October 16, 2019
3 min read

Few patients truly have PPI-refractory heartburn caused by GERD, researchers learn

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Researchers recently conducted a randomized trial of treatments for patients with heartburn who were not responsive to proton pump inhibitors, or PPIs, but it turns out that GERD caused heartburn in only a minority of patients. For that select group, surgery was superior to medical treatment, they said.

“The best medical treatment that we have for GERD are the PPIs,” Stuart J. Spechler, MD, co-director of the Center for Esophageal Diseases at Baylor University Medical Center at Dallas, told Healio Primary Care. “They are the most powerful acid-suppressants and considered the mainstay of treatment for GERD. But up to 40% of patients who take a PPI complain of persistent symptoms like heartburn. One of the most frequent reasons to refer a patient to a gastroenterologist is because of this PPI-refractory GERD.”

In the trial, patients who were referred to the Veterans Affairs gastroenterology clinics for PPI-refractory heartburn received a standardized trial of 20 mg of omeprazole twice daily for 2 weeks. Those with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry and multichannel intraluminal impedance-pH monitoring. If patients were found to have reflux-related heartburn, they were randomly assigned to one of three arms:

  • surgical treatment — specifically, laparoscopic Nissen fundoplication;
  • active medical treatment, including omeprazole plus baclofen, with desipramine added depending on the patients’ symptoms; or
  • control medication treatment, including omeprazole plus placebo.

Following pre-randomization procedures, 288 patients were excluded: 99 had functional heartburn (not caused by GERD or other histopathologic, motility or structural abnormalities), 70 did not complete trial procedures, 54 were not included for other reasons, 42 had heartburn relief as a result of taking omeprazole, and 23 had non-GERD esophageal disorders.

“In many studies we largely ignore the patients who don’t qualify,” Spechler said. “But what’s really key here is that most people who are referred to clinics for PPI-refractory heartburn didn’t have GERD as the cause for the heartburn. Meaning it would be a terrible mistake to recommend surgery.”

According to researchers, 67% who underwent surgery had treatment success, compared with only 28% who received active treatment (P = .007) and 12% in the control medical treatment group (P < .001).

These findings surprised David Greenwald, MD, director of clinical gastroenterology and endoscopy at Mount Sinai Hospital in New York City, who was not involved in the study.

“The PPI-refractory group included patients who likely had reflux hypersensitivity as the root cause of their symptoms, and that group might not have been expected to improve clinically with a surgical procedure that reduces reflux but does not alter esophageal pain perception,” Greenwald told Healio Primary Care.

The study showed the importance of ascertaining if a patient truly has reflux-related PPI-refractory heartburn before recommending a treatment, according to Spechler.

“The failure [of a patient] to respond to PPIs is really a red flag to strongly consider that something besides GERD is going on,” Spechler said. “Multichannel intraluminal impedance–pH monitoring would be a very important test to do to make sure the heartburn is reflux-related before considering surgery.”

Spechler believes the findings can be replicated in the general population, whereas Greenwald believes a larger study to show that the results are generalizable is needed. However, they did agree about some of the study’s implications.

“[This] systematic evaluation [showed] that a considerable number of ‘PPI-refractory patients with heartburn’ get relief when taking PPIs twice daily and 30 minutes before meals, showing that simply taking the medication correctly made many in the PPI refractory group better,” Greenwald said in the interview. “Many other ‘PPI refractory patients with heartburn’ did not have GERD as the cause of their heartburn. As such, a systemic evaluation of these patients is critical to managing patients with heartburn felt to be PPI refractory.” – by Janel Miller


Spechler SJ, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1811424.

Disclosures: Healio Primary Care was unable to determine Spechler’s relevant financial disclosures at the time of publication. Greenwald reports no relevant financial disclosures.