Clinical characteristics of patients
The clinical characteristics of the patients are presented in Table 1. The study included 93 male patients and 32 female patients with a mean age of 62.3±12.2 years, and 118 of the 125 patients (94.4%) had cirrhosis. The main causes of cirrhosis were viral hepatitis (51 cases, 40.8%) and alcohol consumption (68 cases, 54.4%). The numbers of patients with Child-Pugh (CP) grades A, B, and C were 9, 62, and 47, respectively, with an average CP score (CPS) of 8.90±2.0. There were 27 patients (21.6%) with hepatocellular carcinoma (HCC), and seven patients had advanced portal vein tumor thrombus (PVTT) that progressed proximally to the primary branch of the portal vein.
Table 1 Clinical characteristics of patients
Number of patients
|
125
|
|
Sex (male/female)
|
93/32
|
|
Age, years (mean±SD)
|
62.3±12.2
|
(range 32–83)
|
Liver cirrhosis
|
|
|
presence
|
118
|
94.4%
|
absence
|
7
|
5.6%
|
Etiology
|
|
|
viral hepatitis
|
51
|
40.8%
|
alcohol consumption
|
68
|
54.4%
|
others
|
22
|
17.6%
|
Child-Pugh grade
|
|
|
grade A
|
9
|
7.6%
|
grade B
|
62
|
52.5%
|
grade C
|
47
|
39.8%
|
Child-Pugh Score (mean±SD)
|
8.9±2.0
|
|
HCC
|
|
|
presence
|
27
|
21.6%
|
absence
|
89
|
71.2%
|
unknown
|
9
|
7.2%
|
PVTT presence
|
7
|
5.6%
|
SD: standard deviation; HCC: hepatocellular carcinoma; PVTT: portal vein tumor thrombus.
Bleeding sites included the esophagus (76.8%, 96 patients), stomach (20.0%, 25 patients), duodenum (2.4%, three patients), and rectum (0.8%, one patient) (Table 2). Therapeutic methods included EVL (64.0%, 80 patients), EIS-Eo (17.6%, 22 patients), EIS-CA (16.0%, 20 patients), and BRTO (2.4%, three patients) (Table 2).
Table 2 Bleeding sites and therapeutic methods
Bleeding sites
|
|
|
Esophagus
|
96
|
76.8%
|
Stomach
|
25
|
20.0%
|
Duodenum
|
3
|
2.4%
|
Rectum
|
1
|
0.8%
|
Therapeutic methods
|
|
|
EVL
|
80
|
64.0%
|
EIS-Eo
|
22
|
17.6%
|
EIS-CA
|
20
|
16.0%
|
BRTO
|
3
|
2.4%
|
EVL: endoscopic variceal ligation; EIS-Eo: endoscopic injection sclerotherapy with 5% ethanolamine oleate; EIS-CA: endoscopic injection sclerotherapy using cyanoacrylate; BRTO: balloon-occluded retrograde transvenous obliteration.
Short-term results
Successful primary hemostasis was achieved in 123 patients (98.4%), while fatal bleeding occurred in two patients (1.6%) and seven patients (5.6%) died of liver failure within two weeks after treatment (Figure 1). Of the seven patients who died within two weeks, five patients had CP grade C, and two patients had a CPS ≥9 points within CP grade B.
Long-term outcomes
The one-, two-, three-, and five-year overall cumulative survival rates after treatment (median follow-up, 1389 days) were 72.6% (n=65), 59.4% (n=45), 54.8% (n=29), and 45.6% (n=16), respectively (Figure 2). The death cases consisted of 35 liver-related deaths (68.6%, 24 due to liver failure, 11 due to liver cancer), eight due to other causes, and eight of unknown causes. The one-, two-, three-, and five-year cumulative survival rates for CP grades A and B (median follow-up, 2826 days) were 81.3 (n=48), 68.4% (n=34), 63.4% (n=24), and 55.4% (n=13), respectively, while those for CP grade C (median follow-up, 518 days) were 58.1% (n=18), 44.1% (n=13), 40.1% (n=7), and 17.8% (n=4) respectively (p=0.001) (Figure 3).
The univariate and multivariate analyses showed that CP grade C (hazard ratio (HR), 2.37; 95% confidence interval (CI), 1.05-5.38; p=0.038) and HCC (HR, 4.03; 95% CI, 1.56-11.1; p=0.005) were associated with a poor prognosis (Table 3).
