中医药干预缺血性中风病3年随访结局研究与风险模型的构建
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摘要
1研究背景
大样本、长时间的随访有助于研究疾病的远期预后,而死亡、复发是对缺血性中风病影响最大、患者最想避免的临床事件,是终点结局指标。目前,国内中医药领域缺血性中风病研究随访时间较短,一般不超过1年,且样本量有限,较少以死亡、复发作为评价指标。此外,针对缺血性中风病患者采用早期介入的综合康复方案研究较少,对于其远期预后的影响尚不清楚。
另一方面,风险预测模型能够指导疾病的早期预警,国内外研究中多以现代危险因素预测疾病的预后,尚缺乏中医学内容,难以满足中医临床实际的需求。在建立风险模型时,影响因素筛选是最关键的步骤,Cox单因素与多因素分析是最常用的方法,但是其无法自动处理生存数据中的缺失数据,分析大量协变量数据时会丢失部分信息。
2研究目的
观察早期介入康复方案的患者出院后自然条件下疾病的转归,研究中医药早期干预后是否影响疾病的3年死亡与复发结局。分析缺血性中风病患者发生死亡与复发的影响因素,对筛选出的现代危险因素与中医证候等影响因素建立风险预测模型,为缺血性中风病患者二级预防提供参考依据。评价两种生存数据影响因素筛选的方法,为今后模型构建提供方法学指导。
3研究内容
3.1观察缺血性中风病3年随访的死亡与复发结局事件,比较早期介入中医综合康复方案与现代综合康复方案的患者远期预后的总生存与复发情况,以及与本病相关、直接相关、间接相关的死亡与复发情况,并进行死亡与复发NNT评价。
3.2运用Cox单因素与多因素方法、随机生存森林方法分别筛选缺血性中风病患者发生死亡与复发的现代危险因素和中医证候等影响因素,构建缺血性中风病3年预后的风险模型。
3.3根据ROC曲线下面积判断所建立风险模型的3年预测性能,评价两种筛选影响因素的方法。
4研究方法
4.1病例选择
纳入病例为2008年6月27日至2010年6月3日期间分布在全国12家临床单位急性缺血性中风病住院患者1059例。具有与研究相关的中西医诊断、纳入、排除、退出、剔除标准。
4.2研究设计
4.2.1设计类型
采取前瞻性、多中心、实用性随机对照试验方法。
4.2.2随机分组
采用“临床研究中央随机系统”,按照2：1的比例将1059例患者随机分为中医综合康复方案组705例和现代康复方案组354例,实现随机分配方案的隐藏。
4.2.3治疗方案
中医组在内科治疗的基础上,给予中药汤剂、中药注射剂、针刺、推拿,疗程10-21天；西医组在内科治疗的基础上,给予现代康复治疗,包括良肢位的设定、被动关节的运动、肢体功能训练、抑制痉挛的康复过程,疗程10-21天。内科基础治疗遵循2007年《中国脑血管病防治指南》制定的具体方法。
4.2.4评价指标
随访3年的死亡、复发事件。
4.2.5影响因素采集指标
影响因素指标包括：人口学特征、基础病情、血压、血糖、血脂数值、中医证候、合并疾病、出院后是否坚持服用抗栓药、基础治疗药、中药等27个因素。
4.3统计分析方法
运用SPSS160软件对不同组别间27个影响因素、死亡与未死亡患者特征、复发与未复发患者特征进行一般描述,采用R2.153软件中的imput.rsf, survival, Random Survival Forest, survivalROC软件包进行数据分析。
4.3.1结局研究
利用生存分析方法描述发生3年死亡与复发的趋势,通过log-rank检验比较不同组别间全因死亡、与缺血性中风病相关、直接相关、间接相关死亡、复发比例的差异,并计算死亡与复发的NNT。
4.3.2影响因素分析与风险模型建立
以27个调查因素作为协变量,分别运用Cox单因素与多因素方法、随机生存森林方法筛选预后的影响因素,基于筛选出的影响因素建立多元Cox风险模型,预测3年死亡或复发的风险。4.3.3风险模型3年预测性能评价
利用ROC曲线下面积评价风险模型的3年预测性能,比较Cox单因素与多因素方法、随机生存森林两种筛选影响因素方法的能力。
5研究结果
5.1随访完成情况
截止2012年12月底,1059例患者完成3年随访的患者为860例(含死亡患者80例),随访率为81.2%。完成3年随访的患者,中医组平均随访时间为3.22年,最长随访为4.37年；西医组平均随访时间为3.18年,最长随访为4.35年。
5.2一般描述
两组患者一般特征对比,其中中医组患者出院后选择服用中药的比例高于西医组,有显著统计学差异(P<0.05),其余无显著统计学差异(P>0.05)。
死亡患者与未死亡患者特征比较,结果显示死亡较未死亡患者年龄、NIHSS评分、痰湿蒙神证与复发比例、入院时收缩压、舒张压、低密度脂蛋白数值偏高(P<0.05),而FMA评分、BI评分、高密度脂蛋白数值、出院后坚持服用抗栓药与基础治疗药比例较未死亡患者偏低(P<0.05)。
复发患者与未复发患者特征比较,结果显示复发较未复发患者入院时低密度脂蛋白数值、合并血脂异常比例偏高(P<0.05),而高密度脂蛋白数值较未死亡患者偏低(P<0.05)。
5.3结局评价
5.3.1死亡事件分析
5.3.1.1全因死亡事件分析
随访3年,共死亡80例,中医组死亡风险为6.95%(49/705),平均生存时间为2.38年；西医组死亡风险为8.76%(31/354),平均生存时间为2.32年。中医组发生死亡风险低于西医组,经log-rank检验无显著统计学差异(P>0.05)。
5.3.1.2与缺血性中风病相关的死亡事件分析
随访3年,与缺血性中风病相关发生的死亡为28例,中医组死亡15例,死亡风险比例为2.13%(15/705),西医组死亡13例,死亡风险比例为3.67%(13/354),经log-rank检验无显著统计学差异(P>0.05)。
5.3.1.3与缺血性中风病直接相关的死亡事件分析
随访3年,与缺血性中风病直接相关发生的死亡为15例,中医组死亡9例,死亡风险比例为1.28%(9/705),西医组死亡6例,死亡风险比例为1.69%(6/354),经log-rank检验无显著统计学差异(P>0.05)。
5.3.1.4与缺血性中风病间接相关的死亡事件分析
随访3年,与缺血性中风病间接相关发生的死亡为13例,中医组死亡6例,死亡风险比例为0.85%(6/705),西医组死亡7例,死亡风险比例为1.98%(7/354),经log-rank检验无显著统计学差异(P>0.05)。
5.3.2复发事件分析
随访3年,共复发76例,中医组复发风险为6.67%(47/705),平均未复发时间为2.28年；西医组复发风险为8.19%(29/354),平均未复发时间为2.22年.中医组发生复发风险低于西医组,经log-rank检验无显著统计学差异(P>0.05)。
5.3.3死亡NNT评价
中医组每治疗55例患者,比西医组少1例死亡。NNT的95%CI:-59-18。此时NNT的95%CI包括0,即两种方案对于降低死亡风险比较,无统计学意义。
5.3.4复发NNT评价
中医组每治疗66例患者,比西医组少1例复发。NNT的95%CI：-53-20。此时NNT的95%CI包括0,即两种方案对于降低复发风险比较,无统计学意义。
5.4死亡与复发的影响因素筛选与风险模型建立
5.4.1基于Cox单因素与多因素分析的变量筛选与模型建立
5.4.1.1死亡的风险预测模型
以生存时间为结局变量,3年死亡的影响因素为：年龄(X1, P=0.000)、FMA评分(X2,P=0.000)、痰湿蒙神证(X3,P=0.000)、复发(X4,P=0.000)、收缩压(x5,P=0.000)、低密度脂蛋白(X6,P=0.014)、高密度脂蛋白(X7,P=0.002)、出院后是否坚持服用抗栓药(X8,P=0.001)、出院后是否坚持服用基础治疗药(X9,P=0.003)。风险预测模型为：
5.4.1.2复发的风险预测模型
以未复发时间为结局变量,3年复发的影响因素为：BI评分(X1,P=0.032)、空腹血糖(X2,P=0.037)、合并血脂异常(X3,P=0.003)。风险预测模型为：
5.4.2基于随机生存森林分析的变量筛选与模型建立
5.4.2.1死亡的风险预测模型
以生存时间为结局变量,3年死亡的影响因素为：年龄(X1,P=0.000).BI评分(X2,P=0.000)、痰湿蒙神证(X3,P=0.003)、是否复发(X4,P=0.000)、收缩压(X5,P=0.000)、低密度脂蛋白(X6,P=0.003)、高密度脂蛋白(X7,P=0.000)、合并血脂异常(X8,P--0.002)、出院后是否坚持服用抗栓药(X9,P=0.000)、出院后是否坚持服用基础治疗药(X1o,P=0.000)。风险预测模型为：
5.4.2.2复发的风险预测模型
以未复发时间为结局变量,3年复发的影响因素为：年龄(X1,P=0.076)、NIHSS评分(X2,P=0.051)、BI评分(X3,P=0.037)、痰湿蒙神证(X4,P=0.062)、空腹血糖(X5,P=0.038)、合并血脂异常(X6,P=0.000)。风险预测模型为：
5.5死亡与复发的风险模型评价
5.5.1死亡风险模型评价
基于随机生存森林方法筛选影响因素建立的多元Cox死亡预测模型(AUC均值=0.795),3年预测性能优于Cox单因素与多因素筛选方法(AUC均值=0.782)。
5.5.2复发风险模型评价
基于随机生存森林方法筛选影响因素建立的多元Cox复发预测模型(AUC均值=0.621),3年预测性能优于Cox单因素与多因素筛选方法(AUC均值=0.605)。
6研究结论
6.1随访3年,中医组全因死亡风险、与缺血性中风病相关、直接相关、间接相关的死亡风险均低于西医组(P>0.05),复发风险亦低于西医组(P>0.05),并且生存时间与未复发时间均高于西医组,提示中医康复方案能够降低死亡或复发的风险。死亡NNT结果表明中医组每治疗55例患者,比西医组少1例死亡,复发NNT结果表明中医组每治疗66例患者,比西医组少1例复发。考虑到本研究受样本量等因素的影响,尚未显示出明显的统计学差异。
6.2以生存时间为结局变量,随机生存森林方法筛选出年龄、BI评分、痰湿蒙神证、复发、收缩压、低密度脂蛋白、高密度脂蛋白、合并血脂异常、出院后是否坚持服用抗栓药、出院后是否坚持服用基础治疗药是3年死亡的影响因素。
6.3以未复发时间作为结局变量,随机生存森林方法筛选出年龄、NIHSS评分、BI评分、痰湿蒙神证、空腹血糖、合并血脂异常是3年复发的影响因素。
6.4研究建立了缺血性中风病患者发生3年死亡与复发的预测模型和预后指数,基于随机生存森林方法影响因素筛选构建的多元Cox风险模型,预测缺血性中风病患者发生死亡或者复发的概率,与Cox单因素与多因素方法筛选影响因素后所构建的模型相比,3年预测性能更好。
7创新点
7.1首次在中医药领域开展缺血性中风病3年的随访研究,并且以死亡、复发事件作为终点结局指标,研究早期介入的中医康复方案对于远期结局的影响；
7.2运用随机生存森林方法,从大量协变量数据中筛选出影响缺血性中风病预后的重要现代危险因素或中医证候特征,并且能够考虑生存数据的缺失值问题；
7.3缺血性中风病预后风险预测模型中,融入中医证候学的特色内容,增加中医临床的意义。
1Background
Large sample, long time follow-up helps to study the long-term prognosis of disease, while mortality and recurrence are the clinical events which are the greatest impact on ischemic stroke and the patients most want to avoid, and are the end outcome evaluation index. At present, ischemic stroke study time is not long, usually less than one year, and the sample size is limited, taking the long-term outcome of death and recurrence as the evaluation index is unusual in the field of traditional Chinese medicine(TCM) follow-up. In addition, early comprehensive rehabilitation program intervention study for ischemic stroke patients is less, and the influence on the long-term prognosis remains unclear.
