Randomised Clinical Trial

Randomised Clinical Trial: Oesophageal Radiofrequency Energy Delivery Versus Sham for PPI-Refractory Heartburn

Frank Zerbib; Sylvie Sacher-Huvelin; Emmanuel Coron; Benoit Coffin; Chloé Melchior; Thierry Ponchon; Franck Cholet; Edouard Chabrun; Fabienne Vavasseur; Caroline Gorbatchef; Alberto Zalar; François Mion; Michel Robaszkiewicz; Marc Le Rhun; Maxime Leroy; Jean Paul Galmiche; Stanislas Bruley des Varannes

Disclosures

Aliment Pharmacol Ther. 2020;52(4):637-645. 

In This Article

Abstract and Introduction

Abstract

Background: Oesophageal radiofrequency reduces use of proton pump inhibitors (PPIs) in patients with gastro-oesophageal reflux disease responding to PPIs.

Aim: To determine the efficacy of oesophageal radiofrequency in patients with PPI-refractory heartburn.

Methods: A randomised, double-blind, sham-controlled multicentre study was designed to assess the efficacy of oesophageal radiofrequency in PPI non-responding patients with heartburn. Patients had moderate-to-severe heartburn defined by at least 3 occurrences a week, and not improved by continuous PPI treatment. The primary endpoint was clinical success at week 24, defined by intake of less than 7 PPI doses over the 2 preceding weeks and adequate symptom control determined by the patient.

Results: Sixty two patients were randomised, 29 to the oesophageal radiofrequency group and 33 to the sham group. Intention-to-treat analysis showed that 1/29 (3.4%) and 5/33 (15.1%) achieved the primary endpoint in the oesophageal radiofrequency and sham groups, respectively (NS). There was no significant difference between oesophageal radiofrequency and sham regarding the number of days without heartburn, days with PPI consumption in the last 2 weeks, and patients not taking PPIs. No pH-impedance parameter was associated with clinical response. The occurrence of adverse events was similar in both groups.

Conclusion: This sham-controlled, randomised study did not demonstrate any efficacy of oesophageal radiofrequency for the treatment of PPI-refractory heartburn regarding symptom relief or consumption of PPIs. ClinicalTrials.gov NCT01682265.

Introduction

Typical gastro-oesophageal reflux disease (GORD) symptoms, ie heartburn and regurgitation, affect 25%-30% of adults in Western countries.[1] Acid suppression with proton pump inhibitors (PPIs) is the mainstay of therapy for GORD. However, approximately 30% of patients report partial or nonresponse to PPI therapy,[2,3] and PPI-refractory GORD has become one of the most common presentations of GORD in gastrointestinal clinical practice.[4]

The underlying mechanisms of reflux-related refractory heartburn may be a poorly controlled acid reflux ("true refractory GORD") or hypersensitivity to acidic or weakly acidic reflux episodes while a subgroup of patients have functional heartburn, ie heartburn refractory to PPIs not associated with any type of reflux on pH-impedance monitoring.[5,6]

The therapeutic management of PPI-refractory heartburn is challenging. In patients with reflux-related symptoms, several approaches have been proposed: laparoscopic fundoplication in well-selected patients,[7] anti-reflux medications such as baclofen (which use is limited by side-effects)[8] and pain modulators targeting visceral hypersensitivity.[9,10] Neuromodulators represent the only therapeutic option in patients with functional heartburn,[5] presuming that visceral hypersensitivity is a major determinant of symptom generation.

Radiofrequency energy delivery (Stretta® procedure) has been proposed two decades ago as an alternative to long-term medical or surgical treatment for GORD. The exact mechanism of action of oesophageal radiofrequency remains unclear. The procedure may induce inflammation and fibrosis at the level of the lower oesophageal sphincter (LOS) and subsequently increase LOS pressure,[11] decrease oesophago-gastric junction compliance[12] and occurrence of transient LOS relaxations.[13] The efficacy of oesophageal radiofrequency regarding improvement in both physiologic parameters (acid exposure time) and symptoms remains controversial. A meta-analysis of all randomised controlled trials and cohort studies concluded that oesophageal radiofrequency improved both subjective (symptoms and quality of life) and objective endpoints (acid exposure time),[14] while when only randomised controlled trials were considered, no significant changes could be demonstrated.[15] Most of these studies have included GORD patients dependent of a long-term PPI therapy, with the objective to decrease or stop medications. Few cohort studies have focused on patients with refractory GORD symptoms. Hillman et al have collected the results of six cohort studies in PPI nonresponsive patients and, although significant symptomatic improvement was observed (possibly related to a placebo effect), there was a wide range of PPI discontinuation rate and a marginal effect on oesophageal acid exposure.[16] The discrepancy between symptom improvement and marginal effect on acid exposure time[17] has raised the hypothesis that oesophageal radiofrequency may decrease oesophageal sensitivity.

Of note, all oesophageal radiofrequency studies performed included patients with documented GORD and complete or partial response to PPIs. Since most of the patients with refractory heartburn have functional oesophageal disorders (reflux hypersensitivity or functional heartburn) and considering a possible effect of oesophageal radiofrequency on oesophageal sensitivity, we designed a randomised sham-controlled study of oesophageal radiofrequency in unselected patients with refractory heartburn.

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