Long-Term Outcomes After Endoscopic Sequential Therapy in Patients With Gastroesophageal Variceal Bleeding as the First Decompensated Event

Abstract

INTRODUCTION:

Limited data exist regarding the portal hypertension progression in cirrhotic patients with variceal bleeding as the initial decompensation event. This study evaluated the impact of sequential endoscopic therapy on long-term clinical outcomes.

METHODS:

196 hospitalized cases were included and divided into esophageal varices (EV), type 1 gastroesophageal varices (GOV1), type 2 GOV (GOV2), and type 3 GOV (GOV3) groups. The Fine-Gray test was used to analyze the cumulative incidence of outcome events. Survival was calculated using the Kaplan-Meier method, and the Cox proportional risk regression model was used for multivariate analysis of factors affecting outcomes.

RESULTS:

During a median follow-up period of 104.9 months, distinct cumulative outcomes were observed across esophageal and gastric variceal subtypes. The 1-, 3-, and 5-year cumulative rebleeding rates progressively increased across subtypes: EV (16.2%, 29.7%, 41.9%), GOV1 (18.8%, 39.6%, 45.8%), GOV2 (19.1%, 34.0%, 46.8%), and GOV3 (44.4%, 63.0%, 66.7%) (Gray test, P = 0.009). Corresponding survival rates demonstrated an inverse pattern, declining with longer follow-up: EV (91.9%, 82.4%, 58.1%), GOV1 (91.7%, 79.2%, 60.4%), GOV2 (91.5%, 76.6%, 55.3%), and GOV3 (74.1%, 55.6%, 48.1%) (log-rank test, P = 0.016). Rebleeding was an independent risk factor associated with survival (hazard ratio: 3.518, P < 0.001). Multivariate analysis showed that variceal shape, variceal type, and the treatment courses to variceal eradication (whether > 3) were significant risk factors for rebleeding (P < 0.05).

DISCUSSION:

In this study, rebleeding dominated the clinical course of different subtypes and was an independent predictor of death. More aggressive treatments, such as salvage transjugular intrahepatic portosystemic shunt, should be considered in patients who were at higher risk of rebleeding.

INTRODUCTION

Esophageal and gastric variceal bleeding (EGVB) is a life-threatening complication of cirrhosis, with acute variceal bleeding (AVB) mortality rates reaching 20%–30% and high risks of rebleeding (7%–28%) and in-hospital mortality (10%–15%) (1,2). AVB occurs in 16%–75.6% of patients who have not been previously treated for esophageal varices (EV) and 25% of patients who have not been previously treated for gastric varices (GV). The natural course and frequency of variceal bleeding depend on the location and type of EV and GV (3). The most widely used classification is that proposed by Sarin et al (4), which classifies gastroesophageal varices (GOV) into 4 different types, namely, type 1 gastroesophageal varices (GOV1), type 2 GOV (GOV2), type 1 isolated gastric varices (IGV1), and type 2 IGV (IGV2). Clinical practice has added to this list type 3 GOV (GOV3) (EV extending to both the lesser curvature and the fundus). GOV1 is the most common of all GVs. GOV2 and IGV1 have been associated with a higher incidence of variceal hemorrhage with a higher mortality rate in patients with GOV2 (4,5). Studies have demonstrated that the EV originates predominantly from the anterior branch of the left gastric vein and that GVs originate from the hilar collateral branches of the short gastric vein or the retrosternal vein (6,7). Differences in the origin of the portal side branches may lead to a different course of esophageal and gastric variceal (EGV). However, there are limited data on the further course of portal hypertension after first bleeding in patients with different types of EGVs.

Endoscopic treatment has been recommended as the first-line treatment option for recurrent variceal bleeding and control of acute bleeding (8). Multiple cycles of sequential treatment can achieve complete variceal occlusion (9–11). Data from clinical studies have shown that sequential endoscopy has significant advantages over other treatment strategies for the treatment of AVB (12). In this study, we present the results of sequential endoscopy based on the long-term clinical outcomes of patients with EV or GOV, such as rebleeding, ascites, development of portal vein thrombosis (PVT), new-onset hepatic encephalopathy (HE), spontaneous portosystemic shunt (SPSS), and overall survival, comparing the differences in the course of portal hypertension in various subgroups, and evaluating prognostic markers for rebleeding and death.

METHODS

Study population

Patients with liver cirrhosis with EGVB who were admitted to Tianjin Third Central Hospital from May 2011 to December 2019 were collected and evaluated according to the following criteria: Inclusion criteria: (i) All patients were diagnosed with liver cirrhosis based on clinical manifestations, imaging and blood tests, or liver biopsy; (ii) the presence of EGVB was confirmed by electronic endoscopy, and there was no history of EGVB, ascites, or HE. Exclusion criteria: (i) age younger than 18 years or older than 80 years; (ii) combination of hepatocellular carcinoma (HCC) or other occupying lesions; (iii) previous endoscopic treatment, splenectomy, transjugular intrahepatic portosystemic shunt (TIPS), or liver transplantation; (iv) concurrent with other conditions that may cause bleeding, such as ulcers and coagulation disorders; and (v) less than 5 years of follow-up or missing data. A total of 196 patients with complete 5-year follow-up data or confirmed death or rebleeding during follow-up were finally included in this study (Figure 1). This study followed the Declaration of Helsinki and was approved by the Medical Ethical Committee of the Tianjin Third Central Hospital (approval number: IRB2021-047-01).

Figure 1.

Study population selection and study design. EGVB, esophageal and gastric variceal bleeding; EV, esophageal varices; GOV, gastroesophageal varices; HE, hepatic encephalopathy; HCC, hepatocellular carcinoma; TIPS, transjugular intrahepatic portosystemic shunt.