On the other hand, risk prediction model could guide the early warning. Research at home and abroad almost paid attention to modern risk factors predicting the prognosis of the disease, lack of the TCM items, which was difficult to meet the clinical needs of TCM clinical practice. Influencing factors screening is the most important step in the construction of risk model. Cox single-factor and multi-factor analysis is the general method, while it unable to automatically handle missing data in the survival data, analysis of numerous covariate data will lost some information.
2Objective
The paper has three aims. In the first place, we want to observe natural outcome of the ischemic stroke patients treated by early rehabilitation program intervention after discharge, and study whether early TCM intervention program can influence ischemic stoke death and recurrence in3years. In the second place, this study analyses the death and recurrence influencing factors of ischemic stroke patients, and construct the corresponding risk model based on modern risk factors and TCM syndrome, in order to provide reference proposal for second prevention. In the third place, we hope to evaluate two influencing factors screening method used in the survival data, so as to provide methodological guidance for model building in the future.
3Content
3.1Observe the all-cause mortality, mortality related to ischemic stroke, mortality directly related to ischemic stroke, mortality indirectly related to ischemic stroke, and recurrence of ischemic stroke, and compare survival and recurrence of the long-term prognosis in patients with early intervention of TCM comprehensive rehabilitation plan and modern rehabilitation through3-year follow up. In addition, death and recurrence number needed to treat(NNT) are assessed.
3.2Build a3-year prognosis risk model of ischemic stroke by screening modern risk factor and TCM syndrome which are influencing factors of death and recurrence between the two groups. Cox single-factor and multi-factor analysis and random survival forests(RSF) are the two screening methods used by us.
3.3Evaluate the two screening methods of influencing factors according to the3-year forecasting performance of the risk model judged by area under the receiver operating characteristic curve(ROC).
4Method
4.1Cases criterion
1059patients with acute ischemic stroke were enrolled in12clinical units throughout the country in2008June27to June3,2010. The TCM and Western medicine(WM) diagnosis, inclusion, exclusion, exit, withdrawal criteria respectively was established.
4.2Research Design
4.2.1Design Type
A prospective, multicenter, pragmatic randomized controlled trial method was adopted.
4.2.2Random Allocation
Clinical research central stochastic system, in accordance with the ratio of2:1,1059patients were randomly divided into705cases of Chinese medicine comprehensive rehabilitation program group and354cases of modern rehabilitation programs group, achieving the concealment of random allocation program.
4.2.3Treatment Programs
TCM group was given decoction of Chinese medicine, traditional Chinese medicine injections, acupuncture and massage therapy, treatment for10-21days. WM group was given the modern rehabilitation, including the setting of the limbs in good position, passive movement of the joint, limb function training, the rehabilitation process of suppressing spasms, the course of10-20days. Basic medical treatment to follow the specific methods of "prevention and treatment guidelines of China cerebrovascular disease" developed in2007.
4.2.4Evaluation Index
Death and recurrent events were followed up for3years.
4.2.5Influencing factors collected index
Influencing factors collected index include:general information, basic condition, TCM syndrome, primary comorbidities, whether to insist on taking drugs after discharge,27factors, etc.
4.3Statistical analysis methods
We generally described the characteristics of the different groups, death and without death crowd, recurrence and without recurrence crowd by SPSS16.0software. Using imput.rsf, survival, Random Survival Forest, survivalROC software package of R2.15.3software for data analysis.
4.3.1Outcome Research
Describe the the all-cause mortality, mortality related to ischemic stroke, mortality directly related to ischemic stroke, mortality indirectly related to ischemic stroke, and recurrence of ischemic stroke occurred of different groups in3years by the method of survival analysis, comparing the differences in proportion of death and recurrence of different groups by the log-rank test.
4.3.2Influence factors analysis and the establishment of risk models
With27survey factors as the covariate, we screen the influencing factors of prognosis of different groups respectively using the Cox single-factor and multi-factor method, RSF method, establish multivariate Cox risk model based on the screening influencing factors to predict the risk of death and recurrence in3years.
4.3.3Risk model long-term predict performance evaluation
The area under ROC curve to evaluate the long-term forecast performance of the risk model, compare the ability of screening influence factors using Cox single-factor and multi-factor approach and RSF method.
5Result
5.1Completion of follow-up
860cases(including80cases death) has completed the3-year follow-up work in1059cases by the end of December2012, the follow-up rate was81.2%. The average follow-up time of TCM group and WM group is3.22and3.18years respectively, and the longest follow-up time is4.37and4.35years respectively.
5.2The general description
The proportion of TCM group patients after discharge insisting on taking the Chinese medicine is higher than WM medicine group, there is statistically significant(P<0.05), while other items shows no significance between the groups(P>0.05).
Take Whether to death as a grouping variable, the results shows that age, national institute of health stroke scale(NIHSS) score, the proportion of tanshimengshen syndrome and relapse, systolic blood pressure, diastolic blood pressure, low density lipoprotein cholesterol(LDL-C) values on admission are higher in the death group(P<0.05). However, fugl-meyer assessment(FMA) score, barthel index(BI) score, high density lipoprotein cholesterol(HDL-C) values on admission are lower in the death group(P<0.05).
Take Whether to relapse as a grouping variable, the results shows that LDL-C values on admission and the proportion of combined with dyslipidemia are higher in the relapse group(P<0.05). However, HDL-C values on admission are lower in the relapse group(P<0.05).
5.3Outcome Research
5.3.1Mortality analysis
5.3.1.1All-cause mortality
Through3-year follow up,80cases died.49cases died in the TCM group(N=705), risk proportion of death is6.95%.31cases died in the WM group(N=354), risk proportion of death is8.76%. The average survival time of TCM group and WM group is2.38and2.32years respectively, no statistical significance is found between the groups through log-rank test(P>0.05).
5.3.1.2mortality related to ischemic stroke
Through3-year follow up, there are28cases died because of ischemic stroke.15cases died in the TCM group(N=705), risk proportion of death is2.13%.13cases died in the WM group(N=354), risk proportion of death is3.67%, no statistical significance is found between the groups through log-rank test(P>0.05).
5.3.1.3mortality directly related to ischemic stroke
Through3-year follow up, there are15cases died directly related to ischemic stroke.9cases died in the TCM group(N=705), risk proportion of death is1.28%.6cases died in the WM group(N=354), risk proportion of death is1.69%, no statistical significance is found between the groups through log-rank test(P>0.05).
