Therapeutic outcomes and predictors of efficacy for endoscopic variceal ligation plus propranolol in liver cirrhosis-related upper gastrointestinal bleeding

Abstract

BACKGROUND

Cirrhosis-related upper gastrointestinal bleeding (UGIB) poses a fatal risk, and endoscopic ligation as a sole intervention shows inadequate effectiveness.

AIM

To evaluate the therapeutic efficacy of endoscopic variceal ligation (EVL) plus propranolol vs EVL monotherapy in patients with cirrhosis complicated with acute UGIB and identify predictors for clinical outcomes.

METHODS

This study enrolled 99 consecutive patients with cirrhosis presenting with acute UGIB between January 2024 and January 2025. Participants were allocated to either the control group (n = 49) receiving EVL alone or (2) the research group (n = 50) receiving EVL plus propranolol. Primary outcomes included treatment efficacy, venous blood flow [portal venous flow (PVF)/splenic venous flow (SVF)], and postoperative outcomes (hemostasis time, length of hospital stay, and rebleeding rates). Univariate and multivariate regression analyses were conducted to determine independent predictors of treatment response.

RESULTS

Compared with the control group, the research group demonstrated significantly better outcomes, including higher overall treatment efficacy, greater reductions in PVF and SVF, shorter hemostasis time and hospital stay, and lower rebleeding rates. Univariate analysis demonstrated significant associations between treatment efficacy and age, cirrhosis duration, Child-Pugh grade, bleeding duration, and treatment approach in patients with cirrhosis complicated with acute UGIB. Multivariate logistic regression identified three independent risk factors for poor outcomes, namely, advanced age (> 55 years), prolonged cirrhosis duration (≥ 4 years), and delayed bleeding intervention (> 24 hours).

CONCLUSION

The EVL plus propranolol regimen demonstrates significant efficacy in treating UGIB in cirrhosis, outperforming EVL alone in improving hemodynamics (PVF/SVF), shortening hemostasis and hospitalization duration, and reducing rebleeding rates. Moreover, advanced age, prolonged disease duration, and longer bleeding times are independent risk factors for poor therapeutic outcomes.

Key Words: Liver cirrhosis; Gastrointestinal bleeding; Endoscopic variceal ligation; Propranolol; Hemodynamic response; Efficacy and prognostic factor analysis

Core Tip: To date, few studies have analyzed the therapeutic effects and influencing factors of endoscopic variceal ligation (EVL) plus propranolol for cirrhotic upper gastrointestinal bleeding (UGIB). This study enrolled 99 patients with cirrhosis complicated with UGIB, comparing the intervention effects between EVL plus propranolol and EVL alone. Consequently, the combined therapy achieved markedly better efficacy, with outstanding hemostasis, ameliorated hemodynamic conditions, facilitated postoperative recovery, and featured a notably lower rebleeding rate.

INTRODUCTION

Liver cirrhosis, a chronic, progressive hepatic disorder, develops through multiple pathogenic pathways, such chronic alcohol exposure, non-alcoholic fatty liver disease, viral hepatitis infections, and autoimmune disorders. The disease process is characterized by two fundamental pathological alterations: Extensive hepatic fibrosis and architectural reorganization of liver tissues into regenerative nodules[1]. A critical complication of cirrhosis is the development of upper gastrointestinal varices, which predisposes patients to life-threatening upper gastrointestinal bleeding (UGIB)[2]. Clinically, UGIB is defined as bleeding originating anywhere between the oral cavity and the ligament of Treitz and represents a medical emergency characterized by hematemesis, melena, or hematochezia, which is prevalent and fatal. The clinical presentation may range from subtle blood loss manifesting as fatigue and dyspnea to life-threatening hemorrhagic shock associated with substantial mortality risk[3,4].

