芪龙颗粒、芪蛭颗粒治疗非小细胞肺癌高凝状态的比较性研究
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摘要
目的第一部分：通过回顾性临床研究,探索恶性肿瘤血液高凝状态的实验室诊断标准,并对血栓弹力图仪指标、血常规及凝血试验相关指标在恶性肿瘤血液高凝状态诊断中的作用进行评价,从而更好地指导临床,提高医生对恶性肿瘤血液高凝状态的识别率。
第二部分：通过随机对照临床试验方法,观察芪龙颗粒、芪蛭颗粒治疗非小细胞肺癌患者血液高凝状态和气虚血瘀证的临床疗效,并进行比较性研究。
方法第一部分：以住院的恶性肿瘤患者为研究对象,以血栓弹力图仪相关指标、血常规相关指标、凝血试验相关指标为观察指标,制定调查表,收集病例。以血栓弹力图仪测得的结果为参照,分析不同标准诊断恶性肿瘤血液高凝状态的发病率、灵敏度和特异度,探讨适用于临床、简便易行的恶性肿瘤血液高凝状态实验室诊断标准,并用Fisher判别分析各项指标在诊断恶性肿瘤血液高凝状态中的价值。
第二部分：以门诊及住院的非小细胞肺癌血液高凝状态并符合气虚血瘀证的患者为研究对象,以血小板相关指标、凝血试验相关指标、血栓弹力图仪相关指标、中医气虚血瘀证症状积分及KPS评分为观察指标,按1：1：1的比例将符合纳入标准的患者随机分为三组：芪龙颗粒组、芪蛭颗粒组、对照组,连续用药14天后评价各组药物的疗效。
结果第一部分：纳入统计分析的恶性肿瘤患者共132例。(1)用血栓弹力图仪(TEG)筛选恶性肿瘤血液高凝状态,发病率为37.12%。(2)①凝血酶原时间(PT)缩短>3s；②活化的部分凝血活酶时间(APTT)缩短>3s；③纤维蛋白原含量(FIB)>4g/dL；④D-二聚体含量(DD)>300ug/L;⑤血小板计数(PLT)>300×109/L；以满足上述2项或2项以上为标准筛选恶性肿瘤血液高凝状态,测得的发病率为38.64%,灵敏度为71.4%,特异度为80.7%。(3)用Fisher判别对全部观察指标,包括R、K、ANG、MA、 CI、WBC、HGB、PLT、MPV、PDW、PT、APTT、TT、FIB、DD在恶性肿瘤血液高凝状态诊断中的价值进行分析,得到诊断方程:6.8×K+1.8×MA-3.3xR>100,该诊断方程测得的发病率为38.64%,灵敏度为91.8%,特异度为92.8%。(4)用Fisher判别对除TEG指标以外的其它指标包括WBC、HGB、PLT、MPV、PDW、PT、APTT、TT、FIB、DD在恶性肿瘤血液高凝状态诊断中的价值进行分析,得到诊断方程：8.1×PLT+O.7×DD-36.8、APTT>1000,该诊断方程测得的发病率为32.58%,灵敏度为63.3%,特异度为85.5%。
第二部分：纳入统计分析的非小细胞肺癌血液高凝状态并符合气虚血瘀证患者共61例,其中芪龙颗粒组21例,芪蛭颗粒组20例,对照组20例。(1)芪龙颗粒组患者治疗后的各项实验室观察指标与治疗前比较经统计学分析均无显著差异(P>0.05)；芪龙颗粒组患者治疗后的气虚血瘀证症状总积分、体倦乏力、肌肤甲错、肢体麻木症状积分均较治疗前下降(P<0.05)；芪龙颗粒组患者治疗后的KPS评分与治疗前比较经统计学分析无显著差异(P>0.05)。芪龙颗粒治疗非小细胞肺癌气虚血瘀证的有效率为66.7%,生活质量疗效判定21例患者均为稳定。(2)芪蛭颗粒组患者治疗后的DD、PDW, ANG、CI值均较治疗前下降(P<0.05),K值较治疗前延长(P<0.05)；芪蛭颗粒组患者治疗后的气虚血瘀证症状总积分、面色晦暗、体倦乏力、疼痛、肌肤甲错、肢体麻木、头目眩晕症状积分均较治疗前下降(P<0.05)；KPS评分较治疗前升高(P<0.05),但升高的幅度无临床意义。芪蛭颗粒治疗非小细胞肺癌气虚血瘀证的有效率为60%,生活质量疗效判定20例患者中1例改善,19例稳定。(3)芪龙颗粒组、芪蛭颗粒组患者治疗后的FIB、DD值、气虚血瘀证症状总积分均低于对照组(P<0.05)。芪龙颗粒组患者治疗后的KPS评分与对照组比较经统计学分析无显著差异(P>0.05),芪蛭颗粒组患者治疗后的KPS评分高于对照组(P<0.05),但高出的幅度无临床意义。(4)芪龙颗粒组与芪蛭颗粒组患者治疗后的各项实验室观察指标、中医气虚血瘀证症状总积分、KPS评分在两组间的比较中经统计学分析均无显著差异(P>0.05)。
