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Efficacy of Vonoprazan vs. Pantoprazole or Non-Acid Suppression in Prevention of Post-Variceal Ligation Ulcer Bleeding in Portal Hypertension: A Multi-Arm Randomized Controlled Trial
Up-to-date, data about the role of acid suppression therapy e.g. proton-pump inhibitors; to reduce post-endoscopic variceal ligation (EVL) ulcer-bleeding are conflicting. Vonoprazan; a recently introduced potassium-competitor acid blocker, has not been studied to prevent post-EVL ulcer/bleeding. The aim was to evaluate the efficacy of vonoprazan vs. pantoprazole or non-acid suppression to prevent post-EVL ulcer/bleeding in portal hypertension patients.
Material and methods
We enrolled 275 portal hypertension patients undergoing EVL in a three-arm randomized, single-blind, controlled study. A clinico-laboratory baseline evaluation was performed. Following EVL, patients were randomly and equally assigned to receive vonoprazan 20 mg once daily, pantoprazole 40 mg once daily, or no acid suppression therapy. Post-EVL ulcer bleeding, ulcer dimensions, odynophagia as well as vonoprazan safety were evaluated after 2 weeks of EVL.
Results
Post-EVL ulcer bleeding occurred among 2.15% of vonoprazan, 8.7% of pantoprazole, and 14.2% of the non-acid suppression groups (p < 0.001). Post-ligation ulcer frequency and dimensions were higher among non-acid suppression and pantoprazole groups vs. vonoprazan (p < 0.05). Chest pain and odynophagia were encountered among 73.6% and 54.9% of the non-acid suppression group vs. 39.6% and 45.1% in pantoprazole, and 17.2% and 21.5% in vonoprazan groups, respectively (p < 0.05). There were no vonoprazan-related adverse events. Non-use of vonoprazan was the strongest independent predictor for post-EVL bleeding.
Conclusion
Short course of vonoprazan 20 mg/day is safe and superior to pantoprazole 40 mg/day in the reduction of post-EVL ulcer dimensions at 2 weeks post-EVL, and prevention of ulcer-related bleeding. Acid suppression is superior to no acid suppression to prevent post-EVL complications.
Bleeding from Esophagogastric varices is a fatal condition in cirrhotic patients. The standard of care (SOC) for the prevention of esophageal varices bleeding/re-bleeding in patients with portal hypertension (PHTN) and high-risk varices is endoscopic variceal ligation (EVL) and non-selective beta-blockers (NSBB).(
) EVL implies the application of elastic bands over the varix, causing varix strangulation, which usually falls after 3-5 days, leaving a shallow ulcer that rejuvenates over two weeks.(
Local complications of EVL include esophageal lacerations, strictures, chest pain, transient dysphagia/odynophagia, and post-ligation ulcers. Although shallow, the post-ligation ulcer can cause upper gastrointestinal bleeding, resulting in morbidity and mortality in 5% of patients.(
), controlled trials have shown that patients who received pantoprazole after elective EVL had smaller post-banding ulcers than placebo participants. Several studies have shown that proton-pump inhibitors (PPIs) can delay re-bleeding or reduce the risk of early bleeding after EVL, as well as reduce ulcer sizes through acid suppression and mucosal healing.(
) However there are no established guidelines for the prescription of PPIs for this indication and in our center, it is not the SOC to prescribe PPIs or an alternate like sucralfate suspension following EVL.
Recently, potassium-competitive acid blockers (PCABs), have been introduced into clinical practice. PCABs inhibit the proton pump (H+, K+-ATPase α subunit) quickly, effectively, and reversibly. Vonoprazan is an orally active PCAB that has been approved to treat erosive esophagitis (EE) and H. pylori infection. Unlike PPIs, Vonoprazan is an acid-stable, active molecule (rather than a prodrug), with rapid and sustained activity, and works on both active and inactive proton pumps. It’s also not affected by food in the stomach, and not influenced by CYP2C19 polymorphism like other PPIs.
