The secondary prophylactic efficacy of beta-blocker after endoscopic gastric variceal obturation for first acute episode of gastric variceal bleeding

Patients

This study was based on a retrospective analysis of medical record review in multicenter setting. This study targeted the 661 patients diagnosed with GV at the Soonchunhyang University Bucheon, Seoul and Cheonan Hospital from June 2001 and March 2010. Among these, patients who treated in GVO were 113.

Inclusion criteria were as follow: (1) age was between 18 and 80 years old (2) cirrhotic patients with endoscopically proved acute GVB; (3) type 1 gastro-esophageal varices (GOV1) or type 2 gastro-esophageal varices (GOV2) or type 1 isolated gastric varices (IGV 1); (4) GVO for therapeutic purpose within 12 hours of bleeding.12

Patients were excluded if they presented with one or more of the followings: (1) association with cerebral vascular accident, uremia, sepsis or other debilitating disease; (2) have a history of previous treatment of GV, including endoscopic therapy, BB, TIPS, or BRTO; (3) have a history of contraindications of BB, such as bronchial asthma, severe chronic obstructive pulmonary disease, severe heart failure, atrioventricular block, sinus bradycardia (pulse rate <55/min) or arterial hypotension (systolic blood pressure <90 mmHg); (4) did not reduce resting pulse rate up to 25% or 55 beats per minute; (5) deep jaundice (serum bilirubin >10 mg/dL); (6) hepatorenal syndrome; (7) lack of consent.

Total of 93 patients with the first acute GVB were enrolled consecutively. Two groups of patients who became hemodynamically stable for 3-5 days after initial GVO for the first GVB were compared: Group GVO included 42 patients who underwent only GVO; Group GVO+BB included 51 patients who also underwent GVO and additional BB therapy (Fig. 1).

Figure 1

Study flow chart. GV, gastric varices; GVO, gastric variceal obturation; GVO+BB, gastric variceal obturation plus beta-blocker.

Technique of endoscopic Histoacryl® injection

An endoscopist with experience of more than 5 years performed Histoacryl® injection. The endoscopic Histoacryl® injection was performed using a GIF-H260 or GIF-XQ240 endoscope (Olympus Co., Tokyo, Japan) and 7 French injection needle catheter (MTW Endoskopie, Wesel, Germany). Usually 1 mL of a 1:1 mixture of 0.5 mL Histoacryl® and equal volume of lipiodol (Guerbet GmbH, Sulzbach, Germany) was administered per injection. The injection needle catheter was advanced through the endoscope into the stomach, and then inserted directly into the GV. After injection, the location of lipiodol in the GV was identified using fluoroscopy. After that, the injection needle catheter was flushed with sterile water. Histoacryl® injections were repeated until GV appeared to be completely obliterated in one session. If a second session was considered to be necessary, it was done within one week of the initial session. If the GV was not completely obturated, Histoacryl® was reinjected until all the GV became solidified.

Beta-blocker therapy

Propranolol was started at a dose of 20 mg, twice daily as soon as hemodynamic stability was achieved after GVO. The dose of propranolol was increased by 20 mg every 3-5 days, if the target dose was not reached. Propranolol was adjusted according to the dosage that reduced resting pulse rate up to 25% or 55 beats per minute or reached to the maximal dose of 80 mg/day if the medication was well tolerated and the systolic blood pressure was >90 mmHg. The compliance was assessed by reduction of pulse rate or by quantifying the amount of tablets consumed.

Definitions

The classification of GV was described by Sarin et al3. GOV1 is a continuation of EV and extend for 2 to 5 cm below from the gastroesophageal junction along the lesser curvature side of the stomach, GOV2 is a continuation of EV and extend into the fundus. IGV1 is a GV in the absence of EV and the isolated GV located in the fundus of the stomach. The form of GV was classified into three types by Hashizume et al tortuous (F1), nodular (F2), and tumorous (F3).7

The severity of cirrhosis was classified according to Child-Pugh score and model for end-stage liver disease (MELD) score.22,23

Rebleeding of GV was defined as hematemesis: vomitus of red blood or coffee grounds material, melena: black, tarry, foul-smelling stool, hematochezia: passage of bright red or maroon blood from the rectum, or death within 6 weeks after endoscopic Histoacryl® injection.12 The primary end point was rebleeding-free survival and the secondary end point was overall survival.

