本文選題：中醫(yī)藥 + 冠心病心絞痛�。� 參考：《中國中醫(yī)科學(xué)院》2012年博士論文

【摘要】：研究思路： 中醫(yī)學(xué)認(rèn)為“有諸內(nèi)必形諸外”,主張“司外揣內(nèi)”,無論是認(rèn)識人體生命活動規(guī)律、疾病發(fā)生發(fā)展規(guī)律,還是評價(jià)治療效果,都十分重視患者的“不適”癥狀。中醫(yī)傳統(tǒng)古籍及理論體系中雖未有療效評價(jià)的概念,但并不缺乏預(yù)后結(jié)局與療效評價(jià)內(nèi)容的記載,而當(dāng)前人們也普遍認(rèn)為在中醫(yī)藥臨床療效中,證候的改善程度應(yīng)是評價(jià)指標(biāo)的內(nèi)容。雖然證候已廣泛應(yīng)用于中醫(yī)藥臨床療效評價(jià)中,但是證候評價(jià)的對象在疾病結(jié)局層面的定位上目前卻并不明確。 我們認(rèn)為分析中醫(yī)評價(jià)結(jié)局——證候的動態(tài)變化特征,并比較與西醫(yī)評價(jià)結(jié)局變化特征的異同,對于明確證候評價(jià)的疾病結(jié)局層面是非常重要的環(huán)節(jié)。因此本課題選擇了中醫(yī)藥有明確治療優(yōu)勢的冠心病心絞痛(心血瘀阻證)為例,選擇體現(xiàn)中醫(yī)藥治療特色的中西醫(yī)評價(jià)結(jié)局指標(biāo)——中醫(yī)證候評分、心絞痛評分以及硝酸甘油使用量做為待分析的療效評價(jià)指標(biāo),在對既往完成冠心病心絞痛(心血瘀阻證)中藥新藥臨床試驗(yàn)項(xiàng)目數(shù)據(jù)進(jìn)行回顧性研究的基礎(chǔ)上,探討冠心病心絞痛中西醫(yī)評價(jià)結(jié)局——中醫(yī)證候評分、硝酸甘油使用量及心絞痛評分(即西醫(yī)癥狀評分,包括心絞痛疼痛程度、持續(xù)時(shí)間、發(fā)作頻率)隨時(shí)間的變化趨勢,構(gòu)建中醫(yī)證候評分、硝酸甘油使用量與心絞痛評分的變化曲線模型,并通過小樣本前瞻性序列研究進(jìn)行驗(yàn)證,明確冠心病心絞痛中西醫(yī)評價(jià)結(jié)局動態(tài)變化特征。 研究目的： 以中醫(yī)藥治療冠心病心絞痛心血瘀阻證為例,對中西醫(yī)評價(jià)結(jié)局指標(biāo)隨時(shí)間的變化特征進(jìn)行探索性研究,構(gòu)建中醫(yī)證候評分、硝酸甘油使用量及心絞痛評分變化曲線模型,最終為中醫(yī)藥治療冠心病心絞痛臨床療效評價(jià)提供新思路與方法,為明確證候評價(jià)的結(jié)局層面奠定基礎(chǔ)。 研究方法： 本研究主要分為兩部分內(nèi)容： 研究內(nèi)容一：回顧性分析。以1190例既往中藥新藥治療冠心病心絞痛(心血瘀阻證)臨床試驗(yàn)數(shù)據(jù)為基礎(chǔ),所有的臨床試驗(yàn)均為嚴(yán)格的隨機(jī)、雙盲、多中心、平行對照研究,所有受試者均明確診斷為冠心病心絞痛(穩(wěn)定型勞累性心絞痛),且辨證為心血瘀阻證的患者,心功能為Ⅰ、Ⅱ、Ⅲ級。對于原有數(shù)據(jù)庫進(jìn)行整理及合并,將其轉(zhuǎn)換為縱向數(shù)據(jù),通過描述性統(tǒng)計(jì)分析、趨勢分析、相關(guān)分析、線性混合效應(yīng)模型廣義估計(jì)方程等統(tǒng)計(jì)分析方法,探討中醫(yī)證候評分、硝酸甘油使用量及心絞痛評分三個(gè)變量隨時(shí)間變化的趨勢,構(gòu)建心血瘀阻證中醫(yī)證候評分、硝酸甘油使用量及心絞痛評分變化曲線模型,明確冠心病心絞痛中西醫(yī)評價(jià)結(jié)局動態(tài)變化特征。 研究內(nèi)容二：前瞻性驗(yàn)證。在研究內(nèi)容一中醫(yī)藥治療冠心病心絞痛心血瘀阻證中西醫(yī)評價(jià)結(jié)局動態(tài)變化特征研究的基礎(chǔ)上,連續(xù)定向收集100例冠心病心絞痛(心血瘀阻證)患者,所有患者均明確診斷為冠心病心絞痛(穩(wěn)定型勞累性心絞痛),且辨證為心血瘀阻證,心功能為Ⅰ、Ⅱ、Ⅲ級。