Should potassium-competitive acid blockers replace proton pump inhibitors as first-line therapy for patients with severe (Los Angeles grade C or D) esophagitis?

WHAT IS ESOPHAGITIS, AND HOW IS IT GRADED?

Esophagitis is inflammation of the esophagus, commonly caused by gastroesophageal reflux disease, allergies (eosinophilic esophagitis), infections, or drug-induced injury. Symptoms include heartburn, dysphagia, regurgitation, and chest or abdominal pain.¹

Reflux esophagitis is classified as nonerosive (symptoms without visible mucosal damage on endoscopy) or erosive (visible mucosal breaks on endoscopy). Erosive esophagitis, more common in men, is graded by using the Los Angeles classification²:

• Grade A: mucosal break 5 mm or less, not extending between folds

• Grade B: mucosal break greater than 5 mm, not extending between folds

• Grade C: continuous mucosal break less than 75% of the esophageal circumference

• Grade D: mucosal break 75% or more of the esophageal circumference.

Patients with higher grades (C and D) have a greater risk of stricture formation, Barrett esophagus, esophageal carcinoma, and significant gastrointestinal bleeding.

HOW IS ESOPHAGITIS TREATED?

Treating esophagitis includes controlling symptoms, recommending lifestyle modifications, and confirming that healing has occurred with endoscopy. The American Gastroenterological Association³ recommends a once-daily PPI for at least 8 weeks as first-line therapy for patients with mild nonerosive esophagitis (grade A or B), increasing to a twice-daily dose if patients do not respond. In patients with C or D esophagitis, the American College of Gastroenterology¹ recommends endoscopy after an initial 8-week course of once-daily PPI treatment to evaluate healing and to screen for Barrett esophagus, with the lowest-dose PPI therapy continued indefinitely to prevent recurrence.

HOW DO PPIs WORK, AND WHAT ARE THE DRAWBACKS OF USING THEM TO TREAT ESOPHAGITIS?

PPIs are prodrugs that irreversibly bind to inactive hydrogen-potassium adenosine triphosphate (the proton pump) in the stomach. The acidic environment in the stomach converts the PPI into its active form, thereby reducing acid production.

Omeprazole equivalent, a measure of how effectively PPIs sustain elevation of gastric pH, is used to compare their relative potency.⁴ Dexlansoprazole and rabeprazole are among the most potent PPIs, while lansoprazole and pantoprazole are the least potent (Table 1).^4,5 Twice-daily dosing increases drug levels and sustains gastric pH. High-grade (C or D) esophagitis is often treated with PPIs once or twice daily for 8 weeks and adjusted based on healing response.^4–6

Although PPIs are highly effective, treatment failure can occur. Up to 30% of patients with high-grade esophagitis do not heal after a full course of PPI therapy, and 20% to 30% relapse within a year, especially those with severe disease.⁷

Additionally, observational data have linked long-term use of PPIs to various possible adverse effects. Potential risks include the following⁸:

• Vitamin B₁₂ and calcium deficiencies leading to osteoporosis

• Small intestinal bacterial overgrowth

• Clostridioides difficile infection

• Kidney disease (interstitial nephritis with rare progression to chronic kidney disease).

These concerns have fueled interest in alternative treatments like PCABs.

WHAT ARE PCABs?

PCABs, including vonoprazan, tegoprazan, and fexuprazan, are a newer alternative to PPIs. They reversibly inhibit both active and inactive hydrogen-potassium adenosine triphosphate pumps, thus providing faster onset and longer acid suppression.⁹

Vonoprazan, first approved in Japan in 2014, is the only PCAB approved by the US Food and Drug Administration to treat Helicobacter pylori infection (in 2022), erosive esophagitis (in 2023), and nonerosive gastroesophageal reflux disease (in 2024). It is the most extensively studied PCAB, so it has the data available to compare with PPIs.

An integrated safety analysis of 14 clinical trials that evaluated up to 5 years of vonoprazan use, as well as 9 years of postmarketing surveillance data, did not show an increased risk of serious complications.¹⁰ Side effects included constipation, diarrhea, indigestion, and abdominal pain. Serious adverse events were rare and were similar to PPIs; the most common was hypergastrinemia. Other rare adverse events reported were elevated levels of alanine aminotransferase, aspartate aminotransferase, or both; tubulointerstitial nephritis; and gastric cancer.

As PCABs are relatively new, longer-term use is needed to clarify their full side-effect profile.

DO PCABs OUTPERFORM PPIs FOR HIGH-GRADE ESOPHAGITIS?

Using PCABs as a potential alternative to PPIs has been explored, particularly for erosive esophagitis. Most initial randomized controlled trials were noninferiority studies that were designed to show treatment is not worse than standard care. These trials set a predefined margin that determines the acceptable loss of efficacy—typically requiring at least 50% preservation of the minimal treatment effect—based on previous studies. While PCABs were shown to be as effective as PPIs, none has shown superiority over PPIs optimized for dose and potency.

