Potassium-competitive acid blockers: rethinking acid suppression for gastroesophageal reflux disease and Helicobacter pylori

Figures & data

Figure 1. Parietal cell physiology and mechanism of action of acid-suppressive therapies. See text for details [28].

Table 1. Comparison of key characteristics of proton pump inhibitors (PPIs) and vonoprazan.

	PPIs	Vonoprazan^a
Mechanism	Covalent binding of acid-activated drug to cysteine residues on luminal face of active H+/K+ ATPase [25]	Noncovalent reversible binding to K+ binding site of active and inactive H+/K+ ATPase; does not require acid activation [13,38,39]
Requirement for Food	Yes, to stimulate parietal cell acid production [14]	No, activity is independent of food [30]
Time to maximum effect	Cumulative with repeated dosing; maximum inhibition reached in ≥3 days [14]	~4-5 hours after each dose [40]
Half-life	0.6 to 2 h [25]	7–8 h [43]
Metabolism	CYP2C19 [25]	CYP3A4 [12]

^aAs the only PCAB currently approved in the United States, the characteristics listed here are from studies of vonoprazan.

Figure 2. Hours and percentage of time per 24-hour period above pH thresholds of 4 and 6 for lansoprazole 30 mg QD and vonoprazan 20 mg QD in a randomized 7-day crossover trial in healthy US adults (N = 40). Trial drugs were administered to fasted patients and followed by meals 4 h, 9 h, and 12 h later. P < 0.001 for all comparisons [40].

Table 2. Key recommendations and concept statements related to proton pump inhibitor use from the 2022 American College of Gastroenterology Clinical Guidelines for the Diagnosis and Management of Gastroesophageal Reflux Disease. Refer to the complete guideline for a comprehensive summary of recommendations [1].

Diagnosis of GERD

For patients with classic GERD symptoms of heartburn and regurgitation who have no alarm symptoms, an 8-week trial of empiric PPIs once daily before a meal is recommended An attempt should be made to discontinue PPIs in patients with classic GERD whose symptoms respond to an 8-week empiric trial of these agents

GERD Management

In patients with NERD, on-demand or intermittent PPI therapy for heartburn symptom relief is recommended Indefinite PPI maintenance therapy (or antireflux surgery) is recommended for patients with Los Angeles Grade C or D esophagitis For patients who require PPI maintenance therapy, the lowest PPIs dose that effectively controls GERD symptoms and maintains healing of reflux esophagitis should be used For patients with extra-esophageal and typical GERD symptoms, a trial of twice daily PPI therapy is suggested before additional testing Switching PPIs can be considered for patients who experience minor PPI side effects, including headache, abdominal pain, nausea, vomiting, diarrhea, constipation, and flatulence

Refractory GERD

Optimization of PPI therapy is the first step in the management of refractory GERD There is conceptual rationale for a trial of switching PPIs for patients who have not responded to one PPI. For patients who have not responded to one PPI, more than one switch to another PPI cannot be supported

Safety

Some studies suggest an association between long-term PPI use and the development of adverse events such as intestinal infections, pneumonia, stomach cancer, osteoporosis-related bone fractures, kidney disease, vitamin and mineral deficiencies, heart attacks, strokes, dementia, and early death; these studies are not considered definitive and do not establish a cause-and-effect relationship. High-quality studies suggest that PPIs do not significantly increase the risk of any of these conditions except intestinal infections Patients should be advised on the potential risks of PPIs while acknowledging that the ‘well-established benefits of PPIs far outweigh their potential risks’

GERD, gastroesophageal reflux disease; NERD, nonerosive gastroesophageal reflux disease; PPI, proton pump inhibitor.

Figure 3. (a) Relationship between esophageal acid exposure (median percentage time spent with pH <4.0) and symptom severity in gastroesophageal reflux disease; (b) Relationship between erosive esophagitis healing at 8 weeks and duration (hours) of intragastic pH is >4.0. Adapted with permission from Joelsson 1989 and S. Karger AG, Basel, Bell 1992 [47,50].

Table 3. First-line treatment strategies for Helicobacter pylori infection, per the 2017 American College of Gastroenterology guidelines [1].

Triple therapy (PPI, clarithromycin, amoxicillin or metronidazole [in regions where H. pylori clarithromycin resistance is <15% and in patients with no prior exposure to macrolides]) for 14 days Quadruple therapy (PPI, bismuth, tetracycline, and a nitroimidazole) for 10 to 14 days Concomitant therapy with a PPI, clarithromycin, amoxicillin, and a nitroimidazole for 10 to 14 days Sequential therapy with a PPI and amoxicillin for 5–7 days followed by a PPI, clarithromycin, and a nitroimidazole Hybrid therapy with a PPI and amoxicillin for 7 days followed by a PPI, amoxicillin, clarithromycin, and a nitroimidazole for 7 days Triple therapy with a PPI, levofloxacin, and amoxicillin for 10–14 days Sequential therapy with a PPI and amoxicillin for 5–7 days followed by a PPI, fluroquinolone, and nitroimidazole for 5–7 days

PPI, proton pump inhibitor.

Figure 4. Eradication rates in a phase 3 trial of 14 days of vonoprazan double (amoxicillin) and triple (amoxicillin + clarithromycin) therapy vs lansoprazole triple (amoxicillin + clarithromycin) therapy. See text for details. Adapted from Chey 2022 [63].

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