Data collection, follow-up, and clinical outcomes

Demographic, clinical, and relevant laboratory parameters were retrieved from the electronic medical record data management system of Tianjin Third Central Hospital. Baseline liver disease-specific scores such as Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores were calculated.

The baseline date was defined as the date of admission for endoscopic treatment. All patients received regular outpatient or telephone follow-ups and were admitted to the hospital if necessary. The primary outcome was death from any cause, and the secondary outcome was further decompensation (ascites, variceal rebleeding, and HE). Detailed information on relevant outcomes was retrieved from the database, including the time these events occurred. In addition, other outcomes such as HCC, PVT, and SPSS were reviewed from serial imaging records available in the database. All patients were followed until a fatal event occurred during follow-up or until December 31, 2024.

Endoscopic therapy

Endoscopic treatment is indicated for high-risk varices, defined as small varices with red signs, medium to large varices with or without red signs, or bleeding varices. If high-risk varices are confined to the esophagus, endoscopic variceal ligation (EVL) is performed at the initial session. When ligation techniques were difficult or active variceal bleeding was observed during the endoscopic examination, endoscopic injection sclerotherapy (EIS) or a combination of EIS and EVL was considered. If only gastric fundal varices (GV) are present, a combination therapy of endoscopic cyanoacrylate injection (ECI) and endoscopic injection sclerotherapy (EIS) is administered. When high-risk varices involve both the esophagus and gastric fundus, combined EVL, ECI, and EIS are applied. EVL is no longer applicable when EV becomes discontinuous or surrounded by scar tissue; in such cases, EIS is used to eradicate any residual varices. After the initial endoscopic treatment session for EGV, the sessions were repeated every 4-6 weeks thereafter until variceal eradication (VE) (13). Eradication of EGV is confirmed endoscopically by the absence of definite varices or the presence of only small varices without red signs. The number of rubber rings to be ligated and the amount of sclerosant or cyanoacrylate to be used depends on the size of the varices and the bleeding situation. After successful eradication, endoscopic monitoring is conducted every 3 months. If varices remain eradicated, the monitoring interval is gradually extended to every 6 months, 1 year, and eventually 2 years. If variceal recurrence (VR) occurs—small varices with red signs or medium to large varices are present, repeat the sequential treatment according to the above endoscopic treatment strategy.

Statistical analysis

Independent samples t-test, Mann-Whitney U test, χ² test, and Fisher exact probability method were used to compare differences between groups. A paired-sample χ² test was used to compare the change in clinical events before and after follow-up. The cumulative incidence of outcome events during follow-up was analyzed using the Fine-Gray test with death as the competing event. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses of factors affecting survival and bleeding were performed using Cox proportional risk regression models. A 2-tailed P value less than 0.05 was considered statistically significant. SPSS version 27.0 software (IBM Corp, Armonk, NY) and R statistics version 4.4.2 (R Core Team, Vienna, Austria) were used for data analysis.

RESULTS

Baseline characteristics

This study included 196 patients with cirrhosis combined with first EGVB, divided into EV (74 patients, 37.75%), GOV1 (48 patients, 24.49%), GOV2 (47 patients, 23.98%), and GOV3 (27 patients, 13.78%) according to the location of the varices and consisted of 129 men (65.82%) and 67 women (34.18%) with a median age of 55 years (range 18–78 years). In these patients, viral hepatitis was the main cause of cirrhosis (54.59%). The patients' CTP grades were A, B, and C in 70 (35.71%), 111 (56.63%), and 15 (7.65%) patients, respectively, and the median MELD score was 9.24 (interquartile range [IQR]: 5.75–11.81). Table 1 summarizes more detailed information on the baseline characteristics of the enrolled patients.

Table 1.

Baseline characteristics and outcomes of patients with different subtypes of EGVB