5.3.1.4mortality indirectly related to ischemic stroke
Through3-year follow up, there are13cases died indirectly related to ischemic stroke.6cases died in the TCM group(N=705), risk proportion of death is0.85%.7cases died in the WM group(N=354), risk proportion of death is1.98%, no statistical significance is found between the groups through log-rank test(P>0.05).
5.3.2Recurrence analysis
Through3-year follow up,76cases relapsed.47cases relapsed in the TCM group(N=705), risk proportion of death is6.67%.29cases relapsed in the WM group(N=354), risk proportion of death is8.19%. The average free-relapse time of Chinese medicine group and WM group is2.28and2.22years respectively, no statistical significance is between the groups found through log-rank test(P>0.05).
5.3.3Death NNT evaluation
Compared with WM goup, there was1death case short out of every55patients in TCM group. NNT95%CI is (-59,18). As a result of the95%CI include0, so the comparison between the two rehabilitation programs reducing the risk of death shows no statistical significance.
5.3.4Recurrence NNT evaluation
Compared with WM goup, there was1recurrence case short out of every66patients in TCM group. NNT95%CI is (-53,20). As a result of the95%CI include0, so the comparison between the two rehabilitation programs reducing the risk of recurrence shows no statistical significance.
5.4Screening for influencing factors of death and relapse and risk model establishment
5.4.1Variable screen and model establishment based on Cox single-factor and multi-factor analysis
5.4.1.1Death within three years risk prediction model
Take survival time as outcome variable, influencing factors of death within three years are as below:age(X1,P=0.000), FMA score(X2, P=0.000), tanshimengshen syndrome(X3, P=0.000), whether to relapse(X4, P=0.000), Systolic pressure(X5, P=0.000), LDL(X6, P=0.014), HDL(X7,P=0.002), whether the patients continue to take antithrombotic drugs after discharge (Xg, P=0.001), whether the patients continue to receive a basic curative treatment after discharge(X9,P=0.003). Then build the risk model: h(t|X)=h0(t)exp(0.064*X1-0.022*X2+1.874*X3+1.590*X4+0.026*X5+0.329*X6-0.586*X7-0.952*X8-0.935*X9)
5.4.1.2Relapse within three years risk prediction model of
Take no relapse time as outcome variable, influencing factors of relapse are:BI score(X1, P=0.032), fasting plasma glucose level(X2, P=0.037), combined with dyslipidemia(X3, P=0.003). Then build the risk model as below: h(t|X)=h0(t)exp(-0.008*X1+0.072*X2+0.842*X3)
5.4.2Variable screen and model establishment based on RSF
5.4.2.1Death within three years risk prediction model
Take survival time as outcome variable, influencing factors for death within three years are as below:age(X1,P=0.000), BI score(X2, P=0.000), tanshimengshen syndrome(X3, P=0.000), whether to relapse(X4, P=0.000), Systolic pressure(X5, P=0.000), LDL(X6, P=0.003), HDL(X7, P=0.000), combined with dyslipidemia(X8, P=0.002), whether the patients continue to take antithrombotic drugs after discharge (X9, P=0.000), whether the patients continue to receive a basic curative treatment after discharge(Xio, P=0.000). Then build the risk model as follows: h(t|X)=h0(t)exp(0.066*X1-0.023*X2+1.439*X3+1.112*X4+0.026*X5+0.356*X6-0.637*X7+0.804*X8-1.236*X9-1.437*X10)
5.4.2.2Relapse within three years risk prediction model
Take no relapse time as outcome variable, influencing factors of relapse including age(Xi, P=0.076), NIHSS score(Xi, P=0.051), BI score(X3, P=0.037), tanshimengshen syndrome(X4, P=0.062), fasting plasma glucose level(X5, P=0.038), combined with dyslipidemia(X6, P=0.000). Then build the risk model: h(t|X)=ho(t)exp(0.018*X1+0.011*X2-0.009*X3+0.475*X4+0.068*X5+0.817*X6)
5.5Death and relapse risk model evaluation
5.5.1Death risk model evaluation
The Cox death risk prediction model built based on screening influencing factors via RSF method(AUC=0.795) had better performance in3-year predication than Cox single-factor and multiple factors analysis(AUC=0.782).
5.5.2Relapse risk model evaluation
The Cox relapse prediction model built based on screening influencing factors via RSF method(AUC=0.621) performed better in3-year predication than Cox single-factor and multiple factors analysis(AUC=0.605).
6Conclusion
6.1After3-year period follow-up, it inllustrates that for TCM group both all-cause motality, mortality related to ischemic stroke, mortality directly related to ischemic stroke, mortality indirectly related to ischemic stroke, and recurrence hazard are lower than WM group(P>0.05). Indeed, survival time and relapse-free time in TCM group are much higher than WM group, which indicates a better developing trend for TCM group. Compared with WM goup, there was1death case short out of every55patients in TCM group. Compared with WM goup, there was1recurrence case short out of every66patients in TCM group. However, considering that this study is influened by sample size, there is no obvious significance between the groups.
6.2Take survival time as an endpoint variable, and research method is random survival forests (RSF). Consequentially, impact factors in3year are:age, BI score, tanshimengshen syndrome, whether to recurrence, systolic blood pressure, LDL-C, HDL-C, combined with dyslipidemia, insistency of antithrombotic drugs intake after discharged, and insistency of basic treatment drugs.
6.3Set relapse-free time as endpoint variable(Research method:RSF). Influencing factors on3-year recurrence indicate:age, NIHSS score, BI score, tanshimengshen syndrome, fasting blood-glucose, combined abnormal lipid metabolism.
6.4This study has builded ischemic stroke3-year death and recurrence prediction model and prognosis index. Cox proportional hazard model is established by screening infulencing factors under RSF. In comparison to Cox single-factor and multi-factor screening method, the model3-year prediction performance based on RSF shows a better vision.
7Innovation
7.1Taking death and recurrence as assessment indicators, it analyses the outcome effects of early intervention of TCM rehabilitation therpy by a3-year long-trem follow up study in the first time.
7.2Screening important morden risk factors or TCM syndrome of ischemic stroke prognosis among a mass of concomitant variables. Besides, it takes into account missing value of survival data.
7.3Characteristic TCM content is integrated in risk assessment model of ischemic stroke prognosis, which increases TCM clinical significance.