Endoscopic variceal ligation (EVL) has emerged as the cornerstone of management for liver cirrhosis complicated with UGIB. It involves mechanical occlusion of varices through strategically placed rubber bands, achieving immediate hemostasis through vascular compression while promoting subsequent thrombosis and fibrosis[5]. Comparative efficacy studies render EVL as equivalent to endoscopic tissue adhesive injection for type 1 (mild-to-moderate) gastroesophageal varices (GOV1) while demonstrating superior procedural efficiency and lower delayed rebleeding rates[6]. Despite its minimal invasiveness, convenient operation, and effectiveness in primary hemostasis and secondary prophylaxis, EVL has inherent limitations, such as technical complexity and restricted applicability in certain anatomical variations[7]. To optimize therapeutic outcomes, EVL is frequently combined with non-selective β-blockers, such as propranolol. Through the dual blockade of β1- and β2-adrenergic receptors, propranolol exerts a portal pressure-lowering effect by modulating hemodynamics (β1) and splanchnic vasoconstriction (β2), effectively reducing blood flow through portosystemic collateral circulation[8,9]. Razafindrazoto et al[10] revealed clinical evidence showing the non-inferiority of propranolol to carvedilol in preventing variceal rebleeding in hepatosplenic schistosomiasis, with a potentially superior safety profile (the latter was associated with breathing difficulties). Similarly, Singh et al[11] reported comparable efficacy between propranolol and EVL for secondary prophylaxis in patients cirrhosis complicated with ascites. To further maximize therapeutic effectiveness in cirrhotic patients with UGIB, we additionally incorporate meticulous and patient-specific nursing interventions into the relevant treatment plan. This effort aims to foster a supportive and positive perioperative period, thus improving patients' overall holistic experience.

Nevertheless, robust evidence regarding the synergistic effects of combined EVL and propranolol therapy remains scarce. Thus, this study aimed to comprehensively evaluate this dual-modality approach through quantitative assessment of immediate hemostatic efficacy, characterization of hemodynamic modifications, longitudinal analysis of rebleeding prevention, and comparative effectiveness against monotherapy paradigms. Furthermore, this study sought to identify predictive factors influencing therapeutic response, thereby facilitating personalized treatment strategies for this high-risk patient population.

MATERIALS AND METHODS

Study population

This study enrolled 99 consecutive patients diagnosed with liver cirrhosis complicated with acute UGIB who were admitted to Changde First People’s Hospital between January 2024 and January 2025. Patients were randomly allocated into a control group (n = 49) receiving EVL alone and a research group (n = 50) treated with EVL plus oral propranolol.

Eligibility criteria

Inclusion criteria: Confirmed diagnosis of liver cirrhosis complicated with acute UGIB based on endoscopic and ultrasonographic findings[12], age 18-80 years, treatment-naïve status with no contraindications to the proposed interventions, presenting with typical UGIB symptoms (hematemesis and/or melena), classifiable under Child-Pugh grading system[13], no history of psychiatric disorders, and availability of complete medical records.

Exclusion criteria: Non-cirrhotic causes of bleeding (e.g., peptic ulcer disease and stomach mucosal disease), concurrent malignant neoplasms, history of severe drug hypersensitivity, significant cardiovascular or cerebrovascular diseases, or coagulopathy, and coexisting gastric perforation or intestinal obstruction.

Treatment protocols

The control group received EVL under local lidocaine anesthesia. The bleeding site was identified under endoscopic visualization, and a single-band ligator was employed for single-loop ligation of mild-to-moderate varices. Patients with severe disease underwent double-loop ligation. The research group received combination therapy consisting of EVL (as described for the control group) plus oral propranolol, with propranolol administered at an initial dose of 10 mg three times daily (administered at 8-hour intervals: 08:00, 16:00, and 24:00). The dosage was titrated by 1 mg/day based on individual patient response to achieve a target heart rate of 60 bpm. Propranolol was taken for 2 weeks straight. Postoperatively, both groups were closely monitored for vital signs and received standard supportive care such as acid-suppressive therapy and antibiotics as needed. Meanwhile, both cohorts were also given meticulous, standardized care. The nursing team patiently educated patients using simple language. They dedicated time to explaining knowledge about the disease, its treatments, possible complications, and important self-care measures to foster proper disease awareness. They also carefully instructed patients on the necessity of abstaining from food and drinks prior to surgery. During the procedure, the patient's positioning was adjusted as needed, with continuous vital sign monitoring and prompt management of any abnormalities. Postoperative care involved the provision of dietary guidance tailored to patients' conditions (transition from a liquid to a regular diet as tolerated), together with careful observation for signs of complications. Furthermore, patients received discharge guidance and were given telephonic and WeChat follow-ups, stressing the need to take prescribed medicines and return for timely reviews.