Variables	EV (n = 74)	GOV1 (n = 48)	GOV2 (n = 47)	GOV3 (n = 27)	P value
Age (yr)	54 (49–61)	53 (46.5–60.5)	55 (44–60.5)	57 (53–61)	0.282
Male sex	46 (62.2)	34 (26.4)	31 (24.0)	18 (66.7)	0.805
Etiology of liver cirrhosis					0.445
Hepatitis B and C (n, %)	38 (51.4)	27 (56.3)	26 (55.3)	16 (59.3)
Alcohol (n, %)	17 (23.0)	13 (27.1)	15 (31.9)	5 (18.5)
Autoimmune liver disease (n, %)	14 (18.9)	4 (8.3)	5 (10.6)	2 (7.4)
Others (n, %)	5 (6.8)	4 (8.3)	1 (2.1)	4 (14.8)
Diabetes (n, %)	8 (10.8)	13 (27.1)	10 (21.3)	5 (18.5)	0.138
Decompensations
Preparative HE (n, %)	4 (5.4)	1 (2.1)	0 (0)	2 (7.4)	0.24
Ascites (n, %)	46 (62.2)	34 (70.8)	26 (55.3)	19 (70.4)	0.379
PVT (n, %)	7 (9.5)	13 (27.1)	7 (14.9)	6 (22.2)	0.067
SPSS (n, %)	24 (32.4)	18 (37.5)	20 (42.6)	13 (48.1)	0.465
Endoscopy
Variceal size (n, %)					0.044
Small	6 (8.1)	1 (2.1)	4 (8.5)	6 (22.2)
Middle	20 (27)	11 (22.9)	14 (29.8)	2 (7.4)
Large	48 (64.9)	36 (75)	29 (61.7)	19 (70.4)
Red sign (n, %)	66 (89.2)	45 (93.8)	43 (91.5)	25 (92.6)	0.840
Initial bleeding location (n, %)					<0.001
Esophagus	74 (100.0)	17 (35.4)	5 (10.6)	1 (3.7)
Lesser curvature	0 (0.0)	16 (33.3)	0 (0.0)	2 (7.4)
Fundus	0 (0.0)	0 (0.0)	27 (57.4)	8 (29.6)
Esophagus and lesser curvature	0 (0.0)	15 (31.3)	0 (0.0)	5 (18.5)
Esophagus and fundus	0 (0.0)	0 (0.0)	15 (31.9)	11 (40.7)
Initial treatment
Initial endoscopic treatment (n, %)					<0.001
EVL	72 (97.3)	15 (31.3)	3 (6.4)	1 (3.7)
EIS + ECI	0 (0.0)	15 (31.3)	23 (48.9)	9 (33.3)
EVL + EIS + ECI	0 (0.0)	18 (37.5)	19 (40.4)	17 (63.0)
Other	2 (2.7)	0 (0.0)	2 (4.3)	0 (0.0)
NSBBs for primary prevention (n, %)	21 (28.4)	8 (16.7)	9 (19.1)	8 (29.6)	0.349
NSBBs type (n, %)					0.398
Propranolol	4 (19.0)	3 (37.5)	3 (33.3)	4 (50.0)
Carvedilol	17 (81.0)	5 (62.5)	6 (66.7)	4 (50.0)
Propranolol dose, mg/d	15.0 ± 5.8	13.3 ± 2.9	15.0 ± 5.0	17.5 ± 9.6	0.868
Carvedilol dose, mg/d	10.3 ± 4.9	10.0 ± 3.4	11.5 ± 7.3	10.9 ± 3.1	0.957
Laboratory tests
Hemoglobin (g/L)	86 (71–96)	86 (72–97)	89 (75–100)	89 (71–99)	0.892
White blood cell (×109/L)	4.15 (2.63–6.53)	5.09 (3.81–7.89)	4.92 (3.14–6.36)	3.93 (2.55–7.49)	0.393
Platelets (×109/L)	75 (52–112)	73 (54–122)	82 (57–115)	76 (59–97)	0.914
Prothrombin time (s)	16.20 (15.08–18.00)	15.80 (14.70–18.70)	16.10 (14.40–17.50)	16.00 (15.20–17.10)	0.821
International normalized ratio	1.30 (1.18–1.50)	1.30 (1.16–1.55)	1.28 (1.14–1.42)	1.27 (1.18–1.41)	0.739
Creatinine (μmol/L)	60.5 (48.2–73.0)	58 (51–74)	58 (53–75)	61 (57–69)	0.786
Alanine transaminase (U/L)	26 (20–40.25)	32 (19–48)	24 (20–46)	25 (18–35)	0.397
Aspartate transaminase (U/L)	31 (23.5–41.3)	34 (23–48)	32 (22–48)	27 (22–40)	0.875
Gamma-glutamyl transferase (U/L)	50.5 (19.0–105.3)	36.0 (24–71)	40 (25–70)	39 (24–67)	0.942
Total bilirubin (μmol/L)	17.7 (11.9–24.9)	20.6 (14.4–31.0)	20.7 (12.7–29.1)	21.0 (12.5–28.6)	0.335
Albumin (g/L)	33.0 (28.6–37.3)	31.7 (26.8–36.3)	32.7 (29.3–36.1)	34.0 (30.3–37.0)	0.739
CTP grade (n, %)					0.418
A (5–6)	28 (37.8)	11 (22.9)	20 (42.6)	11 (40.7)
B (7–9)	42 (56.8)	32 (66.7)	24 (51.1)	13 (48.1)
C (10–13)	4 (5.4)	5 (10.4)	3 (6.4)	3 (11.1)
CTP score	7.2 ± 1.8	7.5 ± 1.7	7.1 ± 1.7	7.3 ± 1.9	0.588
MELD score	9.06 (5.64–11.49)	9.63 (5.40–12.35)	9.46 (4.33–11.89)	9.19 (7.80–11.95)	0.784
Variceal changes after endoscopic therapy (n, %)
Variceal eradication	69 (93.2)	41 (85.4)	40 (85.1)	21 (77.8)	0.179
Endoscopic therapy times to eradication	2 (1–3)	3 (2–4.5)	3 (2–4)	3 (2–5)	0.021
Variceal recurrencea	45 (65.2)	28 (68.3)	24 (60.0)	14 (66.7)	0.882
Variceal type					<0.001
Absent	8 (10.8)	4 (8.3)	1 (2.1)	1 (3.7)
EV	17 (23.0)	10 (20.8)	11 (23.4)	7 (25.9)
GOV1	28 (37.8)	23 (47.9)	7 (14.9)	3 (11.1)
GOV2	17 (23.0)	11 (22.9)	27 (57.4)	14 (51.9)
GOV3	4 (5.4)	0 (0.0)	1 (2.1)	2 (7.4)
Variceal size					0.003
Absent	8 (10.8)	4 (8.3)	1 (2.1)	1 (3.7)
Small	46 (62.2)	25 (52.1)	16 (34.0)	8 (29.6)
Middle	12 (16.2)	12 (25.0)	14 (29.8)	10 (37.0)
Large	8 (10.8)	7 (14.6)	16 (34.0)	8 (29.6)
Red sign	19 (25.7)	18 (37.5)	23 (48.9)	14 (51.9)	0.025
High-risk varices	20 (27.0)	19 (39.6)	31 (66.0)	18 (66.7)	<0.001
Transfer to TIPS during follow-up
Indication for TIPS (n, %)					1.000
Refractory variceal bleeding	3 (75.0)	3 (75.0)	5 (71.4)	6 (85.7)
Refractory ascites	1 (25.0)	1 (25.0)	2 (28.6)	1 (14.3)
Rebleeding after TIPSb (n, %)	0 (0.0)	1 (25.0)	1 (14.3)	0 (0.0)	0.788
Death in TIPSb (n, %)	3 (75.0)	4 (100.0)	4 (57.1)	6 (85.7)	0.598
New-onset decompensation (n, %)
Rebleeding	35 (47.3)	22 (45.8)	25 (53.2)	20 (74.1)	0.083
Number of rebleeding	1 (1–2)	1 (1–4)	2 (1–3)	2 (1–3)	0.151
Variceal bleeding					0.068
Nonrebleeding	39 (52.7)	26 (54.2)	22 (46.8)	7 (25.9)
Early rebleeding (<1 yr)	12 (16.2)	9 (18.8)	9 (19.1)	12 (44.4)
Late rebleeding (>1 yr)	23 (31.1)	13 (27.1)	16 (34.0)	8 (29.6)
Ascites	29 (39.2)	11 (22.9)	12 (25.5)	8 (29.6)	0.214
HE	10 (13.5)	5 (10.4)	2 (4.3)	5 (18.5)	0.245
All-cause decompensation	48 (64.9)	31 (64.6)	30 (63.8)	21 (77.8)	0.604
New-onset additional events (n, %)
SPSS	28 (37.8)	12 (25.0)	15 (31.9)	10 (37.0)	0.496
PVT	27 (36.5)	14 (29.2)	15 (31.9)	12 (44.4)	0.563
HCC	22 (29.7)	8 (16.7)	11 (23.4)	4 (14.8)	0.260
Death	53 (71.6)	32 (66.7)	30 (63.8)	23 (85.2)	0.243
Cause of death (n, %)					0.039
Gastrointestinal bleeding	9 (12.2)	7 (14.6)	7 (14.9)	4 (14.8)
Hepatic failure	13 (17.6)	5 (10.4)	10 (21.3)	9 (33.3)
Multiple infection	3 (4.1)	1 (2.1)	4 (8.5)	1 (3.7)
Multiple organ failure	9 (12.2)	2 (4.2)	0 (0.0)	3 (11.1)
Other	1 (1.4)	3 (6.3)	0 (0.0)	2 (7.4)
Follow-up time (mo)	106.2 (78.4–131.8)	88.7 (67.1–105.4)	87.9 (66.6–101.5)	74.7 (68.2–87.1)	<0.001

