Potassium-Competitive Acid Blocker Suppression of Gastric Acid in Erosive Esophagitis: Is Stronger and Longer Better?

See “Vonoprazan versus lansoprazole for healing and maintenance of healing of erosive esophagitis: a randomized trial,” by Laine L, DeVault K, Katz P, et al, on page 61. See “Vonoprazan versus lansoprazole for healing and maintenance of healing of erosive esophagitis: a randomized trial,” by Laine L, DeVault K, Katz P, et al, on page 61. Pharmacologic blockade of the parietal cell H+, K+ -ATPase with proton pump inhibitors (PPIs) revolutionized the treatment of peptic esophagitis. As a result, millions of patients who might have experienced chronic heartburn, dysphagia from peptic strictures, or blood loss from chronic esophagitis, or been subjected to the benefits and imperfections of fundoplication, are effectively managed nonsurgically. Furthermore, the safety of chronic PPI therapy is endorsed by an American Gastroenterological Association Best Practice Statement, review articles, meta-analyses, and editorials.1Yadlapati R. Gyawali C.P. Pandolfino J.E. on behalf of the CGIT GERD Consensus Conference Participants. AGA Clinical Practice Update on the personalized approach to the evaluation and management of GERD: expert review.Clin Gastroenterol Hepatol. 2022; 20: 984-994Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,2Salvo E.M. Ferko N.C. Cash S.B. et al.The safety of proton pump inhibitors: an umbrella review of 42 systematic reviews with meta-analyses.Aliment Pharmacol Ther. 2021; 54: 129-143Crossref PubMed Scopus (17) Google Scholar This, despite the multitude of reports associating a wide spectrum of adverse effects with long-term PPI use. Given the enormous success and safety of PPIs, is there really an unmet need for more potent suppression of gastric acid secretion? Data presented in this issue of Gastroenterology pertaining to healing and maintenance of healing of erosive esophagitis,3Laine L. DeVault K. Katz P. et al.Vonoprazan versus lansoprazole for healing and maintenance of healing of erosive esophagitis: a randomized trial.Gastroenterology. 2023; 164: 61-71Abstract Full Text Full Text PDF Scopus (1) Google Scholar as well as prior reports on eradication of Helicobacter pylori,4Chey W.D. Mégraud F. Laine L. et al.Vonoprazan triple and dual therapy for Helicobacter pylori infection in the United States and Europe: randomized clinical trial.Gastroenterology. 2022; 163: 608-619Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar would indicate that the answer is yes. Among their shortcomings, PPIs are far from perfect in healing high-grade (Los Angeles class C and D) esophagitis, resulting in the common practice of twice-daily dosing. Furthermore, up to 35% of patients with Los Angeles class C and D esophagitis remain unhealed at 8 weeks, even with twice-daily PPI use.5Lightdale C.J. Schmitt C. Hwang C. et al.A multicenter, randomized, double-blind, 8- week comparative trial of low-dose esomeprazole (20 mg) and standard-dose omeprazole (20 mg) in patients with erosive esophagitis.Dig Dis Sci. 2006; 51: 852-857Crossref PubMed Scopus (32) Google Scholar,6Zhang H. Yang Z. Ni Z. Shi Y. A meta-analysis and systematic review of the efficacy of twice daily PPIs versus once daily for treatment of gastroesophageal reflux disease.Gastroenterol Res Pract. 2017; https://doi.org/10.1155/2017/9865963Crossref Scopus (15) Google Scholar This has led to the widespread practice of adding an evening dose of an H2 receptor antagonist to a twice-daily PPI regimen, targeting “nocturnal acid breakthrough” as a potential cause of refractory disease.7Peghini P.L. Katz P.O. Castell D.O. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects.Gastroenterology. 1998; 115: 1335Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar,8Fackler W.K. Ours T.M. Vaezi M.F. et al.Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough.Gastroenterology. 2002; 122: 625Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar PPIs also have the following notable pharmacologic shortcomings: they are acid labile, requiring enteric coating, which leads to delayed onset of action; they have a short (1- to 2-hour) half-life and only bind to activated proton pumps, necessitating preprandial dosing for optimal effect; and, because they covalently bind to and inactivate only activated proton pumps, they take several days of repeated dosing to achieve maximal acid inhibition. Furthermore, the frequent need to increase from once-daily to twice-daily dosing introduces problems with adherence; a study of patients taking antibiotics demonstrated a 22% greater chance of being fully compliant on once-daily vs twice-daily medication use, irrespective of duration of treatment.9Falagas M.E. Karagiannis A.K.A. Nakouti T. et al.Compliance with once-daily versus twice or thrice-daily administration of antibiotic regimens: a meta-analysis of randomized controlled trials.PLoS One. 2015; 10e0116207Crossref