AwesomeCapital: Surgery Beats Meds for True Refractory Heartburn

Use of laparoscopic Nissen fundoplication was significantly superior to medical therapy at 1 year in selected patients with true refractory heartburn, although a third of surgery patients did not respond to the procedure, a randomized Veterans Affairs (VA) study found.
The study also found that actual proton pump inhibitor (PPI)-refractory and reflux-related heartburn was present in only a minority of trial-eligible patients.
Stuart J. Spechler, MD, of Baylor University Medical Center in Houston, and colleagues concluded that systematic workup, including esophageal multi-channel intraluminal impedance-pH (MII-pH) monitoring, is needed to identify a subgroup of patients with PPI-refractory heartburn and reflux hypersensitivity that benefits from surgery.
Writing online in the New England Journal of Medicine, the researchers found the following incidence of treatment success at 1 year in 78 patients from VA medical centers; all the patients had true PPI-refractory heartburn, with success defined as a decrease of at least 50% in the Gastroesophageal Reflux Disease Health-Related Quality of Life score:

Anti-reflux surgery: 18 of 27 patients (67%, P<0.001)

Medical treatment: seven of 25 patients (28%, P=0.007)

Control medical treatment: three of 26 patients (12%, P<0.001)

The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% CI –5 to 38, P=0.17).
In 42 patients referred for PPI-refractory heartburn, gastroesophageal reflux disease (GERD) was in fact relieved with a standardized preliminary 2-week trial of omeprazole (Losec, Prilosec) twice daily, the team reported. Systematic evaluation showed that GERD was not the likely cause of heartburn for an additional 122 patients, with 99 diagnosed with functional heartburn, and 23 with a non-GERD organic disorder.
Spechler and co-authors explained that some patients with reflux symptoms unresponsive to PPIs may not respond to surgery either. This outcome might result from preoperative failure to document that symptoms are truly reflux-related. Alternatively, for patients with reflux hypersensitivity, surgical reduction of reflux might not relieve symptoms generated by a hypersensitive esophagus.
One previous study found that surgery was more likely to fail in patients with atypical symptoms, no response to acid-reducing drugs, or morbid obesity.
Study Details
From August 2012 to December 2015, the investigators recruited 366 patients (280 were men), with a mean age of 48.5.
After the 2-week omeprazole trial, participants with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and MII-pH. Following preliminary exclusions, 78 patients, of whom 64 were men and 54 were white, were deemed to have true refractory heartburn. They were randomly assigned to receive the following:

Laparoscopic Nissen fundoplication to strengthen the lower esophageal sphincter

Active medical treatment with omeprazole plus baclofen, which reduces esophageal sphincter relaxation, with the neuromodulator desipramine added depending on symptoms

Control medical treatment (omeprazole plus placebo)

Approximately 40%-50% of patients in each arm of the study had esophageal visceral hypersensitivity alone, with the remainder having abnormal acid reflux on MII-pH monitoring despite continuing PPI use.
The researchers said that despite the superiority of fundoplication shown at 1 year, surgery was not successful in a third of patients, and patients should be advised of that risk beforehand.
“This trial highlights the critical importance of systematic evaluation … for managing the care of patients with PPI-refractory heartburn,” Spechler and associates emphasized.
Last year, an expert panel concluded that anti-reflux surgery was indicated for only a select minority of PPI non-responders.
Not One Disease Process
Writing in an accompanying editorial titled “Think First, Cut Last — Lessons from a Clinical Trial of Refractory Heartburn,” Nicholas J. Talley, MD, PhD, of the University of Newcastle in New Lambton Heights, New South Wales, said it is a mistake to think of GERD as a single disease process responsive to incremental acid suppression. The underlying mechanisms are probably diverse and contribute in varying combinations, he explained. “These range from increased transient relaxations of the esophageal sphincter, to anatomical derangements of the esophageal sphincter, with or without esophageal hypersensitivity plus psychological distress.”
Talley pointed out that 79% of the recruited study patients did not meet the criteria for surgery and, in addition, the results may not be generalizable beyond the population of mostly male veterans. “The findings should not translate into more patients with refractory heartburn being offered surgery without each case being judiciously evaluated on its merits, and only after extended trials of medical therapy,” he said.
Few options exist for patients with persistent reflux after surgery, aside from repeat esophageal testing and another trial of acid suppression, Talley continued, noting that there are no well-established endoscopic alternatives to surgery for acid-related heartburn, although research is ongoing. “Even though behavioral therapy approaches that involve techniques such as diaphragmatic breathing may be of value, clinical trials are few and not definitive. We need personalized medical options that target the underlying causes of GERD.”
Study limitations, the researchers said, include its relatively small sample size and the predominance of white men, reflecting the veteran patient population. In addition, with no sham-surgery group, the study could not determine the contribution of the placebo effect to the incidence of treatment success with surgery. Furthermore, because MII-pH monitoring was performed only while patients were taking PPIs, it was not possible to determine how many of the patients would have abnormal acid reflux when not taking these drugs.
Another limitation involved the intra-trial protocol amendments required to enable completion, Spechler and co-authors noted, adding that although the incidence of success did not differ significantly between active medical treatment and control medical treatment (28% and 12%, respectively), the amended trial was insufficiently powered to rule out an important benefit of medical therapy.

The study was funded by the Department of Veterans Affairs Cooperative Studies Program.
Spechler reported a financial relationship with Ironwood Pharmaceuticals; several co-authors disclosed ties to various private-sector companies.
Talley reported financial relationships with various private-sector companies and reported holding patents on products related to GI disease.