| Acute esophagogastric variceal bleeding(AVB)is a common and fatal complication caused by portal hypertension of cirrhosis and most causes of death in patients with portalhypertension of cirrhosis.Despite the rapid development of endoscopy and pharmaceutical treatment in recent 20 years,the mortality of AVB in patients with cirrhosis is still as high as 20%.Several consensuses recommend that preemptive transjugular intrahepatic portosystemic shunt(TIPS)with 72 hours after admission can be a survival benefit for high-risk patients with AVB.The latest research suggests that for high-risk patients with Child-Pugh C or model for end-stage liver disease(MELD)score >18 points,preemptive TIPS can extend their survival time.But how to define high-risk patients with Child-Pugh B remains controversial.Previous studies have shown the survival benefit provided by preemptive TIPS for patients with Child-Pugh B,such as for those with Child-Pugh C is uncertain.This is mainly due to a lack of awareness of the risk factors for death in Child-Pugh B patients,so patients with Child-Pugh B receiving preemptive TIPS needs to be redefined.In the natural course of liver cirrhosis,hepatic encephalopathy is a clinically usual decompensation event,with a syndrome of central nervous system dysfunction.Occurrence of HE is the cue to thepoor prognosis of patients with cirrhosis.Studies have confirmed HE as a risk factor of death independent of Child-Pugh score and MELD score in patients with cirrhosis.Although TIPS can effectively decrease complications such as ascites or variceal bleeding,the incidence of hepatic encephalopathy after TIPS can be as high as 30-50%,and most of them occur in the early postoperative period.Two previous retrospective studies suggested HE was not related to survival after TIPS.However,the other two retrospective studies showed that the survival time of patients wtih post-HE was shorter than that of those without post-HE.Therefore,it is not clear whether HE is a risk factor for postoperative survival after TIPS.【Objectives】1.PartⅠ: To explore whether clinical staging is a prognostic factor for the survival of cirrhotic patients with acute variceal bleeding receiving medicine plus endoscopy therapy,and to stratify Child-Pugh B patients according to the natural course of cirrhosis,and whether preemptive TIPS can benefit patients with high-risk.2.PartⅡ: To investigate the role of early overt hepatic encephalopathy(OHE)as a clinical marker of prognosis in cirrhosis with TIPS and to assess the relationship between recurrence of OHE and survival after TIPS.【Methods】1.PartⅠ:1.1 The object of study: We collected data of 1425 consecutive patients with cirrhosis and AVB who were admitted to 12 university hospitals in China between December 2010 and June 2016.Medical history,laboratory parameters and radiologic examination were collected at admission.1.2 Therapeutic interventions: All patients were given vasoactive agents and endoscopic treatment according to Baveno V consensus.Combination therapy group: Patients continued vasoactive agents.After the bleeding stopped,they were given non-selective βreceptor blockers and endoscopy for secondary prevention of esophageal variceal rebleeding.Preemptive TIPS group: Patients who received preemptive TIPS received covered TIPS stent implantation 72 hours after admission and the vasoactive drugs were stopped.1.3 The clinical course of cirrhosis: According without or with other decompensated events,patients with AVB were classified as stage 4 and stage 5 of cirrhosis.1.3 Statistical analysis: Firstly,the relationship between the natural course of cirrhosis and the survival after acute variceal hemorrhage was evaluated by the competing risk analysis.When the cumulative incidence of bleeding control failure,rebleeding,OHE,and ascites was assessed,death and liver transplant was used as a competitive risk event.The cumulative incidence of bleeding control failure,rebleeding,OHE,and ascites was further adjusted by liver function and other possible confounding factors.The clinical efficacy of the two treatments in patients with Child Pugh B plus stage 5 of cirrhosis was evaluated by propensity index score and the competing risk analysis.2.PartⅡ:2.1 The object of study: Consecutive patients who received TIPS From January 2012 to December 2013 in Xijing hosipital were included.All patients were followed up by unified professional follow-up personnel.2.2 Diagnosis definitions and endpoint: OHE was referred to as grades 2–4 HE according to the West Haven criteria.Early OHE was defined as OHE within 3 months after TIPS.Early single OHE was defined as only one OHE in 3 months after TIPS.Early recurrent OHE was defined as two or more OHE in three months after TIPS.Primary endpoint is all-cause mortality.2.3 Statistical analysis: Considering that the occurrence time of OHE after TIPS is unpredictable,conventional Cox regression may lead to permanent time bias.Therefore,time-dependent Cox regression was used to evaluate the predictive value of early OHE and the relationship between its occurrence frequency and survival.the propensity score and landmark approach were performed to confirm relationship between early OHE and survival of patients after TIPS.