结论第一部分：(1)通过TEG筛选：①反应时间(R)<5min;②凝固时间(K)72°；④曲线的最宽距离(MA)>70mm。满足上述任何1项,可作为临床诊断恶性肿瘤血液高凝状态的参考标准。(2)通过血常规和凝血试验筛选：①凝血酶原时间缩短(PT)>3s；②活化的部分凝血活酶时间(APTT)缩短>3s；③纤维蛋白原含量(FIB)>4g/dL；④D-二聚体含量(DD)>300ug/L;⑤血小板计数(PLT)>300×109/L。满足上述2项或2项以上者,建议作为临床诊断恶性肿瘤血液高凝状态的参考标准。(3)通过诊断方程筛选：8.1×PLT+0.7×DD-36.8x APTT>1000,满足上述方程,建议作为临床诊断恶性肿瘤血液高凝状态的参考标准。(4)在诊断恶性肿瘤血液高凝状态时,TEG的价值要优于血常规及凝血试验相关指标；TEG的各项指标中R、K、MA的价值要优于ANG、CI,且K>R>MA;血常规及凝血试验相关指标中APTT、DD、PLT的价值要优于FIB、WBC、HGB、MPV、PDW PT、TT,且APTT>PLT>DD。
第二部分：(1)芪龙颗粒与芪蛭颗粒均可以改善非小细胞肺癌(NSCLC)患者的血液高凝状态,改善气虚血瘀证候,缓解相关的临床症状。(2)在改善NSCLC血液高凝状态、治疗气虚血瘀证方面,芪蛭颗粒的疗效优于芪龙颗粒。(3)芪龙颗粒与芪蛭颗粒对NSCLC血液高凝状态患者的生活质量均无改善作用。(4)益气活血的方药选用得当可以用于治疗非小细胞肺癌血液高凝状态。
OBJECTIVE:First part:Through clinical retrospective analysis,to find a kind of laboratory diagnostic criteria to identify the hypercoagulable state related to cancer. Furthermore to value the TEG indicators,CBC and blood coagulation test relevant indicators in diagnosing the hypercoagulable state caused by malignant tumor.
Second part:Though randomized clinical trials,to evaluate and compare the effectiveness of two kinds of Chinese herbal compounds:Qilong granule and Qizhi granule, which are used to treat the hypercoagulable state related to NSCLC, and the blood stasis due to qi deficiency syndrome, which is one TCM syndrome types of NSCLC.
METHODS:First part:Select hospitalized patients who got cancer, design CRF to collect their laboratory test results such as TEG indicators, CBC and blood coagulation test relevant indicators. Compare the incidence, sensitivity and specificity of different kinds of diagnostic criteria of hypercoagulable state related to cancer and choose the most effective, easily used ones. Calculate the weight coefficient of each laboratory indicator through Fisher discriminant analysis.