Table 3 Univariate and multivariate analyses of prognostic factors
Factor
|
Univariate
|
Multivariate
|
HR
(95% CI)
|
p value
|
HR
(95% CI)
|
p value
|
Sex (male)
|
|
0.19
|
|
|
Age (per year)
|
|
0.59
|
|
|
Etiology (alcohol)
|
|
0.24
|
|
|
Method (EVL)
|
|
0.35
|
|
|
CP grade C
|
2.58
(1.23-5.50)
|
0.013
|
2.37
(1.05-5.38)
|
0.038
|
Variceal re-bleeding
|
|
0.35
|
|
|
HCC presence
|
4.40
(1.75-11.9)
|
0.002
|
4.03
(1.56-11.1)
|
0.005
|
Term (latter)
|
|
0.23
|
|
|
EVL: endoscopic variceal ligation; CP: Child-Pugh, HCC: hepatocellular carcinoma; HR: hazard ratio; CI: confidence interval.
Variceal re-bleeding
After a first variceal eradication with emergency hemostatic therapy and additional treatment, 42 patients (33.9%) required re-treatment owing to recurrent varices or variceal bleeding (Figure 1), with an average period until re-treatment of 331 days. In addition, 27 patients (21.8%) had variceal re-bleeding (Figure 1), with an average period until variceal re-bleeding of 358 days. The one-, two-, three-, and five-year cumulative re-bleeding-free rates after the first variceal eradication (median length of follow-up, 1224 days) were 81.3% (n=55), 76.2% (n=35), 63.7% (n=21), and 55.3% (n=11), respectively (Figure 4). In addition, 27 patients with variceal re-bleeding had one-, two-, three-, and five-year cumulative survival rates (median length of follow-up, 912 days) of 80.9% (n=20), 72.4% (n=17), 66.3% (n=11), and 59.7% (n=6), respectively, while 91 patients without variceal re-bleeding (except for seven patients who died within two weeks) had one-, two-, three-, and five-year cumulative survival rates (median length of follow-up: 1389 days) of 75.3% (n=46), 59.0% (n=29), 54.6% (n=19), and 44.1% (n=11), respectively; however, no statistical significance was observed (p=0.24) (Figure 5). The causes of variceal re-bleeding are shown in Table 4. Variceal re-bleeding was triggered by alcohol consumption in 17 of the 27 patients (62.9%). Moreover, recurrent variceal re-bleeding was caused by alcohol consumption in all five patients.
Table 4 Causes of variceal re-bleeding
Alcohol consumption
|
17
|
62.9%
|
Viral hepatitis
|
3
|
11.1%
|
Cryptogenic
|
5
|
18.5%
|
Obstruction of splenic vein
|
1
|
3.7%
|
PVTT
|
1
|
3.7%
|
PVTT: portal vein tumor thrombus.
Combination with drug therapy
Regarding the combination with drug therapy, four patients with and 15 patients without variceal re-bleeding were administered nonselective beta-blockers (NSBB) to improve portal hypertension after hemostatic therapy. There was no statistically significant difference in the presence of variceal re-bleeding regardless of NSBB administration (p=0.93).
Outcomes of cases with advanced PVTT
In the seven HCC patients with advanced PVTT, only one patient (14.3%) had variceal re-bleeding; however, the average survival time was 60.4±21.4 days, and the majority of the patients died within a short period.
Transition of hemostatic therapy for variceal bleeding
Compared to the previous term group, the number of cases with variceal bleeding caused by alcohol consumption increased from 29 cases in the previous term to 42 cases in the latter term (p=0.003) (Figure 6A). As for the therapeutic methods, the number of EVL procedures increased from 30 to 49 cases (p<0.0001), and that of the EIS-Eo procedures decreased from 21 cases to one case (p<0.0001) in the latter term group (Figure 6B).
Except for seven patients who died within two weeks, the one-, two-, three-, and five-year cumulative survival rates after treatment for the 63 patients in the previous term group (median follow-up, 1552 days) were 78.5% (n=40), 62.3% (n=28), 57.5% (n=20), and 45.2% (n=14), respectively, while the rates for the 55 patients in the latter term group (the median follow-up, 729 days) were 75.6% (n=26), 65.5% (n=18), 59.0% (n=10), and 59.0% (n=3), respectively. There was no statistically significant difference between the two groups (p=0.74) (Figure 7). In addition, there was no significant difference in the cumulative survival rates between the EVL and EIS-Eo procedures for esophageal varices (in LC and CP grades A and B) (p=0.25).