麻豆传媒

Gastroesophageal reflux disease (GERD) is one of the most common disorders of the gastrointestinal tract, with a pooled prevalence of 21% in the U.S., accounting for more than 4.6 million a year.

Erosive esophagitis occurs in an estimated 25% to 50% of GERD patients, and proton pump inhibitors (PPIs) are as the therapy of choice for this inflammatory condition.

However, not all patients respond adequately to PPIs. A group led by Loren Laine, MD, of the Yale School of Medicine in New Haven, Connecticut, conducted a double-blind randomized controlled trial, the first in a Western patient population, comparing the efficacy of the PPI lansoprazole (Prevacid) versus the potassium-competitive acid blocker (PCAB) vonoprazan (Voquezna), which was recently published in .

Laine outlined the study's results in the following interview with the Reading Room.

What was the clinical landscape that prompted your group to undertake this study?

Laine: For the past several decades, PPIs have been the mainstay of treatment for erosive esophagitis. Although PPIs are effective for healing erosive esophagitis, some patients do not achieve success with conventional PPI treatment. For example, lack of healing of erosive esophagitis with 8 weeks of treatment can be expected in 5% to 20% of patients, with rates of up to 30% reported in patients with more severe esophagitis.

In addition, after healing, recurrence over 12 months occurs in 10% to 45% of patients, despite PPI therapy, again with higher rates associated with more severe baseline esophagitis. Furthermore, PPIs are restricted in their time of dosing, and so an alternative therapy such as a PCAB, which does not have to be taken around meals, might be useful.

While PCABs provide more potent acid inhibition than PPIs because they have a longer half-life of 7 or 8 hours and appear to bind both active and inactive proton pumps, data on efficacy in erosive esophagitis are limited. A few small studies have been done in Asian patients, but these patients may have different characteristics than their Western counterparts.

Our group felt it was important to compare the two agents in Western patients and so we undertook a large randomized controlled trial at 77 sites in the U.S. and 34 in the U.K. and Europe. We hypothesized that vonoprazan might improve healing in patients with more severe disease because greater acid inhibition is associated with greater healing of erosive esophagitis.

Could you outline the trial design and the patient characteristics?

Laine: Adults with erosive esophagitis (mean age 51-52, 50-56% women) were randomized to once-daily vonoprazan at 20 mg or lansoprazole at 30 mg for up to 8 weeks. Patients who achieved healing were re-randomized to once-daily vonoprazan 10 mg, vonoprazan 20 mg, or lansoprazole 15 mg for 24 weeks.

The primary endpoints were the percentage with healing by week-8 endoscopy and maintenance of healing at week-24 endoscopy. We assessed these outcomes in noninferiority comparisons with margins of 10%.

What were the main findings?

Laine: In the cohort of 1,024 patients in the healing phase, 92.9% of those who received vonoprazan experienced healing by week 8 compared with 84.6% taking lansoprazole. In secondary analyses, the PCAB was noninferior in heartburn-free days, with a difference of 2.7%, and was superior in healing grade C/D esophagitis at week 2, with a difference of 17.6%.

During healing maintenance in 878 patients, vonoprazan was noninferior to lansoprazole in primary analysis and superior on secondary analysis of maintenance, with a difference of 8.7% between 20-mg vonoprazan and lansoprazole and a difference of 7.2% between 10-mg vonoprazan and lansoprazole.

In a secondary analysis of maintenance of healing in grade C/D esophagitis, differences were 15.7% between 20-mg vonoprazan and lansoprazole and 13.3% between 10-mg vonoprazan and lansoprazole.

These differences in healing rates emerged after 2 weeks of therapy and were maintained throughout the study.

Any relative safety concerns?

Laine: Adverse events across groups were similar overall. Severe adverse events were comparable in the healing phase but slightly higher during maintenance at the 20-mg dose of vonoprazan. As expected, serum gastrin levels were higher with vonoprazan, but dropped to 77.0 pg/mL for vonoprazan 20 mg, 65.9 pg/mL for vonoprazan 10 mg, and 59.7 pg/mL for lansoprazole 4 weeks after the end of maintenance therapy.

What about the applicability of the findings?

Laine: These results derive from a mainly white cohort, and so may not be generalizable to other groups. They also may not be applicable to Helicobacter pylori-positive patients, who tend to have a greater response to PPIs, and they may not pertain to those with reflux-like symptoms, but no actual erosive esophagitis. The latter group represents a more heterogeneous group, with less consistent response to gastric acid inhibition.

Do your findings align with previous research?

Laine: Three trials in Asian patients with erosive esophagitis showed lower rates of healing at 8 weeks compared with our results -- only 1.0% to 3.5% higher with the PCAB at 20 mg daily compared with lansoprazole at 30 mg daily -- but, again, this may be because Asian and Western populations differ in factors that may influence acid inhibition.

What are the considerations going forward?

Laine: Our study was too short to adequately evaluate the risk of long-term PCAB use on the development of neoplasia and other histologic outcomes. Changes in gastric histology, as well as in neuroendocrine cell proliferation, were negligible and comparable among treatment groups. We did observe a small net increase in patients with enterochromaffin-like cell hyperplasia in gastric body specimens after maintenance with vonoprazan at 20 mg versus lower-dose vonoprazan or with lansoprazole. No neoplasia was identified in any patient.

Whether the more potent acid inhibition and higher levels of gastrin seen with PCABs induce additional histological or clinical effect with long-term administration compared with PPIs requires further study.

You can read the abstract of the study here, and about the clinical implications of the study here.