Continuous variables were expressed as mean ± SD or median (interquartile range), while categorical variables were presented as n (%).

CTP, Child-Turcotte-Pugh; ECI, endoscopic cyanoacrylate injection; EIS, endoscopic injection sclerotherapy; EV, esophageal varices; EVL, endoscopic variceal ligation; GOV, gastroesophageal varices; GV, gastric varices; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; MELD, model for end-stage liver disease; NSBBs, nonselective beta-blockers; PVT, portal vein thrombosis; SPSS, spontaneous portosystemic shunt; TIPS, transjugular intrahepatic portosystemic shunt.

^aPercentages referred to the total number of patients with variceal eradication.

^bPercentages referred to the total number of patients with TIPS.

Further decompensation and other clinical outcomes

A median of 104.94 (interquartile range: 88.07–116.20) months was achieved in 196 patients, and clinical outcomes during follow-up are detailed in Table 1. Compared with baseline, patients had a significantly higher incidence of PVT and overt HE (50.00% and 11.22%, respectively), whereas the incidence of ascites and SPSS did not change significantly (Table 2). Forty-eight (64.9%) patients with EV, 31 (64.6%) patients with GOV1, 30 (63.8%) patients with GOV2, and 21 (77.8%) patients with GOV3 developed new adverse events (Table 1). Rebleeding was the most common event in patients across all subtypes. The incidence of rebleeding was significantly higher in GOV3 patients after controlling for competing risk events (Gray’s test, p = 0.009). Further multiple comparisons within subgroups (Holm-Bonferroni method) showed that the rebleeding rate in GOV3 was significantly higher than in EV (p-adjust = 0.007) and GOV1 (p-adjust = 0.044), while rebleeding rates among other subtypes were comparable (Supplementary Figure 1a, http://links.lww.com/CTG/B456). The incidence of recurrent ascites, HE, PVT, SPSS, and HCC was similar in all 4 groups (Table 3, Supplementary Figures 1b, c, d, e and f, http://links.lww.com/CTG/B456). Due to the small sample size of the GOV3 subgroup, EV and GOV1 were defined as EVs, and GOV2 and GOV3 were defined as GVs based on the initial bleeding location (Table 1). Consistent with the above conclusions, the cumulative incidence of rebleeding in the GVs group was significantly higher than that in the EVs group (Gray’s test, p = 0.042), while there was no significant difference in the cumulative incidence between the two groups for ascites, HE, PVT, SPSS, and HCC showed no significant differences in cumulative incidence rates between the two groups (Supplementary Figure 2, http://links.lww.com/CTG/B457).

Table 2.

Clinical events and varices changes in enrolled patients

Clinical events	At baseline	At the end of follow-up	P value
Ascites (n, %)	125 (63.78%)	133 (67.86%)	0.492
PVT (n, %)	33 (16.84%)	98 (50.00%)	<0.001
HE (n, %)	7 (3.57%)	22 (11.22%)	0.001
SPSS (n, %)	75 (38.27%)	106 (54.08%)	0.363
Variceal type (n, %)			<0.001
EV	74 (37.75%)	45 (22.96%)
GOV1	48 (24.49%)	61 (31.12%)
GOV2	47 (23.98%)	69 (35.20%)
GOV3	27 (13.78%)	7 (3.6%)
Medium or large varices (n, %)	179 (91.33%)	87 (44.39%)	<0.001
Red sign (n, %)	179 (91.33%)	74 (37.76%)	<0.001
High-risk varices (n, %)	196 (100%)	88 (44.90%)	—

EV, esophageal varices; GOV, gastroesophageal varices; HE, hepatic encephalopathy; PVT, portal vein thrombosis; SPSS, spontaneous portosystemic shunt.

