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AMERICAN THORACIC SOCIETYDOCUMENTS

An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatmentof Idiopathic Pulmonary FibrosisAn Update of the 2011 Clinical Practice GuidelineGanesh Raghu, Bram Rochwerg, Yuan Zhang, Carlos A. Cuello Garcia, Arata Azuma, Juergen Behr, Jan L. Brozek,Harold R. Collard, William Cunningham*, Sakae Homma, Takeshi Johkoh, Fernando J. Martinez, Jeffrey Myers,Shandra L. Protzko, Luca Richeldi, David Rind, Moises Selman, Arthur Theodore, Athol U. Wells, Henk Hoogsteden,and Holger J. Schunemann; on behalf of the ATS, ERS, JRS, and ALAT

This guideline is dedicated to the memory of Mr. William Cunningham (June 7, 1935–October 23, 2014)

THIS oFFICIAL CLINICAL PRACTICE GUIDELINE OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS, MAY 2015, THE EUROPEAN RESPIRATORY

SOCIETY (ERS), APRIL 2015, THE JAPANESE RESPIRATORY SOCIETY (JRS), APRIL 2015, AND THE LATIN AMERICAN THORACIC ASSOCIATION (ALAT), APRIL 2015

Background: This document updates the AmericanThoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American ThoracicAssociation guideline on idiopathic pulmonary fibrosistreatment.

Methods: Systematic reviews and, when appropriate, meta-analyseswere performed to summarize all available evidence pertinent to ourquestions. The evidence was assessed using the GRADE (Grading ofRecommendations, Assessment, Development and Evaluation)approach and then discussed by a multidisciplinary panel.Predetermined conflict-of-interest management strategies were

applied, and recommendations were formulated, written, and gradedexclusively by the nonconflicted panelists.

Results: After considering the confidence in effect estimates, theimportance of outcomes studied, desirable and undesirableconsequences of treatment, cost, feasibility, acceptability of theintervention, and implications to health equity, recommendationswere made for or against specific treatment interventions.

Conclusions: The panel formulated and provided the rationale forrecommendations in favor of or against treatment interventions foridiopathic pulmonary fibrosis.

ContentsOverviewIntroductionMethods

Committee CompositionConfidentiality Agreement andConflict-of-InterestManagement

MeetingsFormulating ClinicalQuestions

Literature Search

Evidence Review andDevelopment of ClinicalRecommendations

Manuscript PreparationRecommendations for SpecificTreatment Questions

Question 1: Should Patientswith IPF Be Treated withAnticoagulation?

Question 2: Should Patients withIPF Be Treated with Imatinib,a Tyrosine Kinase Inhibitor?

Question 3: Should Patientswith IPF Be Treated withCombination Prednisone,Azathioprine, andN-Acetylcysteine?

Question 4: Should Patients withIPFBeTreatedwithAmbrisentan,a Selective ER-A EndothelinReceptor Antagonist?

Question 5: Should Patients withIPF Be Treatedwith Nintedanib,a Tyrosine Kinase Inhibitor?

*Mr. William Cunningham’s active participation in the development of this guideline and his invaluable input were greatly appreciated and respected by theentire committee. Mr. Cunningham, having suffered from idiopathic pulmonary fibrosis for many years, was confronted directly with the issues related tomanaging the condition. The authors strongly believe that his objective, balanced, and in-depth participation as a patient strengthens the guideline’ssignificance and applicability.

An Executive Summary of this document is available at http://www.atsjournals.org/doi/suppl/10.1164/rccm.201506-1063ST

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 192, Iss 2, pp e3–e19, Jul 15, 2015

Copyright © 2015 by the American Thoracic Society

DOI: 10.1164/rccm.201506-1063ST

Internet address: www.atsjournals.org

American Thoracic Society Documents e3

http://www.atsjournals.org/doi/suppl/10.1164/rccm.201506-1063ST

http://www.atsjournals.org

http://10.1164/rccm.201506-1063ST

http://www.atsjournals.org

Question 6: Should Patients withIPF Be Treated withPirfenidone?

Question 7: Should Patients withIPF Be Treated with AntiacidMedication?

Question 8: Should Patients withIPF Be Treated with Sildenafil,a Phosphodiesterase-5Inhibitor?

Question 9: Should Patients withIPF Be Treated with Bosentanor Macitentan, Dual ERAs(ER-A and ER-B)?

Question 10: Should Patientswith IPF Be Treated withN-Acetylcysteine Monotherapy?

Question 11: Should Patientswith IPF Be Treated withBilateral Lung Transplantationversus Single-LungTransplantation?

Question 12: Should PH BeTreated in Patients with IPF?

ConclusionsFuture DirectionsEditor’s Note

Overview

The purpose of this guideline is to analyzeevidence reported since publication of theprior guideline in 2011 and to update thetreatment recommendations accordingly.The guideline should empower clinicians tointerpret these recommendations in thecontext of individual patient values andpreferences and to make appropriate clinical

decisions about treatment of patients withidiopathic pulmonary fibrosis (IPF). For eachrecommendation, it is important to considerboth the summary of evidence reviewed anddiscussed by the nonconflicted members ofthe committee and remarks for each specifictreatment question, including the valuesand preferences, before applying theserecommendations to specific clinicalsