Kristina Rebelo

November 18, 2009

November 18, 2009 (San Diego, California) — Contrary to expectations, there was no evidence of an increased response in gastroesophageal reflux disease (GERD)-associated heartburn relief to increased dosages of the proton pump inhibitor (PPI) esomeprazole, according to new study results presented here in a 2009 Presidential Poster presentation at the American College of Gastroenterology 2009 Annual Scientific Meeting.

This was a multicenter, double-blind, randomized trial of esomeprazole magnesium (Nexium, AstraZeneca LP) in patients aged 18 to 75 years (mean age, 45 years) with a history of 6 months or more of heartburn responsive to antacids or acid suppression therapy who were also positive for an esophageal acid perfusion test. Study participants were postmenopausal or on birth control, negative for Helicobacter pylori infection, and capable of keeping a symptoms diary.

The study consisted of 368 patients with GERD-associated moderate heartburn randomly assigned to 4 weeks of treatment with esomeprazole 20 mg once daily (n = 121), 40 mg once daily (n = 121), or 40 mg twice daily (n = 126).

Patients on esomeprazole doses higher than those under study were excluded.

Patients recorded responses to the following questions periodically throughout the study on an e-diary: "Please rate the severity of your most intense heartburn episode during the previous 24 hours," and "Did you experience nocturnal heartburn during your normal sleeping hours?"

Primary outcome measures were a sustained resolution of heartburn during the fourth week of treatment, defined as a "none" response in their heartburn assessment e-diary. Secondary outcome measures included relief of heartburn during the fourth week of treatment and cumulative daily sustained resolution rate through 4 weeks' treatment.

There was a slightly higher incidence of adverse events (AEs) in 3 patients who were in the 40-mg-twice-daily esomeprazole group (21%) than in patients in the 20-mg-once-daily and in the 40-mg-once-daily groups (17% and 18%, respectively). Study medication was withdrawn because of AEs in 3 patients who were in the 40-mg-once-daily group and in 2 patients who were in the 40-mg-twice-daily group. AEs included severe fatigue, arthralgia, myalgia, hyperhidrosis, blurred vision (1 case), mild nausea and diarrhea (1 case), moderate diarrhea (1 case), and moderate noncardiac chest pain in one patient. Symptomatic relief did not increase with higher PPI dosages or modified timing of PPI administration. The researchers concluded that treatment at all 3 doses provided similar rates of sustained heartburn relief with no statistically significant differences among the 3 doses."There's always the open question of whether doubling the PPI dose or using nighttime dosing could provide additional degrees of acid suppression," coauthor and investigator Marta Illueca, MD, FAAP, US Nexium brand medical director, AstraZeneca LP, Wilmington, Delaware, told Medscape Gastroenterology in an interview at the poster's presentation.

"According to these data, in these patients with GERD-associated heartburn, as determined by the acid perfusion test, there were no differences," Dr. Illueca asserted. "So the concept of a ceiling effect, at least in this study, is that an incremental symptomatic response to esomeprazole was not seen with increased dosage."

She pointed out that other studies have suggested that 30% of patients with GERD are still symptomatic despite PPI treatment. "There's just so much acid suppression that is achievable at any dose," she said. "Lifestyle modification and diet have to go hand in hand with pharmacological treatment."

Future areas of research, Dr. Illueca said, will include studying the effects of varying PPI dose and timing of the drug's administration on acid suppression for resolution of nighttime heartburn.

Philip O. Katz, MD, FACG, the newly elected president of the American College of Gastroenterology and chairman of the Division of Gastroenterology at Albert Einstein Medical Center and clinical professor of Medicine at Thomas Jefferson University in Philadelphia, Pennsylvania, who was not associated with the study, told Medscape Gastroenterology that treating the heartburn or GERD patients was "complex."

"The symptoms of heartburn in the reflux patient come in multiple forms," Dr. Katz said. "In reality, because of the differences in sensitivity, the differences in how reflux is expressed, it appears that there's a point at which increasing the dose is not going to be helpful in individual patients. Is there a ceiling effect? Perhaps in aggregate, but in individual patients, it is not quite as clear. So to round this out, in some people, more is better, and in some, increasing the dose will not be helpful. Everybody needs to be taken as an individual."

This research was supported by an industry grant from AstraZeneca LP, maker of Nexium. Dr. Illueca is an employee of AstraZeneca LP. Dr. Katz has disclosed no relevant financial relationships.

American College of Gastroenterology 2009 Annual Scientific Meeting: Abstract 15. Presented October 25, 2009.