Outcome measures

Treatment efficacy: Therapeutic outcomes were categorized as markedly effective (cessation of bleeding within 24 hours after treatment accompanied by complete resolution of clinical complications, effective (absence of bleeding within 1-3 days after treatment with observable improvement in clinical complications), and ineffective (either persistent or recurrent bleeding beyond 3 days after treatment without improvement or with worsening of clinical complications). The total effective rate was calculated as the proportion of patients achieving either markedly effective or effective outcomes relative to the total study population.

Venous blood flow: Portal and splenic venous hemodynamics were assessed by color Doppler ultrasonography at baseline and 3 days after treatment. The diameter and flow velocity of the total portal and splenic veins were measured. These parameters were used to compute the portal venous flow (PVF) and splenic venous flow (SVF) before and after treatment.

Postoperative outcomes: Key postoperative outcomes included hemostasis time, hospital stay, and rebleeding rate during the 6-week follow-up period.

Statistical analysis

Statistical analyses were conducted using IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, United States). Categorical variables were summarized as frequencies and percentages, whereas continuous variables were expressed as mean ± SE of the mean. Between-group comparisons of categorical variables were conducted using Pearson’s χ² test, and Fisher’s exact test was employed for expected cell frequencies < 5. Continuous variables were compared between groups using independent samples t-tests, whereas within-group comparisons before and after treatment were performed using paired t-tests. Potential factors influencing treatment efficacy in patients with cirrhosis complicated with UGIB were further evaluated through univariate and multivariate regression analyses. Significance was set at a two-tailed P value < 0.05 for all analyses.

RESULTS

Baseline demographic and clinical characteristics

The control and research groups demonstrated comparable baseline characteristics, showing no significant differences in sex distribution, age, or other demographic parameters (all P > 0.05), ensuring balanced group allocation for subsequent analyses. Detailed baseline characteristics are presented in Table 1.

Table 1 Demographic and baseline clinical characteristics of the study population.

Baseline data	Control group (n = 49)	Research group (n = 50)	χ2/t	P value
Gender, n (%)			0.624	0.430
Male	35 (71.43)	32 (64.00)
Female	14 (28.57)	18 (36.00)
Age (years)	53.86 ± 7.03	56.32 ± 9.23	1.490	0.140
Cirrhosis duration (years)	3.61 ± 1.38	4.12 ± 1.75	1.608	0.111
Child-Pugh grade, n (%)			1.974	0.373
A	25 (51.02)	20 (40.00)
B	20 (40.82)	22 (44.00)
C	4 (8.16)	8 (16.00)
Bleeding duration (hour)	21.16 ± 4.45	23.10 ± 6.45	1.739	0.085
Bleeding volume (mL)	598.39 ± 70.59	593.50 ± 73.38	0.338	0.736

Treatment outcomes

The research group demonstrated superior clinical outcomes, with 46 patients (92.0%) achieving effective treatment compared with 37 patients (75.5%) in the control group. This between-group difference in overall treatment efficacy was significant (P = 0.026). Complete efficacy data are provided in Table 2.

Table 2 Comparative analysis of treatment efficacy, n (%).

