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Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials

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Summary

Background

Abnormal acid gastro-oesophageal reflux is common in patients with idiopathic pulmonary fibrosis (IPF) and is considered a risk factor for development of IPF. Retrospective studies have shown improved outcomes in patients given anti-acid treatment. The aim of this study was to investigate the association between anti-acid treatment and disease progression in IPF.

Methods

In an analysis of data from three randomised controlled trials, we identified patients with IPF assigned to receive placebo. Case report forms had been designed to prospectively obtain data about diagnosis and treatment of abnormal acid gastro-oesophageal reflux in each trial. The primary outcome was estimated change in forced vital capacity (FVC) at 30 weeks (mean follow-up) in patients who were and were not using a proton-pump inhibitor or histamine-receptor-2 (H2) blocker.

Findings

Of the 242 patients randomly assigned to the placebo groups of the three trials, 124 (51%) were taking a proton-pump inhibitor or H2 blocker at enrolment. After adjustment for sex, baseline FVC as a percentage of predicted, and baseline diffusing capacity of the lung for carbon monoxide as a percentage of predicted, patients taking anti-acid treatment at baseline had a smaller decrease in FVC at 30 weeks (–0·06 L, 95% CI −0·11 to −0·01) than did those not taking anti-acid treatment (–0·12 L, −0·17 to −0·08; difference 0·07 L, 95% CI 0–0·14; p=0·05).

Interpretation

Anti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression. Controlled clinical trials of anti-acid treatments are now needed.

Funding

National Institutes of Health.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease of unknown cause. Median survival after diagnosis is 2–3 years.1, 2 Several treatments have been studied, but no treatment has been proven to affect clinically meaningful outcomes.3, 4, 5, 6, 7, 8 Evidence-based guidelines for the management of IPF published in 2011 recommended against routine use of all known pharmacological agents.2

Abnormal acid gastro-oesophageal reflux (diagnosed and differentiated from normal gastro-oesophageal reflux through 24-h pH monitoring) is common in patients with IPF9, 10, 11 and is deemed to be a risk factor for development of the disease.1 Data suggest that medical and surgical treatment of abnormal acid gastro-oesophageal reflux in patients with IPF might be beneficial, presumably because acidity and frequency of microaspiration are reduced.2, 12 Small case series have shown long-term stabilisation of forced vital capacity (FVC) and oxygenation in patients with IPF and documented abnormal acid gastro-oesophageal reflux who are treated with drugs or undergo surgery, or both.13, 14 Additional studies have established that pepsin is present in the bronchoalveolar lavage fluid of patients with acute exacerbation of IPF, suggesting that microaspiration of gastric contents as a result of gastro-oesophageal reflux has a role in this important clinical event.15 Most recently, a two-centre retrospective cohort study showed that self-reported use of anti-acid treatment at time of diagnosis (predominantly proton-pump inhibitors [PPIs]) was associated with significantly increased survival time.16 Thus, increasing evidence supports a role for abnormal acid gastro-oesophageal reflux and microaspiration in the pathogenesis and progression of IPF.12

The aim of this study was to establish the association between routine use of anti-acid treatment (PPIs or histamine-receptor-2 [H2] blockers, or both) and disease progression with use of prospective data from the placebo groups of three randomised clinical trials from the Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet).3, 4, 5 Our hypothesis was that individuals who used anti-acid treatment would have slower disease progression and fewer clinically meaningful events than would those who did not use this treatment.

Section snippets

Study participants

In an analysis of data from three randomised controlled trials, we identified patients with IPF in the placebo groups of three studies: Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis (STEP-IPF),3 Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF),4 and Prednisone, Azathioprine, and N-Acetylcysteine: A Study That Evaluates Response in Idiopathic Pulmonary Fibrosis (PANTHER-IPF).5 Patients were enrolled into the trials between Sept 7, 2007, and Oct

Results

480 patients with IPF were enrolled into the three clinical trials (figure 1). Of the 242 patients randomly assigned to the placebo groups, 124 (51%) were taking either a PPI (n=113) or H2 blocker (n=11) at enrolment (figure 1). No patients were taking both a PPI and H2B. We recorded no significant differences in demographics, measures of disease severity, and self-reported outcome measures between patients taking and those not taking a PPI or H2 blocker (table 1). More patients taking a PPI or

Discussion

We have shown that FVC decreases more slowly in patients with well defined IPF who are taking a PPI or H2 blocker than in those who are not. A decrease in FVC has been correlated with reduced survival time in IPF,18, 19, 20, 21 and is used as a measure of disease progression.2 Therefore, our findings suggest that anti-acid treatment might be beneficial in patients with IPF and support the hypothesis that abnormal acid gastro-oesophageal reflux is important in IPF disease progression.22

The

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