Antireflux surgery superior to medical therapy for PPI-refractory heartburn

Patients with heartburn, which is related to gastro-oesophageal reflux disease (GERD) and refractory to proton pump inhibitors (PPIs), may fare better if they undergo fundoplication than medical treatment, according to a recent study.

“[S]ystematic workup including oesophageal multichannel intraluminal impedance (MII)-pH monitoring can identify a subgroup of patients with PPI-refractory heartburn, including those with reflux hypersensitivity, who can have a response to antireflux surgery,” the investigators said.

“MII-pH monitoring is a relatively recent innovation, however, and experts disagree on its clinical usefulness. Surgeons are reluctant to rely on it to select patients for fundoplication, generally preferring traditional oesophageal pH monitoring for that purpose,” they added.

In the trial, the investigators tested their hypothesis that if non-GERD and functional disorders were excluded by systematic workup, then antireflux surgery would be more beneficial than medical therapy for patients with PPI-unresponsive heartburn that MII-pH monitoring identified as being reflux-related.

A total of 366 PPI-refractory heartburn patients (mean age, 48.5 years; 76.5 percent male) received 20 mg of omeprazole twice daily for 2 weeks, and those with persistent heartburn underwent endoscopy, oesophageal biopsy, oesophageal manometry and MII–pH monitoring.

Of the patients, 78 were found to have reflux-related heartburn and were randomly assigned to one of the following treatment arms: surgery (laparoscopic Nissen fundoplication; n=27), active medical treatment (omeprazole plus baclofen, with desipramine added depending on symptoms; n=25) or control medical treatment (omeprazole plus placebo; n=26). [N Engl J Med 2019; 381:1513-1523]

Treatment success, defined as a ≥50-percent decrease in the GERD–Health Related Quality of Life score (range, 0–50, with higher scores indicating worse symptoms) at 1 year, proved to be superior with surgery (18 patients, 67 percent) than with either active medical (7 patient, 28 percent; p=0.007) or control medical treatment (3 patients, 12 percent; p<0.001). There was no significant difference observed between the two medical treatment arms (difference, 16 percentage points, 95 percent confidence interval [CI], −5 to 38; p=0.17).

Among the 288 patients excluded from randomization, 42 achieved heartburn relief during the 2-week omeprazole trial, 70 did not complete trial procedures, 54 were excluded for other reasons, 23 had non-GERD oesophageal disorders, and 99 had functional heartburn (not due to GERD or other histopathologic, motility or structural abnormality).

“This trial highlights the critical importance of systematic evaluation, similar to that recommended by Gyawali and Fass, for managing the care of patients with PPI-refractory heartburn,” the investigators pointed out. [Gastroenterology 2018;154:302-318]

“Many patients would not complete this rigorous evaluation, and among those who did, the cause of heartburn in most of them was not GERD. Furthermore, no demographic or clinical characteristics distinguished patients with reflux-related heartburn from those with functional heartburn, those whose heartburn responded to omeprazole taken properly, and those who would not complete diagnostic evaluation,” they added.

Dr Nicholas Talley, who is not involved in the study, agreed with the investigators, saying that it is a mistake to conceptualize GERD as a single disease process that will respond to increased doses of acid-suppressing drugs. [N Engl J Med 2019;381:1580-1582]

“Before PPI-resistant GERD is diagnosed, the ruling out of disorders that are not primarily driven by acid reflux into the oesophagus [such as functional dyspepsia and eosinophilic oesophagitis] needs consideration,” wrote Talley, who is affiliated with the University of Newcastle, Hunter Medical Research Institute, in NSW, Australia, in a commentary piece.

Just as the investigators did, Talley pointed out that oesophageal MII-pH monitoring during PPI therapy allows an objective assessment of PPI-resistant GERD. However, he acknowledged that even such a test for GERD can return false positive and false negative results.

“Unfortunately, we still have little to offer patients who despite a complete workup have troublesome reflux after surgery (as occurred in one-third of surgical patients in this trial), aside from repeat oesophageal testing and yet another trial of acid suppression,” he said. “We need personalized medical options that target the underlying causes of GERD.”