大样本、长时间的随访有助于研究疾病的远期预后,而死亡、复发是对缺血性中风病影响最大、患者最想避免的临床事件,是终点结局指标。目前,国内中医药领域缺血性中风病研究随访时间较短,一般不超过1年,且样本量有限,较少以死亡、复发作为评价指标。此外,针对缺血性中风病患者采用早期介入的综合康复方案研究较少,对于其远期预后的影响尚不清楚。
另一方面,风险预测模型能够指导疾病的早期预警,国内外研究中多以现代危险因素预测疾病的预后,尚缺乏中医学内容,难以满足中医临床实际的需求。在建立风险模型时,影响因素筛选是最关键的步骤,Cox单因素与多因素分析是最常用的方法,但是其无法自动处理生存数据中的缺失数据,分析大量协变量数据时会丢失部分信息。
2研究目的
观察早期介入康复方案的患者出院后自然条件下疾病的转归,研究中医药早期干预后是否影响疾病的3年死亡与复发结局。分析缺血性中风病患者发生死亡与复发的影响因素,对筛选出的现代危险因素与中医证候等影响因素建立风险预测模型,为缺血性中风病患者二级预防提供参考依据。评价两种生存数据影响因素筛选的方法,为今后模型构建提供方法学指导。
3研究内容
3.1观察缺血性中风病3年随访的死亡与复发结局事件,比较早期介入中医综合康复方案与现代综合康复方案的患者远期预后的总生存与复发情况,以及与本病相关、直接相关、间接相关的死亡与复发情况,并进行死亡与复发NNT评价。
3.2运用Cox单因素与多因素方法、随机生存森林方法分别筛选缺血性中风病患者发生死亡与复发的现代危险因素和中医证候等影响因素,构建缺血性中风病3年预后的风险模型。
3.3根据ROC曲线下面积判断所建立风险模型的3年预测性能,评价两种筛选影响因素的方法。
4研究方法
4.1病例选择
纳入病例为2008年6月27日至2010年6月3日期间分布在全国12家临床单位急性缺血性中风病住院患者1059例。具有与研究相关的中西医诊断、纳入、排除、退出、剔除标准。
4.2研究设计
4.2.1设计类型
采取前瞻性、多中心、实用性随机对照试验方法。
4.2.2随机分组
采用“临床研究中央随机系统”,按照2：1的比例将1059例患者随机分为中医综合康复方案组705例和现代康复方案组354例,实现随机分配方案的隐藏。
4.2.3治疗方案
中医组在内科治疗的基础上,给予中药汤剂、中药注射剂、针刺、推拿,疗程10-21天；西医组在内科治疗的基础上,给予现代康复治疗,包括良肢位的设定、被动关节的运动、肢体功能训练、抑制痉挛的康复过程,疗程10-21天。内科基础治疗遵循2007年《中国脑血管病防治指南》制定的具体方法。
4.2.4评价指标
随访3年的死亡、复发事件。
4.2.5影响因素采集指标
影响因素指标包括：人口学特征、基础病情、血压、血糖、血脂数值、中医证候、合并疾病、出院后是否坚持服用抗栓药、基础治疗药、中药等27个因素。
4.3统计分析方法
运用SPSS160软件对不同组别间27个影响因素、死亡与未死亡患者特征、复发与未复发患者特征进行一般描述,采用R2.153软件中的imput.rsf, survival, Random Survival Forest, survivalROC软件包进行数据分析。
4.3.1结局研究
利用生存分析方法描述发生3年死亡与复发的趋势,通过log-rank检验比较不同组别间全因死亡、与缺血性中风病相关、直接相关、间接相关死亡、复发比例的差异,并计算死亡与复发的NNT。
4.3.2影响因素分析与风险模型建立
以27个调查因素作为协变量,分别运用Cox单因素与多因素方法、随机生存森林方法筛选预后的影响因素,基于筛选出的影响因素建立多元Cox风险模型,预测3年死亡或复发的风险。4.3.3风险模型3年预测性能评价
利用ROC曲线下面积评价风险模型的3年预测性能,比较Cox单因素与多因素方法、随机生存森林两种筛选影响因素方法的能力。
5研究结果
5.1随访完成情况
截止2012年12月底,1059例患者完成3年随访的患者为860例(含死亡患者80例),随访率为81.2%。完成3年随访的患者,中医组平均随访时间为3.22年,最长随访为4.37年；西医组平均随访时间为3.18年,最长随访为4.35年。
5.2一般描述
两组患者一般特征对比,其中中医组患者出院后选择服用中药的比例高于西医组,有显著统计学差异(P<0.05),其余无显著统计学差异(P>0.05)。
死亡患者与未死亡患者特征比较,结果显示死亡较未死亡患者年龄、NIHSS评分、痰湿蒙神证与复发比例、入院时收缩压、舒张压、低密度脂蛋白数值偏高(P<0.05),而FMA评分、BI评分、高密度脂蛋白数值、出院后坚持服用抗栓药与基础治疗药比例较未死亡患者偏低(P<0.05)。
复发患者与未复发患者特征比较,结果显示复发较未复发患者入院时低密度脂蛋白数值、合并血脂异常比例偏高(P<0.05),而高密度脂蛋白数值较未死亡患者偏低(P<0.05)。
5.3结局评价
5.3.1死亡事件分析
5.3.1.1全因死亡事件分析
随访3年,共死亡80例,中医组死亡风险为6.95%(49/705),平均生存时间为2.38年；西医组死亡风险为8.76%(31/354),平均生存时间为2.32年。中医组发生死亡风险低于西医组,经log-rank检验无显著统计学差异(P>0.05)。
5.3.1.2与缺血性中风病相关的死亡事件分析
随访3年,与缺血性中风病相关发生的死亡为28例,中医组死亡15例,死亡风险比例为2.13%(15/705),西医组死亡13例,死亡风险比例为3.67%(13/354),经log-rank检验无显著统计学差异(P>0.05)。
5.3.1.3与缺血性中风病直接相关的死亡事件分析
随访3年,与缺血性中风病直接相关发生的死亡为15例,中医组死亡9例,死亡风险比例为1.28%(9/705),西医组死亡6例,死亡风险比例为1.69%(6/354),经log-rank检验无显著统计学差异(P>0.05)。
5.3.1.4与缺血性中风病间接相关的死亡事件分析
随访3年,与缺血性中风病间接相关发生的死亡为13例,中医组死亡6例,死亡风险比例为0.85%(6/705),西医组死亡7例,死亡风险比例为1.98%(7/354),经log-rank检验无显著统计学差异(P>0.05)。
5.3.2复发事件分析
随访3年,共复发76例,中医组复发风险为6.67%(47/705),平均未复发时间为2.28年；西医组复发风险为8.19%(29/354),平均未复发时间为2.22年.中医组发生复发风险低于西医组,经log-rank检验无显著统计学差异(P>0.05)。
5.3.3死亡NNT评价
中医组每治疗55例患者,比西医组少1例死亡。NNT的95%CI:-59-18。此时NNT的95%CI包括0,即两种方案对于降低死亡风险比较,无统计学意义。
5.3.4复发NNT评价
中医组每治疗66例患者,比西医组少1例复发。NNT的95%CI：-53-20。此时NNT的95%CI包括0,即两种方案对于降低复发风险比较,无统计学意义。
5.4死亡与复发的影响因素筛选与风险模型建立
