摘要
目的:使用重复测量数据的混合效应模型(MMRM)和分层复合结局(Win Ratio),对含砷中药复方治疗脾肾两虚、毒瘀阻滞型骨髓增生异常综合征(MDS)的一项随机对照试验进行二次分析,包括血液学疗效评估和不良反应的复合结局评价,以更全面地评估该方案的治疗效果。方法:应用MMRM、Win Ratio方法对一项前瞻性、多中心、双盲、随机对照研究进行疗效评价。送中国中医科学院西苑医院检验科检测患者入组时及各疗程末的血常规[血红蛋白浓度(HGB)、中性粒细胞计数(ANC)和血小板计数(PLT)],治疗后的生化指标[天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT),血清肌酐(Cr),血清铁蛋白(SF)];记录入组时及治疗后的患者证候并根据中医病证疗效标准进行积分。采用MMRM分析观察组与对照组的血常规指标,该方法具有数据可信度高、反映干预与时间下的动态疗效的优点。采用Win Ratio方法根据优先级对中医证候积分和生化指标进行复合结局评价,验证含砷中药复方的临床安全性。结果:①MMRM分析:与本组治疗前比较,含砷中药复方组患者HGB显著升高、安慰剂组显著降低(P<0.01);与安慰剂组治疗后比较,含砷中药复方组患者的HGB显著升高,最小二乘(LS)均值差差异有统计学意义(P<0.01)。与本组治疗前比较,两组的ANC、PLT均差异无统计学意义;治疗后两组间的ANC、PLT及LS均值差差异均无统计学意义。②Win Ratio分析结果:含砷中药复方组在复合结局的比较中有显著优势,胜率为2.01[95%置信区间(CI)(1.24,3.27)](P<0.01),其安全性“获胜”的可能性是安慰剂组的2.01倍。含砷中药复方组的安全性优势主要来自中医证候积分、肾功能指标和铁储备能力指标,肝功能结局比较中获胜次数小于失败次数。结论:MMRM分析证明含砷中药复方可以显著改善脾肾两虚、毒瘀阻滞型MDS-难治性血细胞减少伴多系病态造血(RCMD)患者的HGB。该结论不受时间趋势及个体关系干扰,从方法学上提高了含砷中药复方治疗MDS疗效的可信度。Win Ratio评价复合中医证候、肝功能、肾功能和铁储备能力4个结局,证明了含砷中药复方具有提高患者生存质量、降低不良反应的综合优势。Win Ratio结局为不良反应评价提供了清晰的比较指标,使临床应用含砷中药复方的安全性更容易被监管机构、医疗人员和患者理解。
Objective:This paper aims to conduct a secondary analysis of a randomized controlled trial on the treatment of myelodysplastic syndrome(MDS)with deficiency of both the spleen and kidney and blockage of toxin and blood stasis with an arsenic-containing traditional Chinese medicine compound,by applying the mixed model for repeated measure(MMRM)and the method of stratified composite outcome with win ratio.The analysis includes the assessment of hematological efficacy and the composite outcome evaluation of adverse reactions,so as to more comprehensively assess the therapy of this regimen.Methods:The MMRM and win ratio methods were used to evaluate the efficacy of a prospective,multi-center,double-blind,randomized controlled study.The blood routine(hemoglobin concentration,neutrophil count,and platelet count)and biochemical indexes(aspartate aminotransferase,alanine aminotransferase,serum creatinine,and serum ferritin)of the patients were detected at the time of enrollment and at the end of each course of treatment in the laboratory department of Xiyuan Hospital.The patients'syndromes at the time of enrollment and after treatment were recorded and scored according to the therapy standard of traditional Chinese medicine for diseases and syndromes.MMRM was used to analyze the blood routine indexes of the experimental group and the control group.This method has the advantages of high data reliability and dynamic efficacy under intervention and time.The win ratio method was used to evaluate the composite outcome of traditional Chinese medicine syndrome scores and biochemical indexes according to the priority and to verify the clinical safety of arsenic-containing traditional Chinese medicine compound.Results:The results of MMRM analysis showed that the hemoglobin concentration of patients in the group with arsenic-containing traditional Chinese medicine compound increased significantly compared with that before treatment in the group,while that in the placebo group decreased significantly(P<0.01).When compared with that after treatment in the placebo group,the hemoglobin concentration of patients in the group with arsenic-containing traditional Chinese medicine compound increased significantly,and the mean difference of least squares(LS)was statistically significant(P<0.01).When compared with those before treatment in the group,there were no statistically significant differences in the neutrophil count and platelet count in both groups.After treatment,there were no statistically significant differences in the neutrophil count,platelet count,and the mean difference of LS between the two groups.The analysis results of win ratio showed that the group with arsenic-containing traditional Chinese medicine compound had a significant advantage in the comparison of composite outcomes,with a win ratio(95%CI)of 2.01(1.24-3.27)(P<0.01),and that the possibility of"winning"in terms of safety was 2.01 times that of the placebo group.The safety advantage of the group with arsenic-containing traditional Chinese medicine compound mainly came from the traditional Chinese medicine syndrome scores,renal function indexes,and iron reserve capacity indexes,and the number of winning times was less than that of losing times in the comparison of liver function outcomes.Conclusion:The MMRM analysis proves that the arsenic-containing traditional Chinese medicine compound can significantly improve the hemoglobin concentration of patients with myelodysplastic syndrome with refractory cytopenia and multilineage dysplasia(MDS-RCMD)of the type of deficiency of both the spleen and kidney and blockage of toxin and blood stasis.This conclusion is not interfered with by time trends and individual relationships and methodologically improves the credibility of the therapy of the arsenic-containing traditional Chinese medicine compound in treating MDS.Four outcomes are evaluated by the win ratio method,namely traditional Chinese medicine syndromes,liver function,renal function,and iron reserve capacity,proving that the arsenic-containing traditional Chinese medicine compound has the comprehensive advantages of improving the survival quality of the patients and reducing adverse reactions.The win ratio outcome provides clear comparative indexes for the evaluation of adverse reactions,making it easier for regulatory authorities,medical staff,and patients to understand the safety of the arsenic-containing traditional Chinese medicine compound in clinical application.
作者
孙大湘
蒋佩珍
邸海侠
吴冰
刘奇峰
刘健
梁嘉禾
唐旭东
SUN Daxiang;JIANG Peizhen;DI Haixia;WU Bing;LIU Qifeng;LIU Jian;LIANG Jiahe;TANG Xudong(Beijing University of Chinese Medicine,Beijing 100029,China;Xiyuan Hospital,China Academy of Chinese Medical Sciences,Beijing 100091,China;Langfang Hospital of Traditional Chinese Medicine(TCM)Hospital,Langfang 065001,China;Suzhou Hospital of TCM,Suzhou 215100,China;Jilin Provincial People's Hospital,Changchun 130021,China)
出处
《中国实验方剂学杂志》
北大核心
2026年第7期251-259,共9页
Chinese Journal of Experimental Traditional Medical Formulae
基金
国家自然科学基金面上项目(82074258,82274502)
第二批北京市研究型病房示范建设项目(BCRW202108)
中国中医科学院科技创新工程重大攻关项目(CI2021A01701)。
