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Laparoscopic anti-reflux surgery for the treatment of idiopathic pulmonary fibrosis (WRAP-IPF): a multicentre, randomised, controlled phase 2 trial

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Summary

Background

Abnormal acid gastro-oesophageal reflux (GER) is hypothesised to play a role in progression of idiopathic pulmonary fibrosis (IPF). We aimed to determine whether treatment of abnormal acid GER with laparoscopic anti-reflux surgery reduces the rate of disease progression.

Methods

The WRAP-IPF trial was a randomised controlled trial of laparoscopic anti-reflux surgery in patients with IPF and abnormal acid GER recruited from six academic centres in the USA. We enrolled patients with IPF, abnormal acid GER (DeMeester score of ≥14·7; measured by 24-h pH monitoring) and preserved forced vital capacity (FVC). We excluded patients with a FVC below 50% predicted, a FEV1/FVC ratio of less than 0·65, a history of acute respiratory illness in the past 12 weeks, a body-mass index greater than 35, and known severe pulmonary hypertension. Concomitant therapy with nintedanib and pirfenidone was allowed. The primary endpoint was change in FVC from randomisation to week 48, in the intention-to-treat population with mixed-effects models for repeated measures. This trial is registered with ClinicalTrials.gov, number NCT01982968.

Findings

Between June 1, 2014, and Sept 30, 2016, we screened 72 patients and randomly assigned 58 patients to receive surgery (n=29) or no surgery (n=29). 27 patients in the surgery group and 20 patients in the no surgery group had an FVC measurement at 48 weeks (p=0·041). Intention-to-treat analysis adjusted for baseline anti-fibrotic use demonstrated the adjusted rate of change in FVC over 48 weeks was −0·05 L (95% CI −0·15 to 0·05) in the surgery group and −0·13 L (−0·23 to −0·02) in the non-surgery group (p=0·28). Acute exacerbation, respiratory-related hospitalisation, and death was less common in the surgery group without statistical significance. Dysphagia (eight [29%] of 28) and abdominal distention (four [14%] of 28) were the most common adverse events after surgery. There was one death in the surgery group and four deaths in the non-surgery group.

Interpretation

Laparoscopic anti-reflux surgery in patients with IPF and abnormal acid GER is safe and well tolerated. A larger, well powered, randomised controlled study of anti-reflux surgery is needed in this population.

Funding

US National Institutes of Health National Heart, Lung and Blood Institute.

Introduction

Idiopathic pulmonary fibrosis (IPF) is an age-related chronic fibrotic lung disease that is characterised by physiological progression and episodes of acute respiratory worsening.1 Abnormal acid gastro-oesophageal reflux (GER) has been well described in patients with IPF and is thought to play a role in pathogenesis and progression of disease through increased risk for microaspiration of gastric acid and other non-acid components of the gastric refluxate.2, 3

Evidence to date is mixed regarding the clinical impact of abnormal acid GER and treatment of GER on the progression of IPF.4, 5 Several retrospective cohort studies have described the prevalence of abnormal acid GER in patients with IPF6, 7, 8, 9 and assessed the association of anti-acid therapies for GER (H2-receptor antagonists and proton-pump inhibitors) with clinical outcomes in IPF.10, 11 Two large secondary analyses12, 13 of data from clinical trials reached different conclusions; one reported a significant reduction in rate of physiological decline and acute exacerbation with anti-acid therapies,12 the other reported no effect.13

Microaspiration of both acid and non-acid components might be important to progression of IPF. A large retrospective cohort study14 of patients with IPF showed improved survival in patients who had anti-reflux surgery compared with those taking anti-acid therapy. A larger case series15 of 27 patients with progressive IPF who underwent laparoscopic anti-reflux surgery showed excellent safety outcomes and a trend toward stabilisation of physiology—as measured by forced vital capacity (FVC). These data suggest that surgical treatment for GER might provide added benefit for patients with IPF and abnormal acid GER.

Research in context

Evidence before this study

We searched PubMed for reports of clinical trials investigating the role of abnormal acid gastro-oesophageal reflux in the progression of idiopathic pulmonary fibrosis (IPF), published between Jan 1, 1998, and Dec 31, 2013. We used the search terms “idiopathic pulmonary fibrosis” AND “gastro-oesophageal reflux”, and filtered for reports published in English, which yielded 143 results. Abnormal acid gastro-oesophageal reflux is thought to play a role in the progression of IPF. Two large secondary analyses of data from clinical trials reached different conclusions regarding the effect of anti-acid medications on disease progression. Additional data suggest that anti-reflux surgery might provide added benefit.

Added value of this study

This phase 2 randomised, controlled trial aimed to determine whether normalisation of abnormal acid gastro-oesophageal reflux with laparoscopic anti-reflux surgery reduced the rate of disease progression. Laparoscopic anti-reflux surgery was safe and well tolerated but disease progression over 48 weeks—defined as change in forced vital capacity—did not reduce significantly. Respiratory-related hospitalisation and death were less common in the surgical group without statistical significance. These results provide the first prospective controlled data addressing this hypothesis.

Implications of all the available evidence

Laparoscopic anti-reflux surgery is safe and well tolerated in patients with IPF and abnormal acid gastro-oesophageal reflux. Further investigation of the effect of anti-reflux therapies on disease progression is needed.

In this randomised controlled trial, we hypothesised that treatment of patients with IPF and abnormal acid GER with laparoscopic anti-reflux surgery would prevent further insult to the lung and slow the progression of disease (as measured by change in FVC), and reduce the rate of clinically meaningful events, such as acute exacerbation, respiratory-related hospitalisation, and death. To test this hypothesis, we did laparoscopic anti-reflux surgery in patients with IPF and abnormal acid GER and compared outcomes with patients who did not receive such surgery.

Section snippets

Study design

The WRAP-IPF trial was a randomised, unblinded, controlled trial of laparoscopic anti-reflux surgery performed at six academic centres in the USA, with a coordinating centre at the Duke Clinical Research Institute. Sites were chosen on the basis of expertise in the care of patients with IPF and experience with laparoscopic anti-reflux surgery in the IPF population. Five sites were involved in the design of the trial, including standardisation of the surgical intervention; a sixth site was added

Results

Between June 1, 2014, and Sept 30, 2016, we screened 72 patients and randomly assigned treatment to 58 participants (figure 1). 33 (57%) patients were enrolled at one site (University of Washington, Seattle, WA, USA). Of the 29 patients assigned to receive laparoscopic anti-reflux surgery, 28 (97%) had the procedure and 27 (93%) completed the study. The median time from randomisation to surgery was 6·7 weeks (SD 4·4). Of the 29 patients assigned to not receive surgery, two (7%) had laparoscopic

Discussion

This phase 2 randomised controlled trial in patients with IPF and abnormal acid GER showed that laparoscopic anti-reflux surgery is safe and well tolerated but did not show that such surgery significantly slows the rate of FVC decline. This trial was underpowered for the observed effect size, with about 400 patients required to achieve 90% power. We believe the non-significant numerical differences in the primary and secondary endpoints warrant further study of laparoscopic anti-reflux surgery

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