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肝爽颗粒联合恩替卡韦对乙型肝炎肝硬化患者门静脉血栓发生的影响
DOI: 10.3969/j.issn.1001-5256.2022.09.015
伦理学声明：本研究方案于2017年1月15日经由昆明市第三人民医院伦理委员会审批，批号：昆三伦20170115。所纳入患者均由本人或监护人签署知情同意书。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：刘立、李俊义负责课题设计，资料分析，撰写论文；刘春云、常丽仙参与收集数据，修改论文；张丽华负责统计分析；黄红丽、罗煜、高建鹏负责拟定写作思路，指导撰写文章并最后定稿。
Effect of Ganshuang granule combined with entecavir on portal vein thrombosis in patients with hepatitis B cirrhosis
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摘要:
目的 探讨肝爽颗粒联合恩替卡韦对乙型肝炎肝硬化患者门静脉血栓(PVT)发生的影响。 方法 选取2018年1月1日— 2020年12月31日于昆明市第三人民医院就诊及住院的乙型肝炎肝硬化患者356例。将纳入患者随机分为联合组(n=191)和对照组(n=165)，其中联合组应用肝爽颗粒联合恩替卡韦治疗，对照组单独应用恩替卡韦治疗。疗程至少24周。计量资料两组间比较采用t检验或Mann-Whitney U检验。计数资料两组间比较采用χ2检验或Fisher精确检验。应用Kaplan-Meier法绘制两组患者PVT的累积发生率，并以log-rank检验进行比较。采用单因素和多因素Cox比例风险回归模型分析乙型肝炎肝硬化患者PVT的影响因素。 结果 联合组191例患者共随访296.25人年，人均随访时间(1.55±0.65)年，PVT发生率为4.19%(8例)，发病密度1.41/万人年。对照组165例患者共随访253.25人年，人均随访时间(1.53±0.67)年，PVT发生率为12.12%(20例)，发病密度4.79/万人年。两组PVT发生率比较，差异有统计学意义(χ2=7.687，P=0.006)。Kaplan-Meier法绘制两组PVT累积发生率，结果显示联合组PVT的累积发生率明显低于对照组(χ2=7.226，P=0.007)，相对危险度为3.155(95%CI：1.351~7.370)。单因素Cox分析结果显示：合并高血压、TBil、ALT、AST、Alb、ChE、eGFR、AFP、D-D、Child-Pugh、肝爽颗粒联合恩替卡韦治疗是PVT的影响因素(P值均＜0.05)；多因素Cox分析结果显示：AST(HR=1.002，95%CI：1.000~1.004，P=0.025)、D-D(HR=1.907，95%CI：1.554~2.338，P＜0.001)是乙型肝炎肝硬化患者发生PVT的独立危险因素，Alb(HR=0.844，95%CI：0.755~0.944，P=0.003)、肝爽颗粒联合恩替卡韦治疗(HR=0.350，95%CI：0.144~0.851，P=0.021)是乙型肝炎肝硬化患者发生PVT的独立保护因素。 结论 肝爽颗粒联合恩替卡韦治疗可显著降低乙型肝炎肝硬化患者PVT的发生率，对PVT的形成有一定的预防作用。 Abstract:Objective To investigate the effect of Ganshuang granule combined with entecavir on portal vein thrombosis (PVT) in patients with hepatitis B cirrhosis. Methods A total of 356 patients with hepatitis B cirrhosis who attended and were hospitalized in The Third People's Hospital of Kunming from January 1, 2018 to December 31, 2020 were enrolled and randomly divided into combination group with 191 patients and control group with 165 patients. The patients in the combination group received Ganshuang granule combined with entecavir, and those in the control group received entecavir alone. The course of treatment was at least 24 weeks. The t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups. The Kaplan-Meier method was used to analyze the cumulative incidence rate of PVT in both groups, and the log-rank test was used for comparison between two groups. Univariate and multivariate Cox proportional-hazards regression model analyses were used to investigate the influencing factors for PVT in patients with hepatitis B cirrhosis. Results The 191 patients in the combination