These pharmacokinetic/dynamic properties introduce Vonoprazan as a promising acid blocker, overcoming the limitations of PPIs. There is currently no data on the effectiveness of Vonoprazan in the prevention of post-band ligation ulcer-related bleeding. Therefore, we designed this three-arm randomized controlled trial to answer two research questions: First (a non-tested hypothesis yet), is vonoprazan different from pantoprazole in preventing post-EVL ulcer-related bleeding and in minimizing ulcer dimensions in PHTN patients; second (a debatable point up to date); is the use of acid suppression therapy (PCABs or PPIs) superior to non-acid suppression strategy following EVL in the prevention of post-EVL ulcer bleeding.
Subjects, study design, and sample size
Our study was a prospective, parallel, single-blind, three-arm randomized controlled trial. Because of the relatively low incidence of post-EVL ulcer-bleeding, a study powered to assess differences in bleeding risk would need a large number of participants (e.g. referring to bleeding incidence of 7.9% by Elhawari et al.(
), with a 50% effect size, 80% power, and P value of 5%, the number would be > 1600 cases, which is not easily achievable target) So, our study was powered to the ulcer size (one of the primary end-points) as a predictor for risk of bleeding after EVL (ulcer size is correlated to bleeding rate)(
) reported an ulcer size of 82±22 mm2 for placebo and 37±9 mm2 for pantoprazole groups respectively. Based on this, the sample size was calculated using a statistical power of 0.90, a two-tailed α-level of 0.05 with Dunnett’s correction for multiple comparisons, and assuming a 50% reduction (effect size).(
), and who agreed to provide informed consent. Patients were recruited from the Gastroenterology clinic, general internal medicine clinics at the Faculty of Medicine, and gastroenterology clinic at the Medical Research Institute, University of Alexandria, Egypt. The study recruitment started on the 15th of February 2022, and the last follow-up was on the 19th of August 2022. The exclusion criteria: proven pre-existing esophageal ulcers during endoscopy, ongoing therapy with anti-acid agents or NSBB, previous anti-flux procedure, Barrett's esophagus, history of liver transplantation, hepatocellular carcinoma, pregnancy, allergy, or previous drug reactions to acid-suppressive therapy, and estimated glomerular filtration rate < 60 ml/min/1.73 m2).
Ethical approval and informed consent
Before participating, all enrolled patients provided informed written consent. The study was carried out following the provisions of the Helsinki Declaration, as revised in 2013, and the Good Clinical Practice Guidelines. In addition, our institutional ethical committee approved the study (IRB: 0305413). The study was registered on clinicaltrial.gov registry: NCT05227833. Figure 1 shows the CONSORT flow diagram of the study.
Figure 1The CONSORT flowchart of the study. eGFR: estimated glomerular filtration rate.
All eligible patients (n = 275) were clinically evaluated for demographic parameters and history of previous upper GIT bleeding (hematemesis and/or melena). Baseline laboratory investigations included a hemogram, liver profile, and renal function test was done. Esophagogastroduodenoscopy (EGD) was performed to assess the variceal grade, risk signs, gastric varices, and portal gastropathy, and to apply EVL.
Randomization
Using simple parallel randomization (computer-assisted), the enrolled participants were randomly allocated to vonoprazan 20 mg single daily dose [vonoprazan group], OR pantoprazole 40 mg single daily dose [pantoprazole group] one hour before breakfast, OR (no acid suppression group) received no acid suppression therapy; for two weeks at a 1:1:1 ratio. On the same day of EVL, and in addition to NSBB (Carvedilol 6.25 – 25 mg/day as tolerated) as a SOC, patients received the first dose of the assigned acid suppression medication.
For the active treatment groups [vonoprazan and pantoprazole], allocation concealment was made by giving the patient the treatment pills in sealed, opaque, serially numbered, non-labeled jars of equal appearance and weight according to the allocation sequence (provided by the clinical pharmacy unit in our departments). Participants in the “no acid suppression group” did not receive acid suppression therapy. Patients were instructed to return after 2 weeks, or if hematemesis/melena occurred before the end of 2 weeks, for repeat EGD.
We informed participants to contact the study team if they experience chest pain or odynophagia. In this situation, we recorded the event and prescribed Mucogel suspension (Aluminum Hydroxide + MagnesiumHydroxide + Oxethazaine) for symptomatic relief.