Efficacy and Safety of Oral Once-Daily Vonoprazan (TAK-438) in Participants With Erosive Esophagitis, a phase 3 randomized, double-blind, multicenter trial conducted across 56 sites from 2015 to 2017, compared esophagitis healing rates between vonoprazan 20 mg and lansoprazole 30 mg in 481 Asian patients with endoscopically confirmed erosive esophagitis.¹¹ Participants received daily treatment for 8 weeks, and underwent an endoscopy at weeks 2, 4, and 8 to evaluate healing. The study confirmed vonoprazan’s noninferiority, with a −10% margin. While healing rates were higher with vonoprazan in patients with grade C or D esophagitis, these differences were not statistically significant. Symptom relief also did not significantly differ.

Given that differences in diet and cytochrome P450 metabolism between Asian and Western patients can potentially affect PPI efficacy, another phase 3 randomized, double-blind, multicenter trial, Efficacy and Safety of Vonoprazan Compared to Lansoprazole in Participants With Erosive Esophagitis, evaluated vonoprazan for inducing and maintaining healing of erosive esophagitis.⁹ The study included 1,027 adults (34.1% had grade C or D esophagitis) across 111 sites in the United States and Europe.

Patients received vonoprazan 20 mg or lansoprazole 30 mg daily for 8 weeks (healing phase), and were assessed with endoscopy at weeks 2 and 8. Those who achieved healing were rerandomized to vonoprazan 20 or 10 mg or lansoprazole 15 mg for 24 weeks (maintenance phase). Results showed that vonoprazan was noninferior to lansoprazole for inducing and maintaining esophagitis healing and superior for severe esophagitis based on predefined exploratory and secondary end-point analyses, while symptom relief did not differ significantly.

However, clinical applicability of higher healing rates must consider the chosen PPI comparator. Once-daily dosing with lansoprazole 30 mg, a PPI with a lower omeprazole equivalent, had the lowest esophagitis healing rate when compared with double-dose PPI drug therapies.¹² Similarly, lansoprazole 15 mg was shown to have a sustained healing rate of less than 75%, while higher-dose and -potency PPI regimens have demonstrated healing rates of more than 90%.

To further evaluate vonoprazan’s efficacy in patients with grade C or D esophagitis, a systematic review and network meta-analysis compared the efficacy of PCABs with that of various PPIs.⁷ The analysis included 24 randomized trials covering 9,267 patients in treatment phases and 1,834 patients in maintenance phases. The analysis revealed that, while vonoprazan was superior to lansoprazole in direct comparisons, this finding was not supported when vonoprazan was compared with PPIs of higher dose and potency. The relative risk of initial treatment failure was higher with lansoprazole 30 mg (risk ratio 2.97, 95% credible interval 1.64–6.71) and omeprazole 20 mg (risk ratio 3.5, 95% credible interval 1.31–11.79) compared with vonoprazan 20 mg (Table 2).⁷ (Credible intervals are presented because they are a direct statement of probability that the true value is within the interval by using the Bayesian approach of combining previous knowledge with new data, whereas confidence intervals interpret probability over the long term.) However, when compared with more potent PPIs such as esomeprazole 40 mg, dexlansoprazole 60 mg, and rabeprazole 50 mg, there were no significant differences in treatment failure.

Surface under the cumulative ranking (SUCRA), a probability ranking metric used in network meta-analyses, was also used to assess vonoprazan’s efficacy. Vonoprazan 20 mg ranked highest for both the initial healing and maintenance phases, followed by, in the initial healing phase, dexlansoprazole 60 mg and esomeprazole 40 mg.⁷ For maintenance of healing, however, vonoprazan only demonstrated superiority over lansoprazole 15 mg in direct comparisons.

While SUCRA offers a convenient means of synthesizing complex data into an accessible ranking system, it does not incorporate critical factors such as effect size, safety profiles, or cost. Thus, high SUCRA scores should be interpreted cautiously, as they may overstate the clinical value of treatment when not contextualized within the broader evidence.

WHEN SHOULD WE USE A PCAB?

PCABs, while an alternative to PPIs, have not been shown to have superior efficacy and are significantly more expensive. Their use should be limited to patients who cannot tolerate PPIs, do not respond to treatment, or require an alternative therapy; however, they are not currently recommended as a first-line treatment.

THE BOTTOM LINE

PPIs remain the gold standard for treating erosive esophagitis, despite concerns over long-term efficacy and safety. Although PCABs are an alternative, most existing trials show only noninferiority to PPIs, and data showing superiority in severe esophagitis are based on low-dose, low-potency comparators. While PCABs are a novel pharmacologic mechanism that offer exciting promise, more research is needed to define their role in clinical practice.

DISCLOSURES

The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.