Clinical efficacy	Control group (n = 49)	Research group (n = 50)	χ2	P value
Markedly effective	22 (44.90)	28 (56.00)
Effective	15 (30.61)	18 (36.00)
Ineffective	12 (24.49)	4 (8.00)
Total efficacy	37 (75.51)	46 (92.00)	4.966	0.026

Venous blood flow

No significant intergroup differences in PVF or SVF were observed at baseline (P > 0.05). Following treatment, both groups demonstrated significant reductions in PVF and SVF (P < 0.05), with greater decreases in both indices in the research group (P < 0.05). Figure 1 presents details.

Figure 1 Portal venous flow and splenic venous flow before and after treatment. A: Portal venous flow changes in both groups; B: Splenic venous flow changes in both groups. PVF: Portal venous flow; SVF: Splenic venous flow. ^aP < 0.05; ^bP < 0.01.

Postoperative outcomes

Compared with the control group, the research group achieved significantly better clinical outcomes, including shorter hemostasis time (P < 0.05), reduced hospital stays (P < 0.05), and lower rebleeding rates (P < 0.05). These results are summarized in Figure 2.

Figure 2 Comparative postoperative outcomes between groups. A: Hemostasis time in two groups; B: Hospital stay in two groups; C: Rebleeding rate in two groups. ^aP < 0.05; ^bP < 0.01.

Predictors of treatment efficacy

Univariate analysis identified age, cirrhosis duration, bleeding duration, and treatment approach as significant factors influencing therapeutic outcomes (all P < 0.05). The subsequent multivariate logistic regression confirmed age [odds ratio (OR) = 7.596], cirrhosis duration (OR = 7.750), and bleeding duration (OR = 3.926) as independent risk factors (P < 0.05), whereas the treatment approach (OR = 0.207) served as a protective factor (P < 0.05). Detailed results are presented in Tables 3 and 4.

Table 3 Univariate analysis of efficacy predictors, n (%).

Factor	Ineffective group (n = 16)	Effective group (n = 83)	χ2	P value
Gender			0.234	0.629
Male (n = 67)	10 (62.50)	57 (68.67)
Female (n = 32)	6 (37.50)	26 (31.33)
Age (years)			-	0.014
< 55 (n = 47)	3 (18.75)	44 (53.01)
≥ 55 (n = 52)	13 (81.25)	39 (46.99)
Cirrhosis duration (years)			-	0.013
< 4 (n = 40)	2 (12.50)	38 (45.78)
≥ 4 (n = 59)	14 (87.50)	45 (54.22)
Child-Pugh grade			1.553	0.213
A (n = 45)	5 (31.25)	40 (48.19)
B/C (n = 54)	11 (68.75)	43 (51.81)
Bleeding duration (hour)			5.634	0.018
< 24 (n = 63)	6 (37.50)	57 (68.67)
≥ 24 (n = 36)	10 (62.50)	26 (31.33)
Bleeding volume (mL)			0.159	0.690
< 600 (n = 54)	8 (50.00)	46 (55.42)
≥ 600 (n = 45)	8 (50.00)	37 (44.58)
Treatment approach			-	0.031
Endoscopic variceal ligation (n = 49)	12 (75.00)	37 (44.58)
Endoscopic variceal ligation + propranolol (n = 50)	4 (25.00)	46 (55.42)

Table 4 Multivariate regression analysis of efficacy predictors.

Factor	β	SE	Wald	P value	OR	95%CI
Age (years)	2.028	0.751	7.284	0.007	7.596	1.742-33.114
Cirrhosis duration (years)	2.048	0.868	5.563	0.018	7.750	1.414-42.485
Bleeding duration (hour)	1.368	0.662	4.270	0.039	3.926	1.073-14.366
Treatment approach	-1.575	0.701	5.046	0.025	0.207	0.052-0.818

OR: Odds ratio; 95%CI: 95% confidence interval.