PubMed Scopus (26) Google Scholar What are the characteristics of potassium-competitive acid blockers (PCABs) that might confer an advantage compared with PPIs? The first PCAB approved by the US Food and Drug Administration, vonoprazan, reversibly binds to the α-subunit of H+, K+-ATPase to compete with potassium binding. Vonoprazan is acid stable, eliminating the need for enteric coating and allowing for rapid onset of action. Because it achieves high and sustained (half-life is approximately 9 hours) concentrations rapidly in the parietal cell secretory canaliculi, maximal acid inhibition is achieved quickly after a single dose. In addition, because it is not metabolized through the hepatic CYP2C19 or CYP3A4 enzymes, vonoprazan is much less prone to drug–drug interactions. There is also likely to be much less variability among individuals in the duration of action of vonoprazan attributable to polymorphisms of these enzymes, as seen with PPIs. From a pharmacodynamic perspective, vonoprazan has a more rapid onset of action, more complete inhibition of acid secretion, likely less variability in acid control among individuals, and a more prolonged maximal effect after a single dose compared with PPIs. Nonetheless, one must ask whether these pharmacologic advantages translate to clinical advantages. In this issue of Gastroenterology, Laine et al3Laine L. DeVault K. Katz P. et al.Vonoprazan versus lansoprazole for healing and maintenance of healing of erosive esophagitis: a randomized trial.Gastroenterology. 2023; 164: 61-71Abstract Full Text Full Text PDF Scopus (1) Google Scholar present data from a randomized controlled noninferiority trial of vonoprazan 20 mg vs lansoprazole 30 mg for 8 weeks in 1027 US and European, H pylori–negative, Barrett's esophagus–negative patients with erosive esophagitis. The results demonstrate noninferiority of 8-week healing with 92.9% (vonoprazan) vs 84.6% (lansoprazole) in the healing phase and in the 24-week maintenance phase: 80.7% (vonoprazan 20 mg), 79.2% (vonoprazan 10 mg), and 72.0% (lansoprazole 15 mg). Vonoprazan was also noninferior in the symptom outcomes of heartburn control. However, these outcomes are far from surprising, given vonoprazan’s pharmacodynamic profile. The crux of the matter is whether it succeeds where PPIs often fail; 34.3% of patients enrolled in the acute phase trial and 32.2% in the maintenance phase of the trial had Los Angeles class C or D esophagitis. Vonoprozan was significantly better at healing grade C and D esophagitis than lansoprazole (91.7% vs 72.0%) and in maintenance of healing in this subgroup (77.2% vonoprazan 20 mg, 74.7% vonoprazan 10 mg, 61.5% lansoprazole 15 mg). Keep in mind that this trial was designed for demonstrating noninferiority, not superiority, but these differences all had P values <.05 when tested for superiority. Another factor to consider is the risk of side effects or associated adverse events. Does this alternative mechanism for acid inhibition circumvent the reported side effects and adverse events associated with PPIs? For the issue of idiosyncratic side effects, such as headache, diarrhea, constipation, or bloating, the answer is unknown, and having a medicine in a novel drug class offers the clinician an added tool in their armamentarium. However, for the issue of long-term adverse events associated with PPI use (regardless of whether or not there is any validity to these being causally related), the proposed mechanisms for these primarily relate to the effects of chronic acid inhibition and/or hypergastrinemia, and there is no reason to think that a PCAB would be any different than a PPI. In this 32-week study, although serum gastrin levels were elevated in the vonoprazan groups, the changes from baseline for gastric mucosal atrophy and neuroendocrine cell proliferation were not significant. In conclusion, we will live in a society where bigger is always thought to be better. What will be the place of a medication that is bigger and better than PPIs in blocking gastric acid secretion in the treatment of gastroesophageal reflux disease? For patients with erosive esophagitis and/or clear acid-related symptoms refractory to PPIs, PCABs are a welcome addition and will likely be a key therapeutic tool. These may include patients with poorly controlled nocturnal heartburn and/or hypermetabolism of PPIs. Will the superior pharmacokinetic and pharmacodynamic profiles be enough to replace tried, true, highly effective, and now uniformly generic PPIs? Time will tell. Vonoprazan Versus Lansoprazole for Healing and Maintenance of Healing of Erosive Esophagitis: A Randomized TrialGastroenterologyVol. 164Issue 1PreviewFor decades, proton pump inhibitors (PPIs) have been the mainstay of treatment for erosive esophagitis. The potassium-competitive acid blocker vonoprazan provides more potent acid inhibition than PPIs, but data on its efficacy for erosive esophagitis are limited. Full-Text PDF Open Access