Sildenafil Improves Walk Distance in Idiopathic Pulmonary Fibrosis

doi:10.1378/chest.06-2101

Chest

Volume 131, Issue 3, March 2007, Pages 897-899

https://doi.org/10.1378/chest.06-2101 Get rights and content

Abstract

Pulmonary hypertension is a common finding in patients with idiopathic pulmonary fibrosis (IPF), and is associated with increased morbidity and mortality. Therapy with sildenafil has been shown to decrease pulmonary vascular resistance in patients with pulmonary fibrosis and may improve functional status. Patients with IPF and documented pulmonary hypertension were followed up in an open-label study of sildenafil. The 6-min walk test distance (6MWD) was obtained before and after 3 months of sildenafil therapy. Fourteen patients were followed up in the study; 11 patients completed both 6-min walk tests. The mean improvement in walk distance was 49.0 m (90% confidence interval, 17.5 to 84.0 m). When all 14 patients were dichotomized into groups of “responders” (ie, ≥ 20% improvement in 6MWD) or “nonresponders” (ie, < 20% change or unable to complete), 57% were classified as responders. Sildenafil is a promising and well-tolerated therapeutic agent for use in patients with IPF and pulmonary hypertension, and should be studied in a large, well-controlled trial.

Section snippets

Materials and Methods

All patients were transitioned into this open-label study from a randomized trial of sildenafil at the University of California Los Angeles (ClinicalTrials.gov identifier: NCT00352482). Written informed consent was obtained from each patient. Patients had an established diagnosis of IPF, determined according to accepted criteria,⁸and evidence of pulmonary hypertension defined by either (1) a mean pulmonary artery (PA) pressure of ≥ 25 mm Hg on right-heart catheterization (n = 10), or (2) a PA

Results

Fourteen patients were enrolled in the open-label study (Table 1). Eleven patients successfully completed both the baseline and follow-up 6MWTs. The median time between initial and follow-up testing was 91 days.

Individual walk data on all 14 patients are presented inTable 2. Nine patients showed improvement in their 6MWD; only two patients showed a decline. The mean improvement in the 6MWD among those completing both walk tests (n = 11) was 49.0 m (90% confidence interval, 17.5 to 84.0 m). When

Discussion

Historical data suggest the majority of patients with IPF have PAH. PAH at rest (ie, a mean PA pressure of > 20 mm Hg on right-heart catheterization) was reported in 55% of patients with IPF.¹¹In that cohort, 80% of IPF patients had PAH with exercise (mean PA pressure > 30 mm Hg). Pre-lung transplantation evaluations have corroborated these early findings.3, 4Importantly, the presence of PAH in patients with IPF is a predictor of worse survival.4, 5, 6

This study demonstrates significant

References (16)

CJ Lettieri et al.
Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis
Chest
(2006)
HF Nadrous et al.
The impact of pulmonary hypertension on survival in patients with idiopathic pulmonary fibrosis
Chest
(2005)
HA Ghofrani et al.
Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial
Lancet
(2002)
BP Madden et al.
A potential role for sildenafil in the management of pulmonary hypertension in patients with parenchymal lung disease
Vascul Pharmacol
(2006)
CJ Lettieri et al.
The distance-saturation product predicts mortality in idiopathic pulmonary fibrosis
Respir Med
(2006)
JA Bjoraker et al.
Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis
Am J Respir Crit Care Med
(1998)
AG Nicholson et al.
The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis
Am J Respir Crit Care Med
(2000)
SM Arcasoy et al.
Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease
Am J Respir Crit Care Med
(2003)

There are more references available in the full text version of this article.

Cited by (218)