During the second visit, we checked for treatment compliance by counting the number of pills taken during the treatment phase, and additional clinical and laboratory investigations (like the baseline parameters) were performed. A history of adverse events (e.g., medication-related diarrhea, nausea, vomiting, and headache) was also recorded.
A repeat EGD was performed (at 2 weeks post EVL, or when upper gastrointestinal tract bleeding occurred, whichever is earlier) for all participants who completed the study (refer to figure 1) to determine the presence of post-EVL ulcers (yes/no), and its criteria (number, maximum length, and width) and the source of any bleeding. A guidewire [designed for endoscopic retrograde cholangiopancreatography] and biopsy forceps were used to measure the ulcer sizes. A post-EVL ulcer was defined as any degree of endoscopically discernible depth in the distal third of the esophagus related to the site of band ligation. Ulcer bleeding was defined as bleeding manifested as hematemesis, melena, and/or hematochezia with endoscopic proof of the ulcer as the source of bleeding, with no other identifiable sources during EGD.
Primary outcome
a)
The number (frequency) of participants who experienced post-ligation ulcer bleeding (hematemesis, melena, and/or hematochezia) during the two-week follow-up. Pair-wise comparisons will be run to explore the frequency of post-EVL ulcer bleeding
b)
Presence of post-EVL ulcers (number and dimensions) detected by EGD in each study arm.
Secondary outcomes
a)
The number (frequency) of participants who experienced chest pain, and odynophagia in each study arm.
b)
The safety of vonoprazan in liver cirrhosis patients.
Safety assessment
Treatment-related adverse effects (TRAEs) grouped by Medical Dictionary for Regulatory Activities version 19.1, system organ class and preferred term, and changes from baseline in an abbreviated physical examination including ascites, and encephalopathy. Furthermore, the mean change in laboratory measures such as hemogram, liver profile, serum urea, and serum creatinine was also considered.
Statistical analysis
The sample size calculation was done using the G-Power software (v. 3.1.9.4, Universität Düsseldorf, Germany). Statistical analysis was done using IBM SPSS software package version 26.0 (Armonk, NY: IBM Corp). Qualitative data were described using a number (%), while quantitative data were described using range (minimum-maximum), median, or mean ± standard deviation as appropriate. The normality of data distribution was assessed by the Kolmogorov-Smirnov test. A Chi-square test or Fisher’s exact test was used for categorical variables as appropriate. Repeated measures of one-way ANOVA (Analysis of variance) with Dunnett’s correction post-hoc pairwise comparisons were conducted to explore any significant difference (P < 0.05) between groups. Kruskal Wallis test and Mann-Whitney U test were used to compare means as appropriate. The paired t-test was used to compare repeated measures. A binary logistic regression analysis was done. The analysis in the current study was an intention to treat (ITT). Per-protocol (PP) analysis was done when appropriate. Statistical significance was assessed at P < 0.05. All calculated P values were two-tailed.
Results
The study allocation began with 275 patients randomized to three treatment protocols [vonoprazan group (n = 93), pantoprazole group (n = 91), and no acid suppression group (n = 91)]. During the treatment and follow-up period, we had a total of 7 (2.6%) patients drop out due to incomplete data and follow-up endoscopy. (Figure 1). In the PP analysis, we analyzed data of the remaining 268 patients [vonoprazan group (n = 91), pantoprazole group (n = 89), and no acid suppression group (n = 88)]. The demographic and baseline clinical data are shown in Table 1. Our study groups were matched as regards the baseline characteristics (p > 0.05).
Table 1Baseline clinico-laboratory parameters of the study groups (ITT).
In ITT analysis, post-ligation ulcer bleeding occurred in 2.15% of the vonoprazan group, 8.7% in the pantoprazole group, and 14.2% in the no acid suppression group. The number (%) of patients with post-EVL bleeding was significantly lower in the vonoprazan group vs. pantoprazole group (p = 0.046, FET= 3.95), and vs. no acid suppression group (p = 0.002, χ2 = 9.21), while there was no significant difference between pantoprazole and no acid suppression groups (p = 0.23, χ2 = 1.4), (Figure 2-a). Worth to mention that the mean±SD of carvedilol dose was not different among the three groups (p = 0.47, table 1], and was not different between patients who bled (n = 23) vs. patients who didn’t bleed (n = 245) during the study duration [14.97±7.42 vs. 13.86±5.63 mg, p = 0.39, respectively].