Table 3.

Cumulative incidence of further decompensation and outcome events

Event	Significance	Group	1-yr (%)	3-yr (%)	5-yr (%)
Rebleeding	0.009	EV	16.22	29.73	41.89
		GOV1	18.75	39.58	45.83
		GOV2	19.15	34.04	46.81
		GOV3	44.44	62.96	66.67
HE	0.206	EV	2.7	6.76	8.11
		GOV1	4.17	8.33	8.33
		GOV2	2.13	2.13	2.13
		GOV3	11.11	18.52	18.52
Ascites	0.324	EV	6.76	16.22	27.03
		GOV1	2.08	8.33	14.58
		GOV2	2.13	8.51	23.4
		GOV3	11.11	18.52	22.22
SPSS	0.641	EV	6.76	14.86	24.32
		GOV1	2.08	12.5	22.92
		GOV2	8.51	19.15	25.53
		GOV3	18.52	22.22	29.63
PVT	0.562	EV	4.05	16.22	27.03
		GOV1	8.33	14.58	25
		GOV2	8.51	21.28	27.66
		GOV3	3.7	18.52	22.22
HCC	0.673	EV	4.05	10.81	21.62
		GOV1	4.17	4.17	8.33
		GOV2	6.38	17.02	19.15
		GOV3	0	3.7	7.41

EV, esophageal varices; GOV, gastroesophageal varices; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; PVT, portal vein thrombosis; SPSS, spontaneous portosystemic shunt.

During follow-up, 87.24% (171) of patients achieved VE after a mean number of 3(2-4) treatment courses, but 64.91% (111) of these patients experienced VR (Table 1). Patients who achieved VE had fewer rebleeding (p < 0.001) and higher survival rates (p < 0.001), while those who experienced VR had more rebleeding and lower survival rates (Supplementary Table 1, http://links.lww.com/CTG/B459). By the end of follow-up, the number of patients with varices decreased by 7.1% (Table 1), and the number of high-risk varices patients decreased by 55.1% (Table 2). At the same time, variceal type changed with a decrease in the incidence of EV (22.96%) and GOV3 (3.6%) and an increase in the incidence of GOV1 (31.12%) and GOV2 (35.20%) (Table 2). To explore the relationship between dynamic changes in variceal characteristics and clinical outcomes, variceal size response (VSR) was defined as the transformation of large varices at baseline to small or without varices at the end of follow-up, or the maintenance of small varices or the disappearance of varices at the end of follow-up. Red sign response (RSR) was defined as if the baseline red sign was positive and became negative at the end of follow-up or remained negative at both baseline and follow-up. High-risk varices response (HRVR) was defined as if the baseline high-risk status changed to low-risk at the end of follow-up. Correlation analysis showed that patients with VSR, RSR, and HRVR had lower rebleeding rates and higher survival rates (Supplementary Table 1, http://links.lww.com/CTG/B459).

Additionally, by the end of follow-up, 45 patients (22.96%) had progressed to HCC. A total of 22 patients received additional TIPS during follow-up (17 patients of salvage TIPS for variceal bleeding and 5 patients of salvage TIPS for refractory ascites) with no statistical difference between groups (Table 1). Post-TIPS rebleeding occurred in only 2/22 (9.1%), supporting its efficacy. However, mortality remained high (17/22, 77.3%) and no significant differences were observed among the variceal subtypes.

Survival

None of the patients enrolled in this study received a liver transplant during the follow-up period. The 1-year, 3-year, and 5-year overall survival rates of 196 patients were 89.3%, 76.5%, and 56.6%, respectively, and the cumulative survival rates of GOV3 patients (74.1%, 55.6%, and 48.1%) were lower than those of EV patients (91.9%, 82.4%, and 58.1%), GOV1 patients (91.7%, 79.2%, and 60.4%), and GOV2 patients (91.5%, 76.6%, and 55.3%) (Log rank p = 0.016) (Figure 2a, Supplementary Table 2, http://links.lww.com/CTG/B460). A total of 138 deaths (70.4%) occurred during long-term follow-up, and the causes of death was hepatic failure in 64 patients, gastrointestinal bleeding in 44 patients, multiple infection in 18 patients, multiple organ failure in 7 patients, renal cell carcinoma in 1 patient, acute myocardial infarction in 1 patient, COVID-19 in 1 patient, stroke in 1 patient, and traffic accident in 1 patient, respectively. Most patients died of liver failure rather than variceal bleeding.

Figure 2.

Cumulative survival of enrolled patients (a), different variceal subtypes (b), rebleeding (c), and early rebleeding.

CTP-A patients had higher 1-year, 3-year, and 5-year survival rates than CTP-B/C patients (p = 0.025); the former had 1-year, 3-year, and 5-year survival rates of 95.7%, 81.4%, and 61.4%, respectively, compared with 85.7%, 73.8%, and 54.0% for the latter (Supplementary Table 2, http://links.lww.com/CTG/B460). In addition, patients with GOV3 staging had a significantly lower survival rate than those with other staging (p = 0.016). In contrast, patients with large varices had a lower survival rate than patients with small and medium size varices (p = 0.001), especially the 5-year survival rate, which was 53.8% for the former and 62.5% for the latter. In addition, patients without rebleeding had a higher survival rate than those with rebleeding (p < 0.001), with 1-year, 3-year, and 5-year survival rates of 95.7%, 87.2%, and 79.8%, respectively, for patients without rebleeding compared with the corresponding rates of 83.3%, 66.7%, and 35.3%, for patients with rebleeding (Figure 2b). Since new-onset HCC, PVT and rebleeding happened later than timing of baseline characteristics recorded, to reduce bias, they were treated as time-dependent covariates in the Cox analysis. Multivariate Cox regression analysis identified rebleeding as an independent risk factor associated with survival with a hazard ratio of 5.413 (p < 0.001). In addition, new-onset HCC, higher CTP score and more than 3 treatment courses to variceal eradication were significantly increased the risk of mortality (Table 4).

Table 4.

Factors associated with risk of mortality in enrolled patients

Variables	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Age, yr	0.998 (0.982–1.014)	0.786
Etiology
Nonhepatitis	Reference
Hepatitis	0.990 (0.706–1.386)	0.951
CTP score	1.194 (1.087–1.311)	<0.001	1.194 (1.078–1.323)	<0.001
MELD score	1.046 (0.999–1.094)	0.052
NSBBs
No	Reference
Yes	0.833 (0.548–1.266)	0.393
Variceal type
EV	Reference		Reference
GOV1	1.188 (0.761–1.854)	0.449	0.897 (0.503–1.600)	0.713
GOV2	1.108 (0.691–1.777)	0.672	0.920 (0.488–1.732)	0.795
GOV3	2.203 (1.363–3.562)	0.001	0.819 (0.379–1.772)	0.612
Initial bleeding location
EV	Reference		Reference
GV	1.559 (1.043–2.331)	0.030	1.213 (0.672–2.191)	0.522
Both	1.677 (1.095–2.570)	0.018	1.388 (0.761–2.532)	0.285
Variceal size
Small and medium	Reference		Reference
Large	1.908 (1.257–2.895)	0.002	1.207 (0.825–1.765)	0.332
>3 Tx courses to VE
No	Reference		Reference
Yes	2.118 (1.497–2.997)	<0.001	1.728 (1.176–2.538)	0.005
Ascites
Absent and mild	Reference
Moderate and severe	1.410 (0.975–2.040)	0.068
PVT
Absent	Reference
Present	1.194 (0.799–1.785)	0.386
SPSS
Absent	Reference
Present	0.913 (0.643–1.295)	0.609
HE
Absent	Reference
Present	0.708 (0.271–1.851)	0.482
Rebleedinga
Absent	Reference		Reference
Present	6.812 (4.809–9.648)	<0.001	5.413 (3.742–7.828)	<0.001
New-onset HCCa
Absent	Reference		Reference
Present	1.741 (1.085–2.792)	0.021	2.171 (1.343–3.509)	0.002
New-onset PVTa
Absent	Reference		Reference
Present	2.073 (1.403–3.062)	<0.001	1.453 (0.990–2.132)	0.056

CTP, Child-Turcotte-Pugh; EV, esophageal varices; GOV, gastroesophageal varices; GV, gastric varices; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HR, hazard ratio; MELD, model for end-stage liver disease; NSBBs, nonselective beta-blockers; PVT, portal vein thrombosis; SPSS, spontaneous portosystemic shunt; VE, variceal eradication.

^aTime-dependent covariates.

Of the 102 rebleeding episodes, up to 41.18% of patients experienced rebleeding within 1 year. They were classified as no rebleeding group (94 patients), early rebleeding group (rebleeding within 1 year, 42 patients), and late rebleeding group (rebleeding > 1 year, 60 patients) based on the presence or absence of rebleeding within 1 year. The Cox analysis suggested that the probability of survival for patients with early rebleeding was lower than that for patients with no rebleeding (hazard ratio [HR] 10.284, 95% CI 6.419-16.475, p < 0.001) and patients with late rebleeding (HR 3.749, 95% CI 2.439-5.763, p < 0.001). Also, the probability of survival was lower in patients with late rebleeding than in those without rebleeding (HR 2.743, 95% CI 1.812-4.152, p < 0.001) (Figure 2c).

Rebleeding

All patients achieved hemostasis during hospitalization, and rebleeding occurred in 102 (52.04%) at follow-up, with cumulative 1-year, 3-year, and 5-year rebleeding rates of 21.4%, 37.8%, and 47.4%, respectively. Of the patients with rebleeding, 35 were from EV (47.3%), 22 from GOV1 (45.8%), 25 from GOV2 (53.2%), and 20 from GOV3 (74.1%). The cumulative 1-year, 3-year, and 5-year rebleeding rates were significantly higher for GOV3 (44.4%, 63.0%, and 66.7%) than for the other subtypes (Gray’s test, p = 0.009); 16.2%, 29.7%, and 41.9% for EV; 18.8%, 39.6%, and 45.8% for GOV1; and 19.1%, 34.0%, and 46.8% for GOV2, respectively (Supplementary Figure 1, http://links.lww.com/CTG/B456). After an average of 3 consecutive endoscopic treatments, 87.24% (171 patients) achieved VE. Patients with more than three treatment courses to VE had an approximately 1.15-fold increased risk of rebleeding compared to patients with less than three treatment courses (p < 0.001). In addition, the risk of rebleeding was higher in patients with initially large varices than in patients with small and middle varices (p = 0.011). However, there was no difference in rebleeding rates between patients with initial ascites, PVT, SPSS, and HE and the remaining patients. Multifactorial Cox regression analysis identified variceal size, GOV3, and >3 treatment courses to VE as significant risk factors for rebleeding. Compared with GOV3, the risk of rebleeding was reduced by 46% (p = 0.036), 55% (p = 0.016), and 45% (p = 0.043) for EV, GOV1, and GOV2, respectively. (Table 5, Supplementary Figure 3, http://links.lww.com/CTG/B458)

Table 5.

