Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis

Summary

Background

Gastro-oesophageal reflux disease is a potential risk factor for the development and progression of idiopathic pulmonary fibrosis (IPF). We aimed to investigate the effect of antacid therapy on disease progression in patients randomly assigned to placebo through analysis of three large, phase 3 trials of pirfenidone in IPF.

Methods

Patients with IPF from the placebo groups of three trials of pirfenidone (CAPACITY 004, CAPACITY 006, and ASCEND) were included in this post-hoc analysis. We analysed effects of antacid therapy use from baseline for pulmonary function, exercise tolerance, survival, hospital admission, and adverse events for 52 weeks with and without adjustment for potential confounders. The primary endpoint, disease progression by 1 year, was defined as a decrease in predicted forced vital capacity (FVC) by 10% or more, a decrease in 6 min walk distance (6MWD) by 50 m or more, or death. We did survival analyses with the Kaplan-Meier estimator and evaluated using the log-rank test.

Findings

Of 624 patients, 291 (47%) received antacid therapy and 333 (53%) did not. At 52 weeks, we noted no significant difference between groups for disease progression (114 [39%] for antacid therapy vs 141 [42%] for no antacid therapy, p=0·4844). Rates also did not differ for all-cause mortality (20 [7%] vs 22 [7%], p=0·8947), IPF-related mortality (11 [4%] vs 17 [5%]; p=0·4251), absolute FVC decrease by 10% or more (49 [17%] vs 64 [19%]; p=0·4411), or mean observed change in FVC (% predicted −4·9% [SD 6·4] vs −5·5% [7·2], p=0·3355; observed volume −0·2 L [0·3] vs −0·2 L [0·3], p=0·4238). The rate of hospital admission was non-significantly higher in the antacid therapy group (65 [22%] vs 54 [16%]; p=0·0522). When stratified by baseline FVC (<70% or ≥70%), disease progression, mortality, FVC, 6MWD, and hospital admission did not differ between groups. Adverse events were similar between treatment and no treatment groups; however, overall infections (107 [74%] vs 101 [62%]; p=0·0174) and pulmonary infections (20 [14%] vs 10 [6%]; p=0·0214) were higher in patients with advanced IPF (ie, FVC <70%) who were treated with antacids than not treated with antacids.

Interpretation

Antacid therapy did not improve outcomes in patients with IPF and might potentially be associated with an increased risk of infection in those with advanced disease.

Funding

F Hoffmann-La Roche.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, and progressive lung disease of unknown cause with a median survival from the time of diagnosis of 2–3 years.¹ It is characterised by a progressive decrease in lung function, worsening dyspnoea, and diminished exercise tolerance. Two drugs, pirfenidone and nintedanib, are approved for the treatment of the disorder; both have shown significant slowing of disease progression compared with placebo.2, 3, 4

Gastro-oesophageal reflux disease is prevalent in 10–20% of people living in high-income countries and its symptoms include heartburn, dyspepsia, regurgitation, and chest pain.⁵ Diagnosis can be established by a combination of symptoms, endoscopy testing, ambulatory reflux monitoring, and response to antacid therapy. Recommended treatments include lifestyle interventions—such as weight loss, head-of-bed elevation, tobacco and alcohol cessation, avoidance of late-night meals, and cessation of foods that can potentially aggravate reflux symptoms—and the use of antacids with histamine H2-receptor antagonists (H2 blockers) or proton-pump inhibitors.⁵

The incidence of gastro-oesophageal reflux disease in patients with IPF is higher than that in the general population, and it has been reported to range between 8% and 87%;6, 7, 8, 9 variations in incidence might depend on the method of diagnosis used—such as patient-reported symptoms, physician reports, or pH probe testing—and the variability between sites in the collection and reporting of information. The increased incidence of the disease in patients with IPF could be due to shared risk factors for these disorders, including age and smoking.¹⁰ Additionally, the increased recoil of the fibrotic lung could dilate the lower oesophageal sphincter and potentially increase reflux. Gastro-oesophageal reflux disease might also have an important role in the development and progression of IPF, including acute exacerbations.11, 12 In fact, gastro-oesophageal reflux disease is a risk factor for microaspiration, which might cause repeated lung injury and worsening of IPF. Antacid therapy might decrease the risk for acidic microaspiration-associated lung injury or damage.13, 14, 15

Research in context

Evidence before this study

We searched PubMed for studies published before Jan 25, 2016, with no language restrictions, using the search terms “antacid therapy”, “proton pump inhibitors”, “gastroesophageal reflux”, and “idiopathic pulmonary fibrosis”. In the recently updated 2015 ATS/ERS/JRS/ALAT guidelines on treatment of idiopathic pulmonary fibrosis (IPF), antacid therapy has been given a conditional recommendation for use. This recommendation, which is unchanged from the 2011 guideline document, is based on observational and retrospective studies and post-hoc analysis of patients randomly assigned to placebo in clinical trials of pharmacological interventions, the results of which suggested that patients given antacid therapy had slower disease progression as assessed by decrease in forced vital capacity and improved survival compared with patients not receiving antacid therapy.

Added value of this study

By contrast with previous reports, in this study, which analysed patients randomly assigned to placebo in three large clinical trials of pirfenidone, antacid therapy was not associated with a slower disease progression in IPF. Additionally, in patients with advanced disease (eg, with a forced vital capacity of less than 70%) antacid therapy was associated with a significantly higher incidence of pulmonary and non-pulmonary infections.

Implications of all the available evidence

Although clinicians might reasonably offer antacid therapy to patients with IPF with symptomatic gastro-oesophageal reflux, our data do not support a previously reported benefit of antacid therapy in patients with IPF. Present guidelines give a conditional recommendation for use of antacid therapy in patients with IPF, but overall, the available evidence is inconsistent. Long-term, randomised, placebo-controlled studies are needed to investigate the effect of antacid therapy in patients with IPF, particularly those with advanced disease.

Present guidelines for treatment of IPF give a conditional recommendation for the use of antacid therapy in patients with the disorder, albeit with very low confidence in estimates of effect¹⁶ because data on antacid therapy's effect on outcomes in the disorder are limited. However, a retrospective analysis¹¹ of patients with IPF reported that gastro-oesophageal reflux disease-related treatment, especially antacid therapy, was associated with less radiological fibrosis and was an independent predictor of increased survival time. An additional study¹⁷ reported on the outcome of patients with IPF randomly assigned to placebo in three National Heart, Lung, and Blood Institute IPF Clinical Research Network (IPFnet)-sponsored randomised controlled trials. After adjusting for sex and pulmonary function, patients who received antacid therapy had significantly less deterioration of pulmonary function than those not being treated.

The objective of this study was to further investigate the effect of antacid therapy on the composite endpoint of disease progression in patients randomly assigned to placebo in three large, phase 3 trials of pirfenidone in IPF.