The Clinical Study Of Drug Therapy In Cirrhotic Patients For The Prevention Of Esophageal Variceal Rebleeding

Background:Esophageal variceal bleeding is a serious complication and a main cause of mortality in liver cirrhotic patients. Initial variceal haemorrhage have a mortality of 20～40%. Variceal rebleeding is a common event that develops frequently after acute variceal bleeding, 60 to 80 percent of survivors will rebleed over 1～2 years, with a 20% mortality for each survivor that rebleeds. Most bleeding episodes occurring within 6 months of the index bleed. Therapy to prevent rebleeding from esophageal varices in patients with cirrhosis is essential. There are three treatments usually used in prevent rebleeding from esophageal varices: propranolol (PR), endoscopic therapy and esophagogastric devascularization. Few articles were found to compare the three methods together. Until now some studies that show different results have been published comparing the efficacy of beta-blocker with sclerotherapy in the treatment of oesophageal variceal rebleeding.PR, a nonselective beta-adrenergic blocker, is widely used fo prevent rebleeding . It has been proved that PR was effective in reducing the rebleeding risk in cirrhosis. Howerver, the individual difference of effect on patients with cirrhosis still persist: the existence of a group of nonresponders, regardless of the administered dose. PR alone is still associated with a rebleeding rate as high as 50%, the risk is not abolished.Isosorbide-5-mononitrate (IM), a long-acting venous dilator, has been shown to decrease portal pressure in cirrhotic patients. Regarding pharmacological therapy, the combination of PR and IM has a synergistic portal pressure-reducing effect and could theoretically be more effective than PR alone. There were few studys have performed a direct comparison between the combination of PR plus IM and PR alone in patients with prior variceal hemorrhage. There is not enough data about the association of nitrates and beta-blockers in preventing variceal rebleeding. The effectiveness of the association is less clearly defined and requires further studies.There is extensive first-pass metabolism of PR in the liver, so that the PR plasma levels varied widely among patients with the same dosage. In cirrhotic patients, hepatic elimination of PR is altered depending, in part, on liver function. It might be expected in patients with cirrhosis that plasma levels and pharmacological effects of PR would be affected. It is unknown Whether the PR plasma concentration correlate with the individual difference of effect on patients with cirrhosis. Few articles reported about that abroad, not yet be found in domestic. The relationship between drug concentration, changes of variceal pressure (VP) and portal hemodynamic response in patients with cirrhosis receiving PR need more research.The effect of association of drugs can be judged by repeated Hepatic vein pressure gradient (HVPG) by hepatic vein catheterization, VP by the endoscopic gauge, and Doppler ultrasonography data. The HVPG correlates with the true portal pressure in patients with cirrhosis. A reduction in the portal pressure of greater than 20% or below 12mmHg eliminates the risk of hemorrhage. Repeated HVPG measurement, however is invasive and must be performed in specialized liver units. It was not recommended in clinical pharmacological treatment routinely. VP might be more relevant to variceal haemorrhage than the measurements of HVPG, the latter also has the disadvantage of being an invasion technique. Endoscopic ballon technique is a safe, easy and reproducible method for estimating VP in patients with portal hypertension. The Doppler ultrasonography method establishes another non-invasive diagnosis determining the hemodynamic parameters that define hypertension with cirrhosis. By combined the cross sectional area and the erythrocyte velocity, poral blood flow volume (PBFV) can be assessed. Measurements of PBFV was found to be correlated to HVPG.Objective:The aim of the present study was to compare the clinical efficacy between PR, endoscopic injection sclerotherapy (EIS) and esophagogastric devascularization for the prevention of esophageal variceal rebleeding in cirrhotic patient.The current study compare the efficacy of treatment with PR to that with PR plus IM in patients with cirrhosis for the prevention of esophageal variceal rebleeding, as assessesd by non-invasive methods of endoscopic ballon technique and Doppler ultrasonography. In addition, High Performance Liquid Chromatography (HPLC) method for the determination of PR in serum was established, and correlations was assessed between PR plasma concentration, reduction in VP and portal hemodynamic response.Materials and Methods:Retrospective study was used to analyze 146 cirrhotic patients for the prevention of esophageal variceal rebleeding hospitalization in the first affiliated hospital of Anhui medical university from January 2005 to July 2008. Methods of prophylaxis adopted PR or EIS or esophagogastric devascularization. These patients were followed up by phone or letter.Meanwhile, prospective cohort study of drug therapy was carried out in cirrhotic patients for the prevention of esophageal variceal rebleeding. Fifteen cirrhotic patients were assigned to treatment with PR+IM (7 patients) or PR alone (8 patients) randomly from September 2007 to October 2008. Doppler ultrasound hemodynamic parameters and VP were measured at basal and 1 month after drugs administration. PR was administered twice daily at an initial dose of 10 mg 2 times daily. The dose was increased until the resting heart rate decreases by 20～25% from baseline. In the combined therapy group, after PR titrated to the same target in resting heart rate, The dose of IM was increased progressively up to a dose of 20 mg twice a day. All patients should be followed up at least 6 months. The recurrence rates of rebleeding were observed. In addition, the HPLC detection of PR plasma concentration was in the two groups with cirrhosis.Stastistical Analysis:Analysis of variables were calculated by SPSS 13.0 program. Values are given as mean±S.E. Student's t-test or One-Way ANOVA analysis was used to compare mean differences. Qualitative data were analysed by chi-squared or Fisher's exact test. Rebleeding and survival curves were plotted as Kaplan-Meier estimates, and compared by means of the log rank test. The Cox proportional hazards model was used to identify the variables, predicting time to rebleeding and survival. Correlation was performed by simple linear regression and correlation analysis. Correlation coefficient was evaluated by Student's t-test. Two-sided P-values of≤0.05 were considered to be statistically significant.Result:Rebleeing rates within 6 month after treatment were higher in EIS group than the group of PR and surgery (p=0.001). Time to rebleeing of the three groups showed that the effect of PR was superior to that of EIS, but less than that of surgery(p=0.000). The multivariate Cox analysis indicated both EIS (p=0.001) and massive bleeding (p=0.025) were factors predictive of rebleeding. Multivariate analysis showed that outcome-specific predictive factors for death were EIS (p=0.047), age 0=0.013), massive bleeding (p=0.002) and Child B (p=0.005).In prospective cohort study, both PR and PR plus IM significantly decreased VP, Quantity of portal vein (Qpv) and Quantity of splenic vein (Qsv) after 1-month treatment (p<0.05). The magnitude of changes in the three index mentioned above was greater in patients receiving PR plus IM than PR alone (p<0.05). The probability of rebleeding 6 months was not significant between the two groups (p=1.000).While PR concentrations were detected by HPLC, PR peak appeased at 4.175 min, it was not disturbed by other peak. The standard curve: Y=6020.545X±9974.563, r=0.998; The recovery of PR was in 85.91～93.79%; Within-day and between-day RSD < 8.65%. PR blood levels varied widely among patients. PR blood level were correlated neither with the reduction of VP nor portal hemodynamic effects(p>0.05).Conclusion:Propranolol are preferred as the first-line treatment in secondary prophylaxis of esophageal variceal bleeding; Besides EIS, age, Child-pugh grade, the severity of bleeding were signifiantly positively associated with prognostic in bleeding from esophageal varices.Combined administration of PR plus IM proved to be superior to the monotherapy with PR alone in decreasing VP. These results suggest that the addition of IM improves the efficacy of PR alone in the pharmacological treatment; There were no seriously adverse events were observed in PR plus IM group in patients with Child A～B; Changes of VP and portal hemodynamic response cannot be predicted according to PR blood level.