Factors associated with the rebleeding of the patients

Variables	Univariate analysis			Multivariate analysis
	sHR	95% CI	P value	sHR	95% CI	P value
Age yr	1.00	0.98–1.02	0.96
Sex
Female	Reference
Male	0.87	0.59–1.29	0.49
Etiology
Nonhepatitis	Reference
Hepatitis	1.07	0.73–1.59	0.72
CTP score	1.09	0.97–1.23	0.14	1.08	0.97–1.22	0.17
MELD score	1.00	0.94–1.07	0.97
NSBBs
No	Reference
Yes	0.78	0.48–1.25	0.30
Ascites
Absent and mild	Reference
Moderate and severe	1.20	0.78–1.84	0.42
PVT
Absent	Reference
Present	1.32	0.81–2.14	0.26
SPSS
Absent	Reference
Present	0.97	0.65–1.47	0.90
HE
Absent	Reference
Present	0.82	0.24–2.80	0.75
Variceal type
GOV3	Reference			Reference
EV	0.42	0.24–0.73	0.002	0.53	0.29–0.96	0.036
GOV1	0.44	0.23–0.83	0.011	0.45	0.23–0.86	0.016
GOV2	0.50	0.27–0.91	0.023	0.54	0.29–0.98	0.043
Variceal size
Small and medium	Reference			Reference
Large	1.82	1.14–2.89	0.011	1.67	1.02–2.72	0.041
>3 Tx courses to VE
No	Reference			Reference
Yes	2.25	1.52–3.33	<0.001	1.94	1.25–3.00	0.003

>3 Tx courses to VE, >3 treatment courses to variceal eradication; CI, confidence interval; CTP, Child-Turcotte-Pugh; EV, esophageal varices; GOV, gastroesophageal varices; HE, hepatic encephalopathy; MELD, model for end-stage liver disease; NSBBs, nonselective beta-blockers; PVT, portal vein thrombosis; sHR, subdistribution hazard ratio; SPSS, spontaneous portosystemic shunt.

DISCUSSION

This study analyzes long-term portal hypertension progression and clinical outcomes in cirrhotic patients presenting with first-time EGVB after endoscopic therapy.

Previous studies have shown that endoscopic treatment has significant advantages in rapidly eradicating bleeding lesions and decreasing mortality and rebleeding rates (14). This makes it an effective treatment strategy for EGV. Our results demonstrated the cumulative incidence of rebleeding at 1, 3, and 5 years was 21.4%, 37.8%, and 47.4%, respectively, while the corresponding survival rates were 89.3%, 76.5%, and 56.6%. The prognosis seems to be better than previously reported studies. A cohort study (15) enrolled 174 patients hospitalized for GOV bleeding with an overall mean follow-up of 22 months and showed a 1-year cumulative rebleeding rate of 30% and 1-year and 5-year cumulative survival rates of 73.4% and 37%, respectively. Another study recruited 39 CTP-C patients who underwent endoscopic treatment and showed a 3-year survival rate of 28.2% (16). Therefore, sequential endoscopic therapy may be associated with improved survival outcomes in patients with EGVB. Consistent with previous studies (17), our study demonstrated an increased rate of variceal eradication after sequential endoscopic treatment, with 87.24% (171) of patients achieving variceal eradication after a mean of 3 times of sequential endoscopic treatment courses, suggesting that sequential endoscopic treatment is an effective method to achieve complete variceal eradication in real-world practice. Second, the prevalence of high-risk varices showed a notable reduction from 100% to 44.9% by the end of the follow-up period, leading to a marked decrease in the potential for variceal rebleeding. In addition, Mohan et al showed that fibrosis of the submucosal layer of the esophagus after sclerotherapy may compress the perforating veins, but the deeper perforating veins may remain open, promoting fundal collateral branching (18). This is supported by the results of our study, which showed that the EV and GOV3 incidence decreased, while GOV1 and GOV2 incidence increased during sequential treatment. Notably, EV develops more into GOV1, while GOV3 exhibits a high propensity for progression to GOV2 following endoscopic therapy. Importantly, GOV3 consistently demonstrated significantly poorer outcomes compared to other subtypes in both rebleeding (Gray’s test, p = 0.009) and overall survival (Log-rank test, p = 0.016). These findings align with established literature (4,5), wherein GOV2/IGV1 (anatomically analogous to GOV3) are associated with higher bleeding risk and adverse prognoses. Therefore, emphasis should be placed on endoscopic re-examination during follow-up, and individualized treatment plans should be formulated based on the patient's specific condition.

Studies indicate GV-related bleeding in cirrhosis leads to more severe portal hypertension with higher rebleeding-related mortality, while EV-associated bleeding predisposes to ascites development (19). Another large multinational 21-center database-based screening of 2,028 patients with cirrhosis at the time of the first decompensation showed that further decompensation of cirrhosis (development of a new decompensation or development of a complication of the decompensation event) occurs in more than half of patients within 5 years of the first decompensation event, with ascites being the most common event of further decompensation, but its incidence is relatively low (15% within 5 years) (20). However, rebleeding was the most common further decompensation event in all EGVs in the present study, which may be because all patients enrolled in this study had AVB as their first decompensation event and that shunting portal blood into the systemic circulation through a portal-corporeal shunt reduces the hepatic portal blood supply, leading to visceral vasodilation, exacerbating portal hypertension, and increasing the risk of variceal hemorrhage (21). In addition, there was no statistically significant difference in the incidence of other nonhemorrhagic conditions (ascites and overt HE) in the different variceal subtypes. There was also no significant difference in the incidence of other complications, such as SPSS, PVT, and HCC. These observations suggest that the different subtypes of EGV may follow a similar course of portal hypertension, but the exact causes are beyond the scope of the current study and may include persistent opening of the perforating veins and compensatory dilatation of spontaneous shunts (22).