【Results】1.PartⅠ1.1 The baseline of population included.In combination therapy group,the damage of liver function in patients with stage 5 of cirrhosis is more serious than that in patients with stage 3 of cirrhosis.Compared with patients with stage 3 of cirrhosis,the international standardized ratio,serum bilirubin,serum creatinine and serum albumin of those with stage 5 of cirrhosis are higher.Child-Pugh score and MELD score in patients with stage 5of cirrhosis were higher than those in those with stage 3 of cirrhosis.And in combination therapy,the grade of bleeding in patients with stage 5 of cirrhosis is more serious than that in patients with stage 3 of cirrhosis.The hemoglobin,complications(infection and shock),the needs of blood and plasma in patients with stage 5 of cirrhosis were higher than those in patients with stage 3 of cirrhosis.1.2 The clinical stage of cirrhosis was a risk factor for survival of patients with combination therapy.In combination therapy group,the risk of death in patients with stage 5 of cirrhosis was higher than that in patients with stage 3 of cirrhosis(hazard ratio(HR)= 2.17;95% Confidence interval(CI): 1.4-2.93;P <0.001).But interestingly,this phenomenon disappeared by adjusting for the baseline liver function,severity of bleeding etc(HR = 1.37;95% CI: 0.92-2.03;P = 0.123).However,the risk of death in patients with stage 5 of cirrhosis was 130% higher than that in patients with stage 3 of cirrhosis(HR=2.30;95%CI:1.72-3.40;p<0.001)in 1-year followed-up and 64% higher when adjusted for the confounding factors such as basic liver function and bleeding severity(HR=1.64;95%CI:1.19-2.78;p= 0.002).1.3 Survival rate was higher in patients receiving preemptive TIPS were better than those receiving combination therapy in the short-term and long-term.In patients with Child-Pugh B plus stage 5 of cirrhosis,preemptive TIPS reduced death risk by 66%(HR =0.34;95% CI: 0.12-0.96;P = 0.041)in 6-week and 81%(HR = 0.19;95% CI: 0.06-0.61;P= 0.021)when the follow-up was extended to 1 year.1.4 The rate of treatment failure and rebleeding in preemptive was lower than that in the group combination therapy group.In the patients with Child-Pugh B plus stage 5 of cirrhosis,preemptive TIPS reduces 95%(HR = 0.05;95% CI: 0.01-0.21;P = 0.004)treatment failure rate and rebleeding rate in 6 week followed-up and 77%(HR=0.23;95%CI:0.13-0.41;p<0.001)in 1 year followed-up.1.5 The incidence of OHE was comparable between the combined treatment group and the preemptive TIPS group.The incidence of OHE was statistically insignificant between the combined treatment group and the preemptive TIPS group in both 6 week and1 year follow-up(HR = 0.98;95% CI: 0.62-1.56;P = 0.940),(HR = 1.26;95% CI:0.82-1.94;P = 0.290).1.6 Sensitivity analysis of preemptive TIPS survival benefit.Logistic regression was used to establish the propensity index score to predict the treatment with preferred TIPS or combination therapy,and a total of 102 patients with stage 5 of cirrhosis were matched.The competitive risk model was used to estimate that preferred TIPS could prolong patient survival and reduce the rate of treatment failure or rebleeding.Part Ⅱ.2.1 Baseline of population included: 304 patients(196 males;mean age,52 years)were included in the study.89% of patients were caused by the hepatitis virus and 92.4%patients underwent tips because of variceal bleeding.The mean MELD score was 11.6.The median follow-up time was 28.5 months.2.2 Hepatic encephalopathy after TIPS: OHE occurred in 115 patients,54 of whom experienced twice or more.84 patients had 149 episodes of OHE in three months after tips and 47 of which had only one OHE,while 37 had two or more.2.3 Early recurrent OHE is a risk factor for survival after TIPS: The survival time of patients with early OHE was significantly lower than that of patients without early OHE(HR = 2.75;95% CI: 1.75-4.32,P < 0.001).However,when OHE was divided into early single OHE and early recurrent ohe,the risk of death in patients with early recurrent OHE was significantly higher than that in patients without OHE(P < 0.001),but not in patients with early single OHE(P = 0.24).The survival rate of patients with early recurrent OHE was even lower(HR = 2.91,95% CI: 1.04-4.89;P < 0.001)when MELD score,ascites grade,serum albumin,tips indication and patient age were further adjusted.Besides,landmark and propensity index matching analysis further confirmed that early recurrent OHE was associated with postoperative tips.【Conclusions】1.The clinical course of cirrhosis is a predictor of 1-year survival for patients with AVB receiving combination therapy,independent of Child-Pugh score and MELD score.There is a high risk of one-year death in patients with stage 5 of cirrhosis and AVB receiving combination therapy.More aggressive measures are needed to prevent the occurrence of decompensation events and prolong the survival of patients.2.Preemptive TIPS can improve the survival of patients with Child-Pugh B plus stage 5of cirrhosis,and reduce the incidence of treatment failure without increasing the incidence of OHE.For patients with child Pugh B cirrhosis of stage 5,TIPS should be the first-line treatment.3.Early recurrent of OHE is an independent risk factor of death in cirrhotic patients after TIPS.Secondary prevention of OHE recurrence after TIPS not only reduces the incidence of OHE,but also may benefit long-term survival for patients with cirrhosis undergoing TIPS. |
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