Second part:Selected outpatients and hospitalized patients who are met to inclusion criteria and divided those patients into three groups by the radio of1:1:1, that are Qilong group, Qizhi group and blank control group. Value the observing indicators such as PLT and blood coagulation test relevant indicators, TEG indicators, the scoring of symptoms of blood stasis due to qi deficiency syndrome, and the KPS at the fisrt day and14days later.
RESULTS:First part:There are132patients who are included in statistical analysis.(1) According to TEG, the incidence of hypercoagulable state related to cancer is37.12%.(2)①PT shorten>3s;②APTT shorten>3s;③FIB>4g/dL;④DD>300ug/L;⑤PLT>300×109/L. Reaching2and more than2items of the above are used to diagnose the hypercoagulable state related to cancer.According to that, we got the incidence is38.64%, the sensitivity is71.4%, and the specificity is80.7%.(3)Using Fisher discriminant statistical method to analyse the whole laboratory indicators such as R、K、ANG、MA、CI、WBC、HGB、PLT、MPV、 PDW, PT、APTT、TT、FIB、 DD, we got the diagnostic equation as following:6.8×K+1.8×MA-3.3×R>100. According to the equation, we got the incidence is38.64%, the sensitivity is91.8%, and the specificity is92.8%.(4) Using Fisher discriminant statistical method to analyse the laboratory indicators besides TEG indicators such as WBC、HGB、PLT、MPV、PDW、PT、APTT、TT、FIB、DD, we got the diagnostic equation as following:8.1×PLT+0.7×DD-36.8×APTT>1000. According to the equation, we got the incidence is32.58%, the sensitivity is63.3%, and the specificity is85.5%.
Second part:There are61patients who are collected in statistical analys is, including21cases in Qilong group,20cases in Qizhi group, and20cases in blank control group.(1)In Qilong group, there are no statistical difference of the whole observing laboratory indicators and the KPS between pre-treatment and post-treatment (P>0.05).The scoring of blood stasis due to qi deficiency syndrome and symptoms as fatigue, encrusted skin, numbness of limbs of post-treatment in Qilong group are lower than those of pre-treatment (P<0.05) The efficiency of Qilong granule in treating blood stasis due to qi deficiency syndrome is66.7%, and the therapeutic effect of life qualities of the whole21cases are stable.(2)After14days treating with Qizhi granule, the patients' laboratory indicators such as DD, PDW, ANG, CI are lower, the indicator K is longer, the scoring of blood stasis due to qi deficiency syndrome and symptoms as dim complexion, fatigue, pain, encrusted skin, numbness of limbs, dizziness or blurred vision are lower, and the KPS is higer than those of pre-treatment (P<0.05).But the rising KPS show no clinical significance. The efficiency of Qizhi granule to treat blood stasis due to qi deficiency syndrome is60%. The therapeutic effect of life qualities of the whole20cases in Qizhi group, one of those is improved, and the other19of those are stable.(3) The indicators as FIB, DD, and the scoring of blood stasis due to qi deficiency syndrome of post-treatment in Qilong and Qizhi group are both lower than those of in blank control group (P<0.05).The KPS of post-treatment in Qilong group is no statistical difference from that of in blank control group (P>0.05), while the KPS of post-treatment in Qizhi goup is higher than that of in blank control group (P<0.05). But the higer KSP show no clinical significance.(4) There are no statistical difference of all observing laboratory indicators, scoring of blood stasis due to qi deficiency syndrome, and the KPS of post-treatment between Qilong group and Qizhi group (P>0.05).