Our study demonstrated that rebleeding was associated with a significantly elevated mortality risk (HR = 5.413; 95% CI [3.742-7.828], p < 0.001), with patients experiencing early rebleeding (within 1 year) exhibiting a markedly higher hazard ratio compared with both nonrebleeding individuals (HR = 10.284; 95% CI [6.419-16.475], p < 0.001) and those with late rebleeding (HR = 3.749; 95% CI [2.439-5.763], p < 0.001). This may explain why decompensated cirrhosis has been associated with a high 1-year mortality rate of 60% in previous studies (23). Variceal bleeding, ascites, HE, and other serious bacterial infections with potentially adverse effects on extrahepatic organs accelerate disease progression (24). Consistent with previous studies (5), we found that initially large varices, GOV3, and requiring more than 3 treatment courses to VE significantly increased the risk of rebleeding—a condition often accompanied by substantial ascites. TIPS has been shown to effectively prevent rebleeding and manage ascites simultaneously. However, a meta-analysis has shown that TIPS is effective in reducing the incidence of variceal rebleeding but has no significant effect on mortality and is associated with a higher incidence of HE (3,25). These findings are corroborated by the results of the present study. Among the 22 patients who underwent salvage TIPS following endoscopic therapy, the rebleeding rate was 9.1% (2/22), yet mortality remained high (17/22). Notably, the majority of patients receiving TIPS were high-risk—81.8% had large varices, 31.8% had GOV3, and 54.5% required more than three treatment courses to achieve VE. Therefore, salvage TIPS should be specifically considered for patients at high risk of rebleeding (e.g., those with large varices, GOV3, or needing multiple treatments for VE), while carefully weighing its benefits against the risk of HE. However, another recent meta-analysis of data from 1,327 patients with cirrhosis, AVB, and CTP-B+AB found that salvage TIPS compared with medical therapy plus endoscopy increased the proportion of patients surviving for 1 year in each of the 2 subgroups (26). Currently, TIPS has emerged as the most effective way to improve outcomes in selected patients with AVB. There is an urgent need for more long-term prognosis comparisons between endoscopic sequential therapy and TIPS in patients with acute variceal bleeding to inform more scientifically grounded treatment decisions.

There are some limitations to this study. First, this was a single-center retrospective study, which may have potential selection bias, but all data were obtained from a prospective database. Further population expansion is needed for future validation. Second, only a few patients in this study received β-blocker therapy and TIPS. TIPS was reserved for salvage therapy (refractory bleeding/ascites) per guidelines during the study period. Its low utilization (11.2%) reflects real-world practice patterns for first-decompensation AVB patients, where endoscopy is first-line. We will conduct a larger study in the future to further evaluate the criteria for early TIPS (e.g., based on variceal type, early rebleeding) versus sequential endoscopy. Third, some patients have poor compliance, which may increase the risk of rebleeding or other adverse outcome events. Thus, patient education should be strengthened.

In conclusion, this study found that rebleeding dominated the clinical course of different variceal types and was the independent predictor of patient death. Patients with initially large varices, GOV3, and require more than 3 treatment courses to variceal eradication had a significantly increased risk of rebleeding that should be considered for more aggressive treatment such as salvage TIPS.

CONFLICTS OF INTEREST

Guarantor of the article: Fengmei Wang, PhD.

Specific author contributions: Conceptualization, H.L. and F.W.; methodology, F.W.; formal analysis, J.L. and Y.Y.; investigation, H.L., J.L., Y.Y., M.Z., and Y.Z.; data curation, H.L. M.Z., and Y.Z.; writing—original draft preparation, all authors; writing—review and editing, H.L. and F.W.; supervision, F.W. All authors have made an intellectual contribution to the manuscript and approved the submission.

Financial support: The author(s) declare that no financial support was received for the research and/or publication of this article.

Potential competing interests: None to report.

Study Highlights.

WHAT IS KNOWN

• ✓ Variceal bleeding is common and deadly.

• ✓ The natural course and frequency of variceal bleeding depend on the location of varices.

WHAT IS NEW HERE

• ✓ Rebleeding is the most common event of further decompensation in different types of varices.

• ✓ Rebleeding is associated with a major increased risk of poorer survival.

Supplementary Material

ct9-17-e00971-s001.pdf ^{(557.8KB, pdf)}

ct9-17-e00971-s005.docx ^{(18.3KB, docx)}

ct9-17-e00971-s006.docx ^{(24.6KB, docx)}

ABBREVIATIONS:

AVB

acute variceal bleeding

CTP

Child-Turcotte-Pugh

ECI

endoscopic cyanoacrylate injection

EIS

endoscopic injection sclerotherapy

EGV

esophageal and gastric variceal

EGVB

esophageal and gastric variceal bleeding

EV

esophageal varices

EVL

endoscopic variceal ligation

GV

gastric varices

GOV

gastroesophageal varices

HCC

hepatocellular carcinoma

HE

hepatic encephalopathy

IGV

isolated gastric varices

MELD

model for end-stage liver disease

NSBB

nonselective beta-blocker

PVT

portal vein thrombosis

SPSS

spontaneous portosystemic shunt

TIPS

transjugular intrahepatic portosystemic shunt