對于所有納入患者進(jìn)行中醫(yī)藥治療,療程為6周,訪視點(diǎn)為治療前,治療2周、治療4周、治療6周,評價(jià)的指標(biāo)包括中醫(yī)證候評分、硝酸甘油使用量及心絞痛評分,對于這三個(gè)變量進(jìn)行描述性統(tǒng)計(jì)分析、趨勢分析、相關(guān)分析、線性混合效應(yīng)模型、廣義估計(jì)方程等統(tǒng)計(jì)分析方法,驗(yàn)證研究內(nèi)容一的結(jié)論。 研究結(jié)果： (1)研究內(nèi)容一：通過對于1190例中藥新藥治療冠心病心絞痛(心血瘀阻證)臨床試驗(yàn)的相關(guān)數(shù)據(jù)進(jìn)行回顧性分析,我們可以看出： ①描述性統(tǒng)計(jì)分析：不論是單個(gè)藥的數(shù)據(jù)庫分析,還是合并后的數(shù)據(jù)庫分析,通過描述性統(tǒng)計(jì)分析,結(jié)果均顯示：中醫(yī)證候總分、心絞痛評分、硝酸甘油每日使用總量這3個(gè)變量的平均值有隨著時(shí)間點(diǎn)而明顯減小的變化趨勢,但是不同藥的數(shù)據(jù)庫,這三個(gè)變量下降的幅度不盡相同。 ②趨勢分析：不論是單個(gè)藥的數(shù)據(jù)庫分析,還是合并后的數(shù)據(jù)庫,將數(shù)據(jù)轉(zhuǎn)換為縱向數(shù)據(jù),結(jié)果均顯示：中醫(yī)證候總分、心絞痛評分、硝酸甘油每日使用總量這3個(gè)變量之間的個(gè)體差異是很明顯存在的,但是對所有個(gè)體而言,都有均數(shù)隨著用藥時(shí)間的延長而下降,并呈線性減少的趨勢。 ③相關(guān)分析：相關(guān)分析是研究變量間密切程度的一種方法,而反應(yīng)兩個(gè)變量間關(guān)系強(qiáng)弱程度和方向的的統(tǒng)計(jì)量稱作相關(guān)系數(shù)(coefficient of correlation)。為分析中醫(yī)證候評分變化與其他西醫(yī)結(jié)局指標(biāo)變化的特征及相關(guān)性。進(jìn)行了如下分析：對每一個(gè)患者,將其中醫(yī)證候總分相鄰兩次觀察時(shí)點(diǎn)、用藥前和用藥4周后作差得到中醫(yī)證候的差值分別與心絞痛評分的差值、硝酸甘油每日使用總量差值計(jì)算配對的相關(guān)系數(shù),并計(jì)算顯著性水平。統(tǒng)計(jì)結(jié)果顯示：無論是用藥前與用藥后4周,用藥前與用藥后2周以及用藥后2周與用藥后4周相關(guān)系數(shù)均有顯著意義,說明中醫(yī)證候總分變化與心絞痛評分變化、中醫(yī)證候總分變化與硝酸甘油每日使用總量變化之間都存在著正相關(guān)關(guān)系,但相關(guān)系數(shù)不是很高。 ④線性混合效應(yīng)模型分析：在此模型分析中因變量為中醫(yī)證候總分、心絞痛評分以及硝酸甘油每日使用總量,這三個(gè)指標(biāo)是一個(gè)在用藥前、用藥后2周和用藥后4周三個(gè)時(shí)間點(diǎn)重復(fù)測量3次的指標(biāo)。設(shè)定重復(fù)測量指標(biāo)變量為用藥后時(shí)間點(diǎn)(TIME)。因此相應(yīng)的影響因素有兩個(gè)：不同藥種類數(shù)據(jù)庫(Database)、用藥后時(shí)間點(diǎn)(TIME),將其作為定性變量(因素)納入模型,統(tǒng)計(jì)分析結(jié)果顯示：對于中醫(yī)證候總分、心絞痛評分以及硝酸甘油每日使用總量這三個(gè)指標(biāo)而言,用藥后時(shí)間點(diǎn)和藥種類數(shù)據(jù)庫的系數(shù)都通過了顯著性檢驗(yàn),說明這兩個(gè)指標(biāo)對個(gè)體中醫(yī)證候總分、心絞痛評分以及硝酸甘油每日使用總量都有影響,并且隨著用藥時(shí)間的延長,中醫(yī)證候總分、心絞痛評分以及硝酸甘油每日使用總量呈現(xiàn)明顯的下降趨勢。 ⑤廣義估計(jì)方程(GEE)分析：廣義估計(jì)方程(generalized estimating equations, GEE)是在廣義線性模型(generalized linear model, GLM)的基礎(chǔ)上發(fā)展而來,專門用來分析縱向數(shù)據(jù),其優(yōu)點(diǎn)在于可區(qū)分群體效應(yīng)和個(gè)體內(nèi)部的各個(gè)變量隨時(shí)間變化趨勢,因此,通過GEE模型,分析中醫(yī)證候評分、硝酸甘油使用量及心絞痛評分的動態(tài)變化特征。分析結(jié)果顯示：觀察時(shí)間點(diǎn)和藥種類數(shù)據(jù)庫對中醫(yī)證候總分、心絞痛評分以及硝酸甘油每日使用總量有影響,并且相對于用藥后4周的患者而言,隨著用藥時(shí)間的延長,各個(gè)患者的中醫(yī)證候總分、心絞痛評分以及硝酸甘油每日使用總量都有下降趨勢。 (2)研究內(nèi)容二：通過連續(xù)定向收集102例冠心病心絞痛(心血瘀阻證)患者進(jìn)行分析,結(jié)果表明： ①描述性統(tǒng)計(jì)分析：中醫(yī)證候總分、心絞痛評分的平均值有隨著用藥時(shí)間延長而明顯減小的變化趨勢,但從用藥4周后到藥6周后的時(shí)間段中平均值的減小趨勢趨緩。 ②趨勢分析：對所有個(gè)體而言,中醫(yī)證候總分、心絞痛評分都有均數(shù)隨著用藥時(shí)間的延長而下降,并呈線性減少的趨勢,但是隨著用藥時(shí)間的延長,下降的趨勢減緩,而硝酸甘油每日使用總量僅在用藥前至用藥2周后呈現(xiàn)出下降的趨勢。 ③相關(guān)分析：中醫(yī)證候總分變化與心絞痛評分變化之間存在正相關(guān)關(guān)系,但相關(guān)系數(shù)不是很高。中醫(yī)證候總分變化與硝酸甘油每日使用總量變化之間不存在相關(guān)關(guān)系。 ④線性混合效應(yīng)模型分析：對于中醫(yī)證候總分、心絞痛評分而言,用藥后時(shí)間點(diǎn)系數(shù)通過了顯著性檢驗(yàn),說明這指標(biāo)對中醫(yī)證候總分、心絞痛評分有影響,并且隨著用藥時(shí)間的延長有下降的趨勢；對于硝酸甘油每日使用總量而言,用藥后時(shí)間點(diǎn)系數(shù)通過了顯著性檢驗(yàn),說明這指標(biāo)對硝酸甘油每日使用總量有影響,但用藥2周后至用藥6周后硝酸甘油每日使用總量變化不大。 ⑤廣義估計(jì)方程(GEE)分析：對于中醫(yī)證候總分、心絞痛評分而言,用藥時(shí)間對其有影響,隨著用藥時(shí)間的延長中醫(yī)證候總分、心絞痛評分有下降的趨勢；用藥后時(shí)間點(diǎn)對硝酸甘油每日使用總量有影響,但用藥2周后至用藥6周后硝酸甘油每日使用總量變化不大。 結(jié)論： 通過以中醫(yī)藥治療冠心病心絞痛(心血瘀阻證)為例,分析中醫(yī)結(jié)局評價(jià)指標(biāo)——中醫(yī)證候評分,西醫(yī)結(jié)局評價(jià)指標(biāo)——心絞痛評分、硝酸甘油使用量的動態(tài)變化特征可以看出： (1)用藥時(shí)間及干預(yù)措施效應(yīng)是冠心病心絞痛中西醫(yī)評價(jià)結(jié)局動態(tài)變化的影響因素。 (2)冠心病心絞痛中西醫(yī)評價(jià)結(jié)局都有隨著時(shí)間延長而呈減少的趨勢,其中,中醫(yī)證候總分、心絞痛評分在用藥前至用藥2周后變化最大,而從用藥4周到用藥6周后減小趨勢趨緩。 (3)治療6周后,中醫(yī)證候總分、心絞痛評分仍在下降,提示評價(jià)中醫(yī)藥治療冠心病心絞痛的療效,6周的治療周期仍顯不足。
[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 .

【學(xué)位授予單位】：中國中醫(yī)科學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R541.4

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