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The ‘No acid, no ulcer’ dictum has dominated the pathogenesis and treatment of peptic ulcer disease for more than 100 years, and since it was proposed in 1910 by Dragutin (Carl) Schwarz (1868–1917).1 The dream of having a relatively potent and safe acid inhibitor was only realised in the mid-1970s with the marketing of cimetidine, later followed by other histamine-2 receptor antagonists (H2RA). The real breakthrough only came by the late 1980s with the introduction of proton pump inhibitors (PPI). The use of these products, particularly the PPIs, continues to increase making them some of the most commonly prescribed or bought over-the-counter agents in the world.2–4 This has added to the credibility of Schwarz’s dictum, as it is exceptional to come across a peptic ulcer that does not respond fully or partially to acid inhibition. The process of healing seems to be triggered or enhanced by the presence of a relatively acid-free medium regardless of aetiological factors: Helicobacter pylori, alcohol, aspirin, non-steroidal anti-inflammatory drugs (NSAID), or even in the case of some atypical ulcers such as those related to Crohn’s disease or malignancy.1–6
Of particular interest is the success of acid inhibitors in the healing or prevention of ulcers in aspirin and NSAID users given the fact that prostaglandin synthesis suppression is the key mechanism of ulcer formation in such patients. In fact, acid inhibitors became more popular than prostaglandin analogues, such as misoprostol, in this field.5–7 The fight against NSAID-related peptic damage was thought to have been won with the advent of selective cyclo-oxygenase-2 enzyme inhibiting NSAIDs in the 1990s. These agents had fewer ulcer side effects than non-selective conventional NSAIDs and became very popular. However, their use had sharply declined with the withdrawal of rofecoxib in 2006 because of cardiovascular concerns. This, in turn, has been followed by a steady resurgence of the use of non-selective and potentially more ulcerogenic NSAIDs, thus requiring more coprescription of acid inhibitors.
Given the popularity of H2RAs and PPIs and the competitive pricing of their generic preparations, it is legitimate to ask why we should be interested in yet newer acid inhibitors. This is because the current agents, namely the PPIs, have been linked to a variety of adverse events. These include renal disorders (acute kidney injury, interstitial nephritis and chronic kidney disease), osteoporosis and bone fracture, dementia, myocardial infarction, micronutrient deficiencies (iron, calcium, magnesium and vitamin B12), malignancies (gastric and colonic cancer), infections (pneumonia, small bowel infections and Clostridium difficile infection) and disturbances of the gut microbiome.2–4 PPIs have also been reported to aggravate the damaging effects of aspirin and NSAIDs on the small bowel and colonic mucosa.7 It has to be stressed at this point that a cause-and-effect relationship has never been proven between PPIs and these adverse events: the evidence has largely been speculative or observational. As for H2RAs, they are less effective than PPIs in healing of erosive oesophagitis; and, with the exception of famotidine, they are also less effective in preventing NSAID-related gastric ulcers than PPIs.5 6
With these concerns in mind, Gut published two studies from Japan that investigate mucosal protection, against aspirin and NSAID-induced peptic ulcer recurrence, of a novel acid inhibitor, vonoprazan.8 9 This is a potassium-competitive acid blocker, which inhibits H+, K+-ATPase at the final stage of the acid secretory pathway in the gastric parietal cells. It does not require enteric coating as it is acid stable; and it exerts a near-maximum inhibitory effect from the first dose, thus remaining effective for 24 hours. This is unlike PPIs, which require approximately 3–5 days to achieve maximal inhibition of gastric acid secretion.8–10
In their study, Dr Mizokami and colleagues aimed to assess the non-inferiority of vonoprazan to a standard PPI, lansoprazole, for secondary prevention of NSAID-induced peptic ulcers, and the safety of vonoprazan during extended use, in a phase-3, 24-week, multicentre, randomised, double-blind, active-controlled study, followed by a phase-3, ≥28 week, extension study.8 The proportions of patients with recurrent peptic ulcers within 24 weeks were 3.3%, 3.4% and 5.5% for vonoprazan 10 mg, 20 mg, and lansoprazole 15 mg, respectively. Similarly, and in patients using aspirin, Dr Kawai and colleagues reported that the 24-week peptic ulcer recurrence rate was 2.8%, 0.5% and 1.5% in the lansoprazole 15 mg, vonoprazan 10 mg and vonoprazan 20 mg groups, respectively.9 Both sets of authors concluded that the non-inferiority of vonoprazan to lansoprazole 15 mg was verified. They also concluded that vonoprazan was effective in preventing ulcer recurrence and it was well tolerated in Japanese patients receiving low-dose aspirin or NSAIDs. These results do not necessarily imply that the doses of vonoprazan, tested in this study, are not inferior to the 30 mg standard dose of lansoprazole licensed for use outside Japan. While vonoprazan has also been shown to be well tolerated, it cannot be claimed that its wider future use would not be linked to adverse events similar to those rightly or wrongly attributed to PPIs.
The results of the studies by Mizokami et al and Kawai et al strengthen the promise of providing a new means of acid inhibition in addition to H2RAs and PPIs. They also provide a different option to the healing and prevention of aspirin and NSAID-related ulcers.
Compared with PPIs, the prompt and longer lasting acid inhibitory advantages of vonoprazan and its class of drugs would make it likely for these novel agents to replace PPIs in increasing numbers of patients with acid-related disorders including H. pylori gastritis, although their role in treating this infection has not yet been established. However, this does not mark the beginning of the end of PPIs: the science behind the adverse events linked to them remains relatively weak. Also, while their indiscriminate use should be discouraged, PPIs continue to have significant benefits in the management of the common conditions of GORDs including Barrett’s oesophagus, treatment of non-variceal upper GI bleeding, healing and prevention of peptic ulcers in the presence or absence of aspirin and NSAIDs, and in the eradication regimes of H. pylori.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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