Figure 2Comparison between the study groups as regards (A) Post-endoscopic variceal ligation ulcer bleeding, (B) Chest pain, and (C) Odynophagia.
The median number of bands applied for variceal ligation was not different among the three groups (p = 0.74); however, during the follow-up endoscopy, the number (%) of patients who developed post-EVL ulcers was significantly lower among vonoprazan group, compared to pantoprazole and no acid suppression groups (p < 0.001). The median number of post-EVL ulcers per patient in the vonoprazan group was significantly lower than in the pantoprazole and no acid suppression groups (p <0.001), however, there was no significant difference between pantoprazole and no acid suppression groups. Furthermore, the maximum length and width of ulcers were shorter in the vonoprazan, compared to pantoprazole and no acid suppression groups (p <0.001).
Chest pain, and odynophagia
Post-EVL chest pain was experienced by 17.2% (17.6% in PP analysis) of vonoprazan group, 39.6% (40.4% in PP analysis) of pantoprazole group, and 73.6% (76.1% in PP analysis) of the no acid suppression group, respectively. This incidence was statistically significant between the three groups (p <0.001), (Figure 2-b). Painful swallowing “odynophagia” was experienced among a significantly lower percentage of patients in the vonoprazan group vs. pantoprazole group (21.5% vs. 45.1%, p < 0.001, χ2 = 11.65), and vs. no acid suppression (21.5% vs. 54.9%, p < 0.001, χ2 = 22.80), while there was no difference between pantoprazole vs. no acid suppression groups (p = 0.10), (Figure 2-c).
Hospitalization, blood transfusion, and mortality
In our study, we don’t have mortality events related to post-EVL ulcer-related bleeding. All patients who experienced post-EVL bleeding were hospitalized for management (EGDThe hospitalization rate was lower in the vonoprazan group compared to pantoprazole and non-acid suppression (all patients who bled were hospitalized routinely for management and performing EGD± blood transfusion if required). The hospitalization rate was lower in the vonoprazan group compared to other groups (the same statistics as for post-EVL bleeding; Figure 2-a.
Blood transfusion was required in 3 (37.5%) patients in the pantoprazole group, and 5 (38.4%) patients in the non-acid suppression group, and no blood transfusion was needed in the vonoprazan group, but the figures were not suitable for statistical analysis.
Regression analysis
Univariate analysis was performed to identify predictors of post-EVL ulcer bleeding. Baseline platelet count, INR, serum bilirubin, serum albumin, Child-Pugh class, Model for End-Stage Liver Disease-sodium (MELD-Na) score [ MELD > 15 could predict bleeding with sensitivity and specificity of 91.3% and 40% respectively, AUC 0.65, P = 0.02, 95% CI: 0.55 – 0.74], esophageal varices grade and non-use of vonoprazan as an acid suppression therapy were all significant predictors of post-EVL ulcer bleeding. However, multinomial logistic regression showed that baseline platelet count, Child-Pugh class, MELD-Na score, variceal grade, and the non-use of vonoprazan were the only independent predictors for post-EVL-ulcer bleeding (Table 3). For the occurrence of post-EVL ulcers, univariate and multivariate analysis showed that the non-use of acid suppression therapy was the only significant predictor (P < 0.001, OR: 7.20, 95% CI: 3.51 – 14.93 and P < 0.001, OR: 3.31, 95% CI: 1.75 – 6.31, for both vonoprazan and pantoprazole, respectively).
Table 3Regression analysis for predictors of the occurrence of post-EVL ulcer bleeding according to the baseline parameters among the study population.
The safety of vonoprazan was evaluated through the comparison between the clinic-laboratory parameters before and after treatment, as well as any patient-reported adverse events. We reported no treatment-related adverse events (TRAEs). We found no deterioration in the hemogram, serum aminotransferases, serum albumin, bilirubin, or INR after treatment duration. In addition, the Child-Pugh score/class didn’t deteriorate after vonoprazan therapy. Serum urea and creatinine also were not negatively affected (Table 4). We reported no severe or life-threatening adverse reactions or allergic manifestations.