group were followed up for 296.25 person-years in total, with a mean follow-up time of 1.55±0.65 years, and there were 8 patients with PVT, with an incidence rate of 4.19% and an incidence density of 1.41 per ten-thousand person-years. The 165 patients in the control group were followed up for 253.25 person-years in total, with a mean follow-up time of 1.53±0.67 years, and there were 20 patients with PVT, with an incidence rate of 12.12% and an incidence density of 4.79 per ten-thousand person-years. There was a significant difference in the incidence rate of PVT between the two groups (χ2=7.687, P=0.006). The cumulative incidence rate of PVT plotted by the Kaplan-Meier method showed that the combination group had a significantly lower cumulative incidence rate of PVT than the control group (χ2=7.226, P=0.007), with a relative risk of 3.155 (95% confidence interval [CI]: 1.351-7.370). The univariate Cox analysis showed that hypertension, alanine aminotransferase, aspartate aminotransferase (AST), albumin (Alb), cholinesterase, estimated glomerular filtration rate, alpha-fetoprotein, D-dimer (D-D), Child-Pugh class, and Ganshuang granule combined with entecavir were influencing factors for PVT (all P < 0.05); the multivariate Cox analysis showed that AST (hazard ratio [HR]=1.002, 95% CI: 1.000-1.004, P=0.025), and D-D (HR=1.907, 95%CI: 1.554-2.338, P < 0.001) were independent risk factors for PVT in patients with hepatitis B cirrhosis, while Alb (HR=0.844, 95%CI: 0.755-0.944, P=0.003) and Ganshuang granule combined with entecavir (HR=0.350, 95%CI: 0.144-0.851, P=0.021) were independent protective factors against PVT in patients with hepatitis B cirrhosis. Conclusion Ganshuang granule combined with entecavir can significantly reduce the incidence rate of PVT in patients with hepatitis B cirrhosis, thereby exerting a certain preventive effect against PVT. -
Key words:
- Liver Cirrhosis /
- Portal Vein Thrombosis /
- Entecavir /
- Ganshuang Granule
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图 1 两组患者PVT累积发生率的比较
Figure 1. Comparison of rates of cumulative incidence of PVT in the two groups
表 1 两组患者的基线特征
Table 1. Baseline characteristics of the two groups of patients
