were the biggest after 2 weeks of treatment .

( 3 ) After 6 weeks of treatment , the total score of TCM syndrome and angina pectoris were still decreasing . The results suggested that the efficacy of traditional Chinese medicine in the treatment of coronary heart disease and angina pectoris was not enough .

【学位授予单位】：中国中医科学院
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R541.4

【参考文献】