Table 4Comparison between clinico-laboratory parameters (mean ± SD) before and after vonoprazan therapy for post-EVL ulcer/bleeding prevention (n = 91, PP analysis).
Practice Guidelines Committee of American Association for Study of Liver Diseases, & Practice Parameters Committee of American College of Gastroenterology (2007). Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis.
The American Journal of Gastroenterology.2007; 102: 2086-2102
) Elective EVL is a common clinical procedure used to reduce subsequent variceal bleeding. Although EVL is effective, it is associated with side effects such as post-ligation ulcers, bleeding, pain, dysphagia, and odynophagia.(
Incidence and management of esophageal stricture formation, ulcer bleeding, perforation, and massive hematoma formation from sclerotherapy versus band ligation.
Previous research has linked the use of PPI after EVL to a reduction in post-EVL ulcer number and size, as well as ulcer bleeding with conflicting results.
Proton Pump Inhibitor Therapy Is Associated with Reduction of Early Bleeding Risk After Prophylactic Endoscopic Variceal Band Ligation: A Retrospective Cohort Study.
To the best of our knowledge, this is the first study to investigate vonoprazan for the prevention of post-EVL ulcer/bleeding in PHTN patients. In the current study, the vonoprazan group showed a significant reduction in the post-EVL bleeding events (2.1%) compared to pantoprazole and no acid suppression. At the same time, the pantoprazole was not statistically superior to the no acid suppression (although numerically lower, 8.7% vs. 14.2% respectively, p = 0.23).
In the current study also, the frequency of post-EVL ulcers and their dimensions were significantly lower in the vonoprazan group compared to pantoprazole and no acid suppression and were lower in the pantoprazole group vs. no acid suppression. This reduction was reflected in the incidence of post-EVL chest pain and odynophagia among our cohort with a better experience in the vonoprazan group vs. pantoprazole and no acid suppression. These findings indicate that vonoprazan is more potent than pantoprazole in reducing post-EVL ulcer frequency, dimensions, bleeding, and short-term complications. Simultaneously, vonoprazan and pantoprazole outperform the no-acid suppression.
Because there have been no previous studies on the utility of vonoprazan in this clinical regard, a comparison to previous studies is not possible. As a result, the data in the literature on the role of acid suppression for the prevention of post-EVL ulcers/bleeding are obtained from PPI studies. Kang et al. found that PPI treatment could lower the risk of post-EVL bleeding. Furthermore, with PPI, bleeding-free survival at 2 months after EVL was substantially longer. Notably, PPI may lower the risk of bleeding after gastric varices treatment. These findings were also supported by univariate and multivariate analyses.(
Proton Pump Inhibitor Therapy Is Associated with Reduction of Early Bleeding Risk After Prophylactic Endoscopic Variceal Band Ligation: A Retrospective Cohort Study.
) We believe that acid reflux plays a role in delayed ulcer healing and pain stimulation after EVL in cirrhotic patients. As a result, starting acid suppression therapy early reduces acid reflux and provides an adequate medium for ulcer healing. However, Lodato et al. suggested conflicting results. Due to a lack of convincing evidence, they concluded that the use of acid suppression to prevent and/or treat esophageal complications following endoscopic ligation or obturation may be a tradition rather than an evidence-based practice. As a result, more large-scale research is still required.(
We believe that vonoprazan may be of better value vs. PPI in the current clinical context. PCABs have many characteristics which introduce them as a potent acid-suppression therapy vs. PPI. PCABs do not need proton pumps to be active to achieve their effect; further, they are rapidly absorbed with rapid onset of action. They have a potent sustained effect on acid secretion due to a steady rise in plasma concentrations from 1st dose (compared to PPIs which need 5-7 doses to reach Cmax). They are also stable in acid medium, active molecules (not pro-drugs), rapidly absorbed with a longer half-life, and independent of CYP2C19 Genotype.(
) These features outweigh PPIs, facilitating a single rather than twice daily dose with better compliance. All these pharmacokinetic-dynamic features may explain the better influence of vonoprazan on acid secretion with better clinical outcomes in our study.