CONCLUSIONS:First part:(1)To diagnose the hypercoagulable state related to cancer through TEG:①R<5min;②K72°;④MA>70mm. To meet any of the above is recommended as the diagnostic criteria.(2)To diagnose the hypercoagulable state related to cancer through CBC and blood coagulation test:①PT shorten>3s;②PTT shorten>3s;③FIB>4g/dL;④DD>300ug/L;⑤PLT>300×109/L. Reaching2and more than2items of the above are suggested as the diagnostic criteria.(3)To diagnose the hypercoagulable state related to cancer through diagnostic equation:8.1×PLT+0.7×DD-36.8×APTT>1000. Meeting the above equation is advised as the diagnostic criteria as well.(4)In diagnosing the hypercoagulable state related to malignancy, the TEG indicators are better than those in CBC and blood coagulation tests. The indicators such as K, R, MA are better than those as ANG, CI in TEG indicators. While the indicators such as APTT, PLT, DD are better than those as FIB, WBC, HGB, MPV, PDW, PT, TT in CBC and blood coagulation tests.
Second part:(1)Qilong granule and Qizhi granule can both alleviate the hypercoagulable state related to NSCLC, modify the blood stasis due to qi deficiency syndrome, and relieve the relevant symptoms.(2)Qizhi granule is better than Qilong granue in treating hypercoagulable state and blood stasis due to qi deficiency syndrome related to NSCLC.(3)Qilong granue and Qizhi granule had no effect on the life qualities of those patients who are got hypercoagulable state related to NSCLC.(4) The Chinese hebal which is able to benefit qi and activate blood circulation can be used for treating hypercoagulable state related to NSCLC.
第二部分：通过随机对照临床试验方法,观察芪龙颗粒、芪蛭颗粒治疗非小细胞肺癌患者血液高凝状态和气虚血瘀证的临床疗效,并进行比较性研究。
方法第一部分：以住院的恶性肿瘤患者为研究对象,以血栓弹力图仪相关指标、血常规相关指标、凝血试验相关指标为观察指标,制定调查表,收集病例。以血栓弹力图仪测得的结果为参照,分析不同标准诊断恶性肿瘤血液高凝状态的发病率、灵敏度和特异度,探讨适用于临床、简便易行的恶性肿瘤血液高凝状态实验室诊断标准,并用Fisher判别分析各项指标在诊断恶性肿瘤血液高凝状态中的价值。
第二部分：以门诊及住院的非小细胞肺癌血液高凝状态并符合气虚血瘀证的患者为研究对象,以血小板相关指标、凝血试验相关指标、血栓弹力图仪相关指标、中医气虚血瘀证症状积分及KPS评分为观察指标,按1：1：1的比例将符合纳入标准的患者随机分为三组：芪龙颗粒组、芪蛭颗粒组、对照组,连续用药14天后评价各组药物的疗效。
结果第一部分：纳入统计分析的恶性肿瘤患者共132例。(1)用血栓弹力图仪(TEG)筛选恶性肿瘤血液高凝状态,发病率为37.12%。(2)①凝血酶原时间(PT)缩短>3s；②活化的部分凝血活酶时间(APTT)缩短>3s；③纤维蛋白原含量(FIB)>4g/dL；④D-二聚体含量(DD)>300ug/L;⑤血小板计数(PLT)>300×109/L；以满足上述2项或2项以上为标准筛选恶性肿瘤血液高凝状态,测得的发病率为38.64%,灵敏度为71.4%,特异度为80.7%。(3)用Fisher判别对全部观察指标,包括R、K、ANG、MA、 CI、WBC、HGB、PLT、MPV、PDW、PT、APTT、TT、FIB、DD在恶性肿瘤血液高凝状态诊断中的价值进行分析,得到诊断方程:6.8×K+1.8×MA-3.3xR>100,该诊断方程测得的发病率为38.64%,灵敏度为91.8%,特异度为92.8%。(4)用Fisher判别对除TEG指标以外的其它指标包括WBC、HGB、PLT、MPV、PDW、PT、APTT、TT、FIB、DD在恶性肿瘤血液高凝状态诊断中的价值进行分析,得到诊断方程：8.1×PLT+O.7×DD-36.8、APTT>1000,该诊断方程测得的发病率为32.58%,灵敏度为63.3%,特异度为85.5%。