DISCUSSION

UGIB occurs in approximately 85.0% of patients with cirrhosis, with 14.0% rebleeding risk. Moreover, these patients exhibit a twofold increase in 45-day mortality (10.0%) compared with those without cirrhosis[14]. Although EVL is highly effective in achieving hemostasis, it may induce visceral congestion and mechanical injury to venous walls by the ligation bands, potentially precipitating rebleeding[15]. The results demonstrate that combining EVL with propranolol provides significant clinical benefits in managing UGIB in cirrhosis.

Notably, the combination therapy (EVL plus propranolol) achieved superior efficacy to EVL monotherapy (92.00% vs 75.51%) in treating UGIB in cirrhosis. In addition to comparable bleeding prevention effects in high-risk variceal hemorrhage, EVL plus propranolol had offered additional advantages in reducing variceal recurrence[16]. Similarly, Sarin et al[17] observed equivalent outcomes between EVL and propranolol in patients with non-cirrhotic portal hypertension, with no significant differences in rebleeding rates, bleeding-free survival, or adverse events. To support these findings, Tevethia et al[18] demonstrated that combined variceal band ligation and carvedilol was more effective than either monotherapy in patients with Child-Turcotte-Pugh B/C cirrhosis with high-risk varices, further corroborating our results.

Additionally, the combination therapy significantly improved hemodynamics in patients with cirrhosis complicated with UGIB, particularly by more effectively reducing PVF and SVF. In cirrhosis, PVF may increase c, whereas SVF can increase abnormally owing to splenic congestion and enlargement. The enhanced reduction in PVF and SVF observed with combination therapy likely stems from the complementary mechanisms of EVL and propranolol: EVL provides immediate hemostasis, whereas propranolol achieves steady-state concentration within 2-4 weeks, enabling sustained reduction in portal pressure. This temporal synergy allows for more effective hemodynamic optimization, leading to more effective optimization of PVF, SVF, and other hemodynamic indicators[19,20]. Moreover, the combination therapy significantly improved the clinical outcomes, evidenced by shorter time to hemostasis, shortened hospital stays, and lower rebleeding rates. In the present study, patients received meticulous nursing interventions beyond the treatment schemes. These included preoperative health education and guidance on fasting and fluid restriction; intraoperative posture adjustments and vital sign surveillance; postoperative nutritional guidance and complication prevention; as well as follow-up support after hospital discharge. All these efforts serve to safeguard treatment outcomes.

Univariate analysis initially identified age, cirrhosis duration, Child-Pugh grade, bleeding duration, and treatment approach as factors significantly associated with therapeutic outcomes. Multivariate analysis further confirmed that age, cirrhosis duration, and bleeding duration were independent risk factors, whereas the treatment approach acted as a protective factor. Advanced age (≥ 55 years) and chronic cirrhosis (≥ 4 years) were associated with poorer treatment responses, likely due to reduced vascular elasticity and impaired compensatory capacity of portal collateral circulation in older patients. Additionally, long-standing cirrhosis exacerbates hepatic sinusoidal capillarization, progressively increasing portal resistance and complicating therapeutic management[21,22]. Moreover, the progressive deterioration of hepatic functional reserve in patients with cirrhosis complicated with UGIB, combined with impaired drug metabolism over time, limits the potential effectiveness of treatment[23,24]. The significant influence of bleeding duration highlights the critical importance of prompt hemostatic intervention, as delayed treatment may worsen systemic hemodynamic instability and exacerbate hepatic ischemia–reperfusion injury[25]. The protective effect of EVL plus propranolol may stem from the synergistic action: EVL provides rapid obliteration of varices, whereas propranolol ensures sustained reduction of portal pressure. Together, these mechanisms optimize local and systemic hemodynamics, improving treatment outcomes.

CONCLUSION

The combination therapy of EVL and propranolol demonstrates superior efficacy to EVL monotherapy in managing UGIB among patients with cirrhosis. This combined approach not only achieves effective hemostasis but also enhances hemodynamic stability, accelerates postoperative recovery, and significantly lowers the rebleeding risk. Consequently, it represents a highly recommendable strategy for clinical application.