项目 联合组(n=191) 对照组(n=165) 统计值 P值 男/女(例) 133/58 118/47 χ2=0.151 0.698 年龄(岁) 48.29±9.89 49.45±10.48 t=-1.062 0.289 BMI(kg/m2) 24.76±5.74 24.75±4.79 t=0.024 0.981 高血压(例) 22 17 χ2=0.134 0.714 糖尿病(例) 18 18 χ2=0.215 0.643 饮酒(例) 22 18 χ2=0.033 0.856 WBC(×109/L) 2.78(2.06~3.65) 2.64(1.92~3.52) Z=-1.095 0.273 PLT(×109/L) 77(41~119) 81(42~162) Z=-0.549 0.583 TBil(μmol/L) 84.2(41.9~150.7) 90.6(41.9~161.6) Z=-0.984 0.325 ALT(U/L) 127(62~221) 124(53~234) Z=-0.649 0.517 AST(U/L) 178(90~303) 192(100~361) Z=-1.664 0.096 GGT(U/L) 78.0(51.1~114.1) 81.8(56.4~115.7) Z=-0.997 0.319 TBA(μmol/L) 33.3(20.2~51.1) 34.7(19.2~58.8) Z=-0.667 0.505 Alb(g/L) 31.79±4.84 30.94±6.02 t=1.475 0.141 ChE(U/L) 2424(1761~3114) 2393(1720~3083) Z=-0.701 0.483 GLU(mmol/L) 4.59±1.60 4.86±1.69 t=-1.554 0.121 BUN(mmol/L) 5.95(3.89~7.94) 5.99(4.43~8.57) Z=-0.981 0.327 Cr(μmol/L) 81.36±19.22 80.62±16.92 t=0.382 0.703 eGFR(mL/min) 103.56±26.45 100.21±26.70 t=1.189 0.234 AFP(ng/mL) 68.6(50.8~91.4) 71.4(48.8~92.2) Z=-0.203 0.839 PT(s) 24.93±4.39 25.25±4.80 t=-0.650 0.516 INR 1.61±0.44 1.67±0.46 t=-1.353 0.177 D-D(mg/L) 3.44±1.33 3.59±1.29 t=-1.063 0.289 HBV DNA(IU/mL) 5.41±1.61 5.66±1.47 t=-0.658 0.501 Child-Pugh B/C(例) 99/92 78/87 χ2=0.736 0.391 肝硬化并发症(例) χ2=0.340 0.987 自发性细菌性腹膜炎 10 8 腹水 17 12 肝性脑病 2 1 肝肾综合征 6 5 上消化道出血 4 4 LSM(kPa) 30.83±8.78 30.79±8.34 t=0.041 0.967 
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表 2 单因素和多因素Cox比例风险分析乙型肝炎肝硬化患者PVT的影响因素
Table 2. Univariate and multivariate Cox proportional hazards analysis of the influencing factors of portal vein thrombosis in patients with hepatitis B cirrhosis
项目 单因素分析 多因素分析 HR 95%CI P值 HR 95%CI P值 性别 0.634 0.257~1.564 0.323 年龄 0.971 0.938~1.005 0.092 BMI 1.055 0.983~1.133 0.140 高血压 2.775 1.276~6.035 0.010 糖尿病 4.033 0.547~29.724 0.171 高血压 1.142 0.344~3.796 0.828 WBC 1.141 0.852~1.529 0.377 PLT 0.992 0.984~1.001 0.080 TBil 1.006 1.003~1.009 ＜0.001 ALT 1.003 1.001~1.006 0.012 AST 1.002 1.001~1.004 0.002 1.002 1.000~1.004 0.025 GGT 1.000 0.992~1.009 0.906 TBA 1.007 0.992~1.022 0.361 Alb 0.842 0.770~0.921 ＜0.001 0.844 0.755~0.944 0.003 ChE 1.000 0.999~1.000 0.027 GLU 1.182 0.961~1.455 0.113 BUN 1.100 0.989~1.223 0.078 Cr 1.019 0.997~1.041 0.096 eGFR 0.986 0.978~0.995 0.001 AFP 1.013 1.000~1.026 0.046 PT 0.997 0.917~1.084 0.952 INR 1.547 0.667~3.590 0.310 D-D 1.908 1.606~2.268 ＜0.001 1.907 1.554~2.338 ＜0.001 HBV DNA 1.071 0.840~1.366 0.579 Child-Pugh分级 0.218 0.083~0.574 0.002 LSM 1.039 0.999~1.081 0.058 肝爽颗粒联合恩替卡韦治疗 0.344 0.151~0.780 0.011 0.350 0.144~0.851 0.021
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表 3 两组患者并发症发生情况比较
Table 3. Comparison of complications between the two groups
并发症 联合组(n=191) 对照组(n=165) χ2值 P值 腹水[例(%)] 10(5.24) 19(11.52) 4.514 0.034 自发性细菌性腹膜炎[例(%)] 3(1.57) 10(6.06) 5.072 0.024 上消化道出血[例(%)] 3(1.57) 9(5.45) 4.100 0.043 肝性脑病[例(%)] 2(1.05) 6(3.64) 0.100 肝肾综合征[例(%)] 2(1.05) 8(4.85) 0.030 肝癌[例(%)] 2(1.05) 3(1.82) 0.538
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