The current study's multivariate analysis revealed that the baseline platelet count, Child-Pugh class C, MELD-Na score (score > 15), variceal grade, and the non-use of vonoprazan use were the only independent predictors for post-EVL-ulcer bleeding. Being the 1st study about vonoprazan in the prevention of post-EVL-ulcer bleeding, no previous data regarding the use of vonoprazan to compare. However, our findings support the findings of Kang et al., who found that the non-use of acid suppression use by PPI and the presence of gastric varices were predictors of post-EVL bleeding.(
Proton Pump Inhibitor Therapy Is Associated with Reduction of Early Bleeding Risk After Prophylactic Endoscopic Variceal Band Ligation: A Retrospective Cohort Study.
) In another study, the risk factors for EVL-induced ulcer bleeding were a MELD-Na > 10, concomitant large varices, and detachment of the rubber bands on follow-up endoscopy.(
In the current study, the safety of vonoprazan was assessed. We observed no TRAEs that the patients had reported. We also didn’t report any clinical manifestations of drug-drug interaction between vonoprazan and carvedilol. When compared to no acid suppression, acid suppression reduced the prevalence of local esophageal complications. At the same time, no biochemical side effects in terms of renal or liver profile deterioration were discovered. Vonoprazan safety has been studied in clinical trials of PCABs for H. pylori eradication and EE treatment. In addition, although vonoprazan can inhibit CYP3A4, CYP2C9, CYP2D6, and CYP2B6 cytochrome enzymes, and is metabolized by cytochrome CYP3A4, no interaction with beta-blockers has been registered. Diarrhea, nausea, and dysgeusia were the most reported side effects. In previous studies, elevated liver enzymes and blood creatinine were reported in 1.3 percent of cases, which was comparable to PPIs.(
Evaluation of the efficacy and safety of vonoprazan in patients with non-erosive gastroesophageal reflux disease: A phase III, randomized, double-blind, placebo-controlled, multicenter study.
) However, no TRAEs were observed in our study, which could be attributed to the short duration of therapy.
The current study has points of strength that should be highlighted. The use of vonoprazan, for the first time, in the prevention of post-EVL ulcer/bleeding, the randomized study design, and the relatively large number of patients. In addition, we; for the 1st time, introduced a potential new indication for vonoprazan. However, the short duration of follow-up is viewed as a limitation. In conclusion, a short course of vonoprazan 20 mg/day seems superior to pantoprazole 40 mg/day in the reduction of post-EVL ulcer-bleeding and ulcer dimensions and their sequelae at 2 weeks. Furthermore, acid suppression therapy is superior to no acid suppression in reducing local post-ligation complications after EVL.
Author contributions
Sameh A. Lashen: conceptualization, design, procedure, data collection, analysis, writing, drafting.
Mohammed M. Shamseya: Procedure, experiment, writing, drafting.
Ayman M. Shamseya: Procedure, design, experiment, data collection, drafting.
Fahmy H. Hablass: Procedure, design, experiment, data collection, drafting.
Funding statement
NIL.
Declaration of Competing Interest
All authors declare that they have no conflict of interest.
Acknowledgments
We acknowledge the clinical pharmacy unit for assistance in the allocation concealment process.
List of abbreviations:
EE
Erosive esophagitis
eGFR
estimated glomerular filtration rate
EVL
endoscopic variceal ligation
ITT
Intention to treat
MELD
Model for End-stage Liver Disease
NSBB
non-selective beta-blockers
PCAB
potassium-competitive acid blockers
PHTN
portal hypertension
PPI
Proton pump inhibitor
PP
Per-protocol
SOC
Standard of care
TAREs
Treatment-related adverse effects
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Practice Guidelines Committee of American Association for Study of Liver Diseases, & Practice Parameters Committee of American College of Gastroenterology (2007). Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis.
The American Journal of Gastroenterology.2007; 102: 2086-2102
Incidence and management of esophageal stricture formation, ulcer bleeding, perforation, and massive hematoma formation from sclerotherapy versus band ligation.
Proton Pump Inhibitor Therapy Is Associated with Reduction of Early Bleeding Risk After Prophylactic Endoscopic Variceal Band Ligation: A Retrospective Cohort Study.
Evaluation of the efficacy and safety of vonoprazan in patients with non-erosive gastroesophageal reflux disease: A phase III, randomized, double-blind, placebo-controlled, multicenter study.
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