5.4.1基于Cox单因素与多因素分析的变量筛选与模型建立
5.4.1.1死亡的风险预测模型
以生存时间为结局变量,3年死亡的影响因素为：年龄(X1, P=0.000)、FMA评分(X2,P=0.000)、痰湿蒙神证(X3,P=0.000)、复发(X4,P=0.000)、收缩压(x5,P=0.000)、低密度脂蛋白(X6,P=0.014)、高密度脂蛋白(X7,P=0.002)、出院后是否坚持服用抗栓药(X8,P=0.001)、出院后是否坚持服用基础治疗药(X9,P=0.003)。风险预测模型为：
5.4.1.2复发的风险预测模型
以未复发时间为结局变量,3年复发的影响因素为：BI评分(X1,P=0.032)、空腹血糖(X2,P=0.037)、合并血脂异常(X3,P=0.003)。风险预测模型为：
5.4.2基于随机生存森林分析的变量筛选与模型建立
5.4.2.1死亡的风险预测模型
以生存时间为结局变量,3年死亡的影响因素为：年龄(X1,P=0.000).BI评分(X2,P=0.000)、痰湿蒙神证(X3,P=0.003)、是否复发(X4,P=0.000)、收缩压(X5,P=0.000)、低密度脂蛋白(X6,P=0.003)、高密度脂蛋白(X7,P=0.000)、合并血脂异常(X8,P--0.002)、出院后是否坚持服用抗栓药(X9,P=0.000)、出院后是否坚持服用基础治疗药(X1o,P=0.000)。风险预测模型为：
5.4.2.2复发的风险预测模型
以未复发时间为结局变量,3年复发的影响因素为：年龄(X1,P=0.076)、NIHSS评分(X2,P=0.051)、BI评分(X3,P=0.037)、痰湿蒙神证(X4,P=0.062)、空腹血糖(X5,P=0.038)、合并血脂异常(X6,P=0.000)。风险预测模型为：
5.5死亡与复发的风险模型评价
5.5.1死亡风险模型评价
基于随机生存森林方法筛选影响因素建立的多元Cox死亡预测模型(AUC均值=0.795),3年预测性能优于Cox单因素与多因素筛选方法(AUC均值=0.782)。
5.5.2复发风险模型评价
基于随机生存森林方法筛选影响因素建立的多元Cox复发预测模型(AUC均值=0.621),3年预测性能优于Cox单因素与多因素筛选方法(AUC均值=0.605)。
6研究结论
6.1随访3年,中医组全因死亡风险、与缺血性中风病相关、直接相关、间接相关的死亡风险均低于西医组(P>0.05),复发风险亦低于西医组(P>0.05),并且生存时间与未复发时间均高于西医组,提示中医康复方案能够降低死亡或复发的风险。死亡NNT结果表明中医组每治疗55例患者,比西医组少1例死亡,复发NNT结果表明中医组每治疗66例患者,比西医组少1例复发。考虑到本研究受样本量等因素的影响,尚未显示出明显的统计学差异。
6.2以生存时间为结局变量,随机生存森林方法筛选出年龄、BI评分、痰湿蒙神证、复发、收缩压、低密度脂蛋白、高密度脂蛋白、合并血脂异常、出院后是否坚持服用抗栓药、出院后是否坚持服用基础治疗药是3年死亡的影响因素。
6.3以未复发时间作为结局变量,随机生存森林方法筛选出年龄、NIHSS评分、BI评分、痰湿蒙神证、空腹血糖、合并血脂异常是3年复发的影响因素。
6.4研究建立了缺血性中风病患者发生3年死亡与复发的预测模型和预后指数,基于随机生存森林方法影响因素筛选构建的多元Cox风险模型,预测缺血性中风病患者发生死亡或者复发的概率,与Cox单因素与多因素方法筛选影响因素后所构建的模型相比,3年预测性能更好。
7创新点
7.1首次在中医药领域开展缺血性中风病3年的随访研究,并且以死亡、复发事件作为终点结局指标,研究早期介入的中医康复方案对于远期结局的影响；
7.2运用随机生存森林方法,从大量协变量数据中筛选出影响缺血性中风病预后的重要现代危险因素或中医证候特征,并且能够考虑生存数据的缺失值问题；
7.3缺血性中风病预后风险预测模型中,融入中医证候学的特色内容,增加中医临床的意义。
1Background
Large sample, long time follow-up helps to study the long-term prognosis of disease, while mortality and recurrence are the clinical events which are the greatest impact on ischemic stroke and the patients most want to avoid, and are the end outcome evaluation index. At present, ischemic stroke study time is not long, usually less than one year, and the sample size is limited, taking the long-term outcome of death and recurrence as the evaluation index is unusual in the field of traditional Chinese medicine(TCM) follow-up. In addition, early comprehensive rehabilitation program intervention study for ischemic stroke patients is less, and the influence on the long-term prognosis remains unclear.
On the other hand, risk prediction model could guide the early warning. Research at home and abroad almost paid attention to modern risk factors predicting the prognosis of the disease, lack of the TCM items, which was difficult to meet the clinical needs of TCM clinical practice. Influencing factors screening is the most important step in the construction of risk model. Cox single-factor and multi-factor analysis is the general method, while it unable to automatically handle missing data in the survival data, analysis of numerous covariate data will lost some information.