第二部分：纳入统计分析的非小细胞肺癌血液高凝状态并符合气虚血瘀证患者共61例,其中芪龙颗粒组21例,芪蛭颗粒组20例,对照组20例。(1)芪龙颗粒组患者治疗后的各项实验室观察指标与治疗前比较经统计学分析均无显著差异(P>0.05)；芪龙颗粒组患者治疗后的气虚血瘀证症状总积分、体倦乏力、肌肤甲错、肢体麻木症状积分均较治疗前下降(P<0.05)；芪龙颗粒组患者治疗后的KPS评分与治疗前比较经统计学分析无显著差异(P>0.05)。芪龙颗粒治疗非小细胞肺癌气虚血瘀证的有效率为66.7%,生活质量疗效判定21例患者均为稳定。(2)芪蛭颗粒组患者治疗后的DD、PDW, ANG、CI值均较治疗前下降(P<0.05),K值较治疗前延长(P<0.05)；芪蛭颗粒组患者治疗后的气虚血瘀证症状总积分、面色晦暗、体倦乏力、疼痛、肌肤甲错、肢体麻木、头目眩晕症状积分均较治疗前下降(P<0.05)；KPS评分较治疗前升高(P<0.05),但升高的幅度无临床意义。芪蛭颗粒治疗非小细胞肺癌气虚血瘀证的有效率为60%,生活质量疗效判定20例患者中1例改善,19例稳定。(3)芪龙颗粒组、芪蛭颗粒组患者治疗后的FIB、DD值、气虚血瘀证症状总积分均低于对照组(P<0.05)。芪龙颗粒组患者治疗后的KPS评分与对照组比较经统计学分析无显著差异(P>0.05),芪蛭颗粒组患者治疗后的KPS评分高于对照组(P<0.05),但高出的幅度无临床意义。(4)芪龙颗粒组与芪蛭颗粒组患者治疗后的各项实验室观察指标、中医气虚血瘀证症状总积分、KPS评分在两组间的比较中经统计学分析均无显著差异(P>0.05)。
结论第一部分：(1)通过TEG筛选：①反应时间(R)<5min;②凝固时间(K)
第二部分：(1)芪龙颗粒与芪蛭颗粒均可以改善非小细胞肺癌(NSCLC)患者的血液高凝状态,改善气虚血瘀证候,缓解相关的临床症状。(2)在改善NSCLC血液高凝状态、治疗气虚血瘀证方面,芪蛭颗粒的疗效优于芪龙颗粒。(3)芪龙颗粒与芪蛭颗粒对NSCLC血液高凝状态患者的生活质量均无改善作用。(4)益气活血的方药选用得当可以用于治疗非小细胞肺癌血液高凝状态。
OBJECTIVE:First part:Through clinical retrospective analysis,to find a kind of laboratory diagnostic criteria to identify the hypercoagulable state related to cancer. Furthermore to value the TEG indicators,CBC and blood coagulation test relevant indicators in diagnosing the hypercoagulable state caused by malignant tumor.
Second part:Though randomized clinical trials,to evaluate and compare the effectiveness of two kinds of Chinese herbal compounds:Qilong granule and Qizhi granule, which are used to treat the hypercoagulable state related to NSCLC, and the blood stasis due to qi deficiency syndrome, which is one TCM syndrome types of NSCLC.
METHODS:First part:Select hospitalized patients who got cancer, design CRF to collect their laboratory test results such as TEG indicators, CBC and blood coagulation test relevant indicators. Compare the incidence, sensitivity and specificity of different kinds of diagnostic criteria of hypercoagulable state related to cancer and choose the most effective, easily used ones. Calculate the weight coefficient of each laboratory indicator through Fisher discriminant analysis.
Second part:Selected outpatients and hospitalized patients who are met to inclusion criteria and divided those patients into three groups by the radio of1:1:1, that are Qilong group, Qizhi group and blank control group. Value the observing indicators such as PLT and blood coagulation test relevant indicators, TEG indicators, the scoring of symptoms of blood stasis due to qi deficiency syndrome, and the KPS at the fisrt day and14days later.