French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis – 2021 update. Full-length version
2023, Respiratory Medicine and Research
Since the latest 2017 French guidelines, knowledge about idiopathic pulmonary fibrosis has evolved considerably.
Practical guidelines were drafted on the initiative of the Coordinating Reference Center for Rare Pulmonary Diseases, led by the French Language Pulmonology Society (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of the entire OrphaLung network, pulmonologists practicing in various settings, radiologists, pathologists, a general practitioner, a health manager, and a patient association. The method followed the "Clinical Practice Guidelines" process of the French National Authority for Health (HAS), including an online vote using a Likert scale.
After a literature review, 54 guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease: epidemiology, diagnostic procedures, quality criteria and interpretation of chest CT scans, lung biopsy indication and procedures, etiological workup, methods and indications for family screening and genetic testing, assessment of the functional impairment and prognosis, indication and use of antifibrotic agents, lung transplantation, management of symptoms, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis.
These evidence-based guidelines are intended to guide the diagnosis and practical management of idiopathic pulmonary fibrosis.
French practical guidelines for the diagnosis and management of IPF – 2021 update, full version
2022, Revue des Maladies Respiratoires
Depuis les précédentes recommandations françaises publiées en 2017, les connaissances concernant la fibrose pulmonaire idiopathique ont évolué sur de nombreux aspects.
Des recommandations pratiques ont été établies à l’initiative du Centre coordonnateur de référence des maladies pulmonaires rares, sous l’égide de la Société de Pneumologie de Langue Française, par un groupe de coordination, un groupe de rédaction, et un groupe de lecture, impliquant l’ensemble du réseau OrphaLung, des pneumologues de divers modes d’exercice, des radiologues, des pathologistes, un médecin généraliste, un cadre de santé, et une association de patients. La méthode a respecté les règles d’élaboration des « Bonnes pratiques cliniques » selon la méthode des « Recommandations pour la pratique clinique » de la Haute Autorité de Santé, incluant un vote en ligne selon une échelle Likert.
Après une analyse bibliographique, 54 recommandations ont été formulées, améliorées, puis validées par les groupes de travail, portant sur des aspects multiples de la maladie : épidémiologie, modalités diagnostiques, critères de qualité et interprétation du scanner thoracique, indication et réalisation de la biopsie pulmonaire, bilan étiologique, modalités et indications de l’enquête familiale et de l’analyse génétique, évaluation du retentissement fonctionnel et du pronostic, indication et emploi des médicaments antifibrosants, transplantation pulmonaire, prise en charge des symptômes, comorbidités et complications, traitement de l’insuffisance respiratoire chronique, diagnostic et prise en charge des exacerbations aiguës de fibrose.
Ces recommandations fondées sur les preuves sont destinées à guider le diagnostic et la prise en charge pratique de la fibrose pulmonaire idiopathique.
Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated.
Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients’ association. The method was developed according to rules entitled “Good clinical practice” in the overall framework of the “Guidelines for clinical practice” of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale.
After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis.
These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.
Treatment of fibrotic interstitial lung disease: current approaches and future directions
2021, The Lancet
Fibrotic interstitial lung disease (ILD) represents a large group of pulmonary disorders that are often progressive and associated with high morbidity and early mortality. Important advancements in the past 10 years have enabled a better understanding, characterisation, and treatment of these diseases. This Series paper summarises the current approach to treatment of fibrotic ILDs, both pharmacological and non-pharmacological, including recent discoveries and practice-changing clinical trials. We further outline controversies and challenges, with discussion of evolving concepts and future research directions.
Group 3 PH: Clinical Features and Treatment
2021, Encyclopedia of Respiratory Medicine, Second Edition
Group 3 pulmonary hypertension (PH) is a broad category of PH caused by chronic lung diseases (CLD) including chronic obstructive pulmonary disease (COPD), diffuse parenchymal lung diseases (DPLD), sleep disordered breathing, chronic exposure to high altitudes and developmental abnormalities. It is the second most common type after group 2 PH which is secondary to left heart disease or pulmonary venous hypertension. Clinical features of group 3 PH are often difficult to discern from the signs and symptoms of the primary lung disease and most of the time, symptoms out of proportion to the severity of lung disease prompts evaluation for group 3 PH. In most patients with group 3 PH, the mean pulmonary artery pressure (mPAP) is usually mildly elevated. However, it is invariably associated with reduced functional ability, impaired quality of life, greater oxygen requirements and an increased risk of mortality. Transthoracic echocardiography is the best screening test to evaluate for underlying PH. Right heart catheterization (RHC) is the gold standard test for confirmation and is performed when significant PH is suspected and the patient’s management will likely be influenced by the RHC results. Treatment of group 3 PH can be divided into four major categories- primary, adjunctive, PH-specific and treatment of refractory disease. Treatment of the primary lung disease is the most important aspect but supportive therapy including supplemental oxygen and pulmonary rehabilitation are also very essential. The role of pulmonary vasodilators in group 3 PH is still unclear and large, randomized controlled trials are in dire need.
Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial
2021, The Lancet Respiratory Medicine
The benefit of sildenafil in patients with advanced idiopathic pulmonary fibrosis (IPF) at risk of poor outcomes from pulmonary hypertension, whether already present or likely to develop, is uncertain. We aimed to assess the efficacy and safety of sildenafil added to pirfenidone versus placebo added to pirfenidone for 52 weeks in patients with advanced IPF and at risk of group 3 pulmonary hypertension.
We did a multicentre, international, double-blind, randomised, placebo-controlled, phase 2b study at 56 university clinics, research hospitals, and tertiary sites in Canada, Europe (Belgium, Czech Republic, Germany, Greece, Hungary, Italy, the Netherlands, Spain, and Turkey), Israel, and Africa (Egypt and South Africa). Eligible patients (aged 40–80 years) had advanced IPF (carbon monoxide diffusing capacity ≤40% predicted at screening), and were at risk of group 3 pulmonary hypertension (mean pulmonary artery pressure of ≥20 mm Hg with pulmonary artery wedge pressure of ≤15 mm Hg on previous right-heart catheterisation, or intermediate or high probability of group 3 pulmonary hypertension on echocardiography as defined by the 2015 European Society of Cardiology and European Respiratory Society guidelines). Patients were randomly assigned 1:1 to oral sildenafil tablets (20 mg three times daily) or placebo, both in addition to oral pirfenidone capsules (801 mg three times daily), using a validated interactive voice-based or web-based response system with permuted block randomisation, stratified by previous right-heart catheterisation (yes or no) and forced expiratory volume in 1 s to forced vital capacity ratio (<0·8 or ≥0·8). The composite primary endpoint was disease progression, defined as either a relevant decline in 6-min walk distance, respiratory-related admission to hospital, or all-cause mortality, after 52 weeks and was assessed in the intention-to-treat population; safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02951429, and is no longer recruiting. The 11-month safety follow-up is ongoing.
Between Jan 13, 2017, and Aug 30, 2018, 247 patients were screened for eligibility, 177 of whom were randomly assigned to a treatment group (n=88 sildenafil; n=89 placebo) and were assessed for the primary outcome. There was no difference in the proportion of patients with disease progression over 52 weeks between the sildenafil (64 [73%] of 88 patients) and placebo groups (62 [70%] of 89 patients; between-group difference 3·06% [95% CI −11·30 to 17·97]; p=0·65). Serious treatment-emergent adverse events were reported in 54 (61%) patients in the sildenafil group and 55 (62%) patients in the placebo group. Treatment-emergent adverse events leading to mortality occurred in 22 (25%) patients in the sildenafil group and 26 (29%) in the placebo group.
Addition of sildenafil to pirfenidone did not provide a treatment benefit versus pirfenidone plus placebo up to 52 weeks in patients with advanced IPF and risk of pulmonary hypertension. No new safety signals were identified with either treatment. Although the absence of a beneficial treatment effect suggests that sildenafil is not an appropriate treatment in the overall population, further research is required to establish if specific subgroups of patients with IPF might benefit from sildenafil.
F Hoffmann-La Roche.
The Trouble With Group 3 Pulmonary Hypertension in Interstitial Lung Disease: Dilemmas in Diagnosis and the Conundrum of Treatment
2020, Chest
Pulmonary hypertension (PH) due to interstitial lung disease (ILD; PH-ILD) can complicate a multitude of ILDs, including idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis, and nonspecific interstitial pneumonia. Development of PH-ILD is associated with increased need for supplemental oxygen, reduced mobility, and decreased survival. A high index of suspicion is required to make the diagnosis, given the substantial overlap in symptoms with those of ILD without PH. Severely reduced diffusing capacity or 6-min walk test distance, prominent exertional desaturation, and impaired heart rate recovery after exercise are all suggestive of the development of PH-ILD. Traditional transthoracic echocardiography is the most commonly used screening test for PH-ILD, but it lacks sensitivity and specificity. Newer echocardiographic tools involving 3-dimensional assessment of the right ventricle may have a role in both prognosis and the monitoring of patients with PH-ILD. Right-sided heart catheterization remains the gold standard for confirming a diagnosis of PH-ILD. Although there is little debate about the use of supplemental oxygen and diuretic therapy in the treatment of PH-ILD, treatment with pulmonary vasodilator therapy remains controversial. Although several studies have been terminated prematurely for harm, the recently completed INCREASE trial of inhaled treprostinil appears to validate the concept of treating PH-ILD with pulmonary vasodilators and, we hope, will serve as a foundation from which future studies can be developed.

View all citing articles on Scopus

Support was provided by National Institutes of Health grants 5U10HL080411 and 5P50HL67665 (Dr. Zisman).

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

View full text

Chest

Selected ReportsSildenafil Improves Walk Distance in Idiopathic Pulmonary Fibrosis

Abstract

Section snippets

Materials and Methods

Results

Discussion

Chest

Chest

Lancet

Vascul Pharmacol

Respir Med

Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis

Am J Respir Crit Care Med

The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis

Am J Respir Crit Care Med

Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease

Am J Respir Crit Care Med

Selected Reports
Sildenafil Improves Walk Distance in Idiopathic Pulmonary Fibrosis