2Objective
The paper has three aims. In the first place, we want to observe natural outcome of the ischemic stroke patients treated by early rehabilitation program intervention after discharge, and study whether early TCM intervention program can influence ischemic stoke death and recurrence in3years. In the second place, this study analyses the death and recurrence influencing factors of ischemic stroke patients, and construct the corresponding risk model based on modern risk factors and TCM syndrome, in order to provide reference proposal for second prevention. In the third place, we hope to evaluate two influencing factors screening method used in the survival data, so as to provide methodological guidance for model building in the future.
3Content
3.1Observe the all-cause mortality, mortality related to ischemic stroke, mortality directly related to ischemic stroke, mortality indirectly related to ischemic stroke, and recurrence of ischemic stroke, and compare survival and recurrence of the long-term prognosis in patients with early intervention of TCM comprehensive rehabilitation plan and modern rehabilitation through3-year follow up. In addition, death and recurrence number needed to treat(NNT) are assessed.
3.2Build a3-year prognosis risk model of ischemic stroke by screening modern risk factor and TCM syndrome which are influencing factors of death and recurrence between the two groups. Cox single-factor and multi-factor analysis and random survival forests(RSF) are the two screening methods used by us.
3.3Evaluate the two screening methods of influencing factors according to the3-year forecasting performance of the risk model judged by area under the receiver operating characteristic curve(ROC).
4Method
4.1Cases criterion
1059patients with acute ischemic stroke were enrolled in12clinical units throughout the country in2008June27to June3,2010. The TCM and Western medicine(WM) diagnosis, inclusion, exclusion, exit, withdrawal criteria respectively was established.
4.2Research Design
4.2.1Design Type
A prospective, multicenter, pragmatic randomized controlled trial method was adopted.
4.2.2Random Allocation
Clinical research central stochastic system, in accordance with the ratio of2:1,1059patients were randomly divided into705cases of Chinese medicine comprehensive rehabilitation program group and354cases of modern rehabilitation programs group, achieving the concealment of random allocation program.
4.2.3Treatment Programs
TCM group was given decoction of Chinese medicine, traditional Chinese medicine injections, acupuncture and massage therapy, treatment for10-21days. WM group was given the modern rehabilitation, including the setting of the limbs in good position, passive movement of the joint, limb function training, the rehabilitation process of suppressing spasms, the course of10-20days. Basic medical treatment to follow the specific methods of "prevention and treatment guidelines of China cerebrovascular disease" developed in2007.
4.2.4Evaluation Index
Death and recurrent events were followed up for3years.
4.2.5Influencing factors collected index
Influencing factors collected index include:general information, basic condition, TCM syndrome, primary comorbidities, whether to insist on taking drugs after discharge,27factors, etc.
4.3Statistical analysis methods
We generally described the characteristics of the different groups, death and without death crowd, recurrence and without recurrence crowd by SPSS16.0software. Using imput.rsf, survival, Random Survival Forest, survivalROC software package of R2.15.3software for data analysis.
4.3.1Outcome Research
Describe the the all-cause mortality, mortality related to ischemic stroke, mortality directly related to ischemic stroke, mortality indirectly related to ischemic stroke, and recurrence of ischemic stroke occurred of different groups in3years by the method of survival analysis, comparing the differences in proportion of death and recurrence of different groups by the log-rank test.
4.3.2Influence factors analysis and the establishment of risk models
With27survey factors as the covariate, we screen the influencing factors of prognosis of different groups respectively using the Cox single-factor and multi-factor method, RSF method, establish multivariate Cox risk model based on the screening influencing factors to predict the risk of death and recurrence in3years.
4.3.3Risk model long-term predict performance evaluation
The area under ROC curve to evaluate the long-term forecast performance of the risk model, compare the ability of screening influence factors using Cox single-factor and multi-factor approach and RSF method.
5Result
5.1Completion of follow-up
860cases(including80cases death) has completed the3-year follow-up work in1059cases by the end of December2012, the follow-up rate was81.2%. The average follow-up time of TCM group and WM group is3.22and3.18years respectively, and the longest follow-up time is4.37and4.35years respectively.
5.2The general description
The proportion of TCM group patients after discharge insisting on taking the Chinese medicine is higher than WM medicine group, there is statistically significant(P<0.05), while other items shows no significance between the groups(P>0.05).
Take Whether to death as a grouping variable, the results shows that age, national institute of health stroke scale(NIHSS) score, the proportion of tanshimengshen syndrome and relapse, systolic blood pressure, diastolic blood pressure, low density lipoprotein cholesterol(LDL-C) values on admission are higher in the death group(P<0.05). However, fugl-meyer assessment(FMA) score, barthel index(BI) score, high density lipoprotein cholesterol(HDL-C) values on admission are lower in the death group(P<0.05).
Take Whether to relapse as a grouping variable, the results shows that LDL-C values on admission and the proportion of combined with dyslipidemia are higher in the relapse group(P<0.05). However, HDL-C values on admission are lower in the relapse group(P<0.05).
5.3Outcome Research
5.3.1Mortality analysis
5.3.1.1All-cause mortality
Through3-year follow up,80cases died.49cases died in the TCM group(N=705), risk proportion of death is6.95%.31cases died in the WM group(N=354), risk proportion of death is8.76%. The average survival time of TCM group and WM group is2.38and2.32years respectively, no statistical significance is found between the groups through log-rank test(P>0.05).
5.3.1.2mortality related to ischemic stroke
Through3-year follow up, there are28cases died because of ischemic stroke.15cases died in the TCM group(N=705), risk proportion of death is2.13%.13cases died in the WM group(N=354), risk proportion of death is3.67%, no statistical significance is found between the groups through log-rank test(P>0.05).
5.3.1.3mortality directly related to ischemic stroke
Through3-year follow up, there are15cases died directly related to ischemic stroke.9cases died in the TCM group(N=705), risk proportion of death is1.28%.6cases died in the WM group(N=354), risk proportion of death is1.69%, no statistical significance is found between the groups through log-rank test(P>0.05).