RESULTS:First part:There are132patients who are included in statistical analysis.(1) According to TEG, the incidence of hypercoagulable state related to cancer is37.12%.(2)①PT shorten>3s;②APTT shorten>3s;③FIB>4g/dL;④DD>300ug/L;⑤PLT>300×109/L. Reaching2and more than2items of the above are used to diagnose the hypercoagulable state related to cancer.According to that, we got the incidence is38.64%, the sensitivity is71.4%, and the specificity is80.7%.(3)Using Fisher discriminant statistical method to analyse the whole laboratory indicators such as R、K、ANG、MA、CI、WBC、HGB、PLT、MPV、 PDW, PT、APTT、TT、FIB、 DD, we got the diagnostic equation as following:6.8×K+1.8×MA-3.3×R>100. According to the equation, we got the incidence is38.64%, the sensitivity is91.8%, and the specificity is92.8%.(4) Using Fisher discriminant statistical method to analyse the laboratory indicators besides TEG indicators such as WBC、HGB、PLT、MPV、PDW、PT、APTT、TT、FIB、DD, we got the diagnostic equation as following:8.1×PLT+0.7×DD-36.8×APTT>1000. According to the equation, we got the incidence is32.58%, the sensitivity is63.3%, and the specificity is85.5%.
Second part:There are61patients who are collected in statistical analys is, including21cases in Qilong group,20cases in Qizhi group, and20cases in blank control group.(1)In Qilong group, there are no statistical difference of the whole observing laboratory indicators and the KPS between pre-treatment and post-treatment (P>0.05).The scoring of blood stasis due to qi deficiency syndrome and symptoms as fatigue, encrusted skin, numbness of limbs of post-treatment in Qilong group are lower than those of pre-treatment (P<0.05) The efficiency of Qilong granule in treating blood stasis due to qi deficiency syndrome is66.7%, and the therapeutic effect of life qualities of the whole21cases are stable.(2)After14days treating with Qizhi granule, the patients' laboratory indicators such as DD, PDW, ANG, CI are lower, the indicator K is longer, the scoring of blood stasis due to qi deficiency syndrome and symptoms as dim complexion, fatigue, pain, encrusted skin, numbness of limbs, dizziness or blurred vision are lower, and the KPS is higer than those of pre-treatment (P<0.05).But the rising KPS show no clinical significance. The efficiency of Qizhi granule to treat blood stasis due to qi deficiency syndrome is60%. The therapeutic effect of life qualities of the whole20cases in Qizhi group, one of those is improved, and the other19of those are stable.(3) The indicators as FIB, DD, and the scoring of blood stasis due to qi deficiency syndrome of post-treatment in Qilong and Qizhi group are both lower than those of in blank control group (P<0.05).The KPS of post-treatment in Qilong group is no statistical difference from that of in blank control group (P>0.05), while the KPS of post-treatment in Qizhi goup is higher than that of in blank control group (P<0.05). But the higer KSP show no clinical significance.(4) There are no statistical difference of all observing laboratory indicators, scoring of blood stasis due to qi deficiency syndrome, and the KPS of post-treatment between Qilong group and Qizhi group (P>0.05).
CONCLUSIONS:First part:(1)To diagnose the hypercoagulable state related to cancer through TEG:①R<5min;②K
Second part:(1)Qilong granule and Qizhi granule can both alleviate the hypercoagulable state related to NSCLC, modify the blood stasis due to qi deficiency syndrome, and relieve the relevant symptoms.(2)Qizhi granule is better than Qilong granue in treating hypercoagulable state and blood stasis due to qi deficiency syndrome related to NSCLC.(3)Qilong granue and Qizhi granule had no effect on the life qualities of those patients who are got hypercoagulable state related to NSCLC.(4) The Chinese hebal which is able to benefit qi and activate blood circulation can be used for treating hypercoagulable state related to NSCLC.
引文
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