Statistical analysis

Results were expressed as mean±SD for continuous variables and as numbers (percentage) for categorical variables. Analysis was performed using the independent t-test or χ² test for continuous variables and Chi-square analysis or Fisher's exact test for categorical variables. Rebleeding-free survival and overall survival were expressed using the Kaplan-Meier analysis and compared by Cox's proportional hazards model. P-value of <0.05 was considered significant. Statistical analysis was done using the Statistical Package for Social Sciences (SPSS 18.0 for Windows, SPSS Inc., Chicago, IL, USA).

Baseline clinical characteristics

Total of 93 patients with first acute GVB were enrolled. The 42 and 51 patients were included in Group GVO and GVO+BB, respectively. The mean follow-up periods after an initial eradication of GV were 18.14±25.22 months. The baseline clinical characteristics are shown in Table 1. There was no significant difference between Group GVO and GVO+BB in age, etiology of portal hypertension, liver function reserve, classification and form of GV.

Table 1.

Baseline clinical characteristics of patients with gastric variceal bleeding

Hemodynamic outcomes

In all patients of Group GVO+BB, the desired heart rate that reduced resting pulse rate up to 25% or 55 beats per minute could be achieved. The mean dose of propranolol was 47±16 mg (20-80 mg). After propranolol adding therapy, the heart rate was decreased more in Group GVO+BB than Group GVO (25.3±12.4 vs. 4.3±9.3 beats per minute, P=0.001). Also, for follow-up period, the heart rate in Group GVO+BB was lower than that in Group GVO (53.4±10.6 vs. 75.4±11.3 beats per minute, P=0.001).

Hemostatic outcomes and mortality

The mean volume of Histoacryl® administered was 2.1±0.9 mL. The mean number of sessions were 1.4±0.5. No treatment-related complications were noted.

The hemostatic outcomes and mortality are shown in Table 2. During follow-up period, rebleeding occurred in 10 patients (23.8%) and 21 patients (41.2%) in Group GVO and GVO+BB, respectively. The most common rebleeding source in two groups was GV. The mean rebleeding-free survival times were 65.40 and 37.40 months, respectively, and were not different significantly (P=0.774) (Fig. 2).

Table 2.

Rebleeding and mortality in patients with gastric variceal bleeding

Figure 2

Rebleeding-free survival rate in patients with gastric variceal bleeding.

In follow-up period, 23 patients (54.8%) died in Group GVO. In Group GVO+BB, 16 patients (31.4%) died. The causes of death were GVB (12), EVB (9), hepatocellular carcinoma (HCC) (7), sepsis (5), hepatorenal syndrome (4), acute myocardial infarction (1) and laryngeal cancer (1). The mean overall survival times were 52.54 and 72.65 months, respectively, and there were significant differences between two groups (P=0.036) (Fig. 3).

Figure 3

Overall survival rate in patients with gastric variceal bleeding.

Factors associated with rebleeding and overall survival

Univariate analysis showed that albumin, total bilirubin, prothrombin time, Child-Pugh score and MELD score were associated with higher incidence of rebleeding (Table 3). On multivariate analysis, Child-Pugh score was an independent determinant of rebleeding. Univariate analysis showed that BB, hepatic encephalopathy, albumin, total bilirubin, prothrombin time, Child-Pugh score and MELD score were associated with higher mortality (Table 4). On multivariate analysis, BB, hepatic encephalopathy, albumin, Child-Pugh score and MELD score were independent determinants of overall survival.

Table 3.

Univariate and multivariate analysis of rebleeding in patients with gastric variceal bleeding

Table 4.

Univariate and multivariate analyses of overall survival in patients with gastric variceal bleeding