5.3.1.4mortality indirectly related to ischemic stroke
Through3-year follow up, there are13cases died indirectly related to ischemic stroke.6cases died in the TCM group(N=705), risk proportion of death is0.85%.7cases died in the WM group(N=354), risk proportion of death is1.98%, no statistical significance is found between the groups through log-rank test(P>0.05).
5.3.2Recurrence analysis
Through3-year follow up,76cases relapsed.47cases relapsed in the TCM group(N=705), risk proportion of death is6.67%.29cases relapsed in the WM group(N=354), risk proportion of death is8.19%. The average free-relapse time of Chinese medicine group and WM group is2.28and2.22years respectively, no statistical significance is between the groups found through log-rank test(P>0.05).
5.3.3Death NNT evaluation
Compared with WM goup, there was1death case short out of every55patients in TCM group. NNT95%CI is (-59,18). As a result of the95%CI include0, so the comparison between the two rehabilitation programs reducing the risk of death shows no statistical significance.
5.3.4Recurrence NNT evaluation
Compared with WM goup, there was1recurrence case short out of every66patients in TCM group. NNT95%CI is (-53,20). As a result of the95%CI include0, so the comparison between the two rehabilitation programs reducing the risk of recurrence shows no statistical significance.
5.4Screening for influencing factors of death and relapse and risk model establishment
5.4.1Variable screen and model establishment based on Cox single-factor and multi-factor analysis
5.4.1.1Death within three years risk prediction model
Take survival time as outcome variable, influencing factors of death within three years are as below:age(X1,P=0.000), FMA score(X2, P=0.000), tanshimengshen syndrome(X3, P=0.000), whether to relapse(X4, P=0.000), Systolic pressure(X5, P=0.000), LDL(X6, P=0.014), HDL(X7,P=0.002), whether the patients continue to take antithrombotic drugs after discharge (Xg, P=0.001), whether the patients continue to receive a basic curative treatment after discharge(X9,P=0.003). Then build the risk model: h(t|X)=h0(t)exp(0.064*X1-0.022*X2+1.874*X3+1.590*X4+0.026*X5+0.329*X6-0.586*X7-0.952*X8-0.935*X9)
5.4.1.2Relapse within three years risk prediction model of
Take no relapse time as outcome variable, influencing factors of relapse are:BI score(X1, P=0.032), fasting plasma glucose level(X2, P=0.037), combined with dyslipidemia(X3, P=0.003). Then build the risk model as below: h(t|X)=h0(t)exp(-0.008*X1+0.072*X2+0.842*X3)
5.4.2Variable screen and model establishment based on RSF
5.4.2.1Death within three years risk prediction model
Take survival time as outcome variable, influencing factors for death within three years are as below:age(X1,P=0.000), BI score(X2, P=0.000), tanshimengshen syndrome(X3, P=0.000), whether to relapse(X4, P=0.000), Systolic pressure(X5, P=0.000), LDL(X6, P=0.003), HDL(X7, P=0.000), combined with dyslipidemia(X8, P=0.002), whether the patients continue to take antithrombotic drugs after discharge (X9, P=0.000), whether the patients continue to receive a basic curative treatment after discharge(Xio, P=0.000). Then build the risk model as follows: h(t|X)=h0(t)exp(0.066*X1-0.023*X2+1.439*X3+1.112*X4+0.026*X5+0.356*X6-0.637*X7+0.804*X8-1.236*X9-1.437*X10)
5.4.2.2Relapse within three years risk prediction model
Take no relapse time as outcome variable, influencing factors of relapse including age(Xi, P=0.076), NIHSS score(Xi, P=0.051), BI score(X3, P=0.037), tanshimengshen syndrome(X4, P=0.062), fasting plasma glucose level(X5, P=0.038), combined with dyslipidemia(X6, P=0.000). Then build the risk model: h(t|X)=ho(t)exp(0.018*X1+0.011*X2-0.009*X3+0.475*X4+0.068*X5+0.817*X6)
5.5Death and relapse risk model evaluation
5.5.1Death risk model evaluation
The Cox death risk prediction model built based on screening influencing factors via RSF method(AUC=0.795) had better performance in3-year predication than Cox single-factor and multiple factors analysis(AUC=0.782).
5.5.2Relapse risk model evaluation
The Cox relapse prediction model built based on screening influencing factors via RSF method(AUC=0.621) performed better in3-year predication than Cox single-factor and multiple factors analysis(AUC=0.605).
6Conclusion
6.1After3-year period follow-up, it inllustrates that for TCM group both all-cause motality, mortality related to ischemic stroke, mortality directly related to ischemic stroke, mortality indirectly related to ischemic stroke, and recurrence hazard are lower than WM group(P>0.05). Indeed, survival time and relapse-free time in TCM group are much higher than WM group, which indicates a better developing trend for TCM group. Compared with WM goup, there was1death case short out of every55patients in TCM group. Compared with WM goup, there was1recurrence case short out of every66patients in TCM group. However, considering that this study is influened by sample size, there is no obvious significance between the groups.
6.2Take survival time as an endpoint variable, and research method is random survival forests (RSF). Consequentially, impact factors in3year are:age, BI score, tanshimengshen syndrome, whether to recurrence, systolic blood pressure, LDL-C, HDL-C, combined with dyslipidemia, insistency of antithrombotic drugs intake after discharged, and insistency of basic treatment drugs.
6.3Set relapse-free time as endpoint variable(Research method:RSF). Influencing factors on3-year recurrence indicate:age, NIHSS score, BI score, tanshimengshen syndrome, fasting blood-glucose, combined abnormal lipid metabolism.
6.4This study has builded ischemic stroke3-year death and recurrence prediction model and prognosis index. Cox proportional hazard model is established by screening infulencing factors under RSF. In comparison to Cox single-factor and multi-factor screening method, the model3-year prediction performance based on RSF shows a better vision.
7Innovation
7.1Taking death and recurrence as assessment indicators, it analyses the outcome effects of early intervention of TCM rehabilitation therpy by a3-year long-trem follow up study in the first time.
7.2Screening important morden risk factors or TCM syndrome of ischemic stroke prognosis among a mass of concomitant variables. Besides, it takes into account missing value of survival data.
7.3Characteristic TCM content is integrated in risk assessment model of ischemic stroke prognosis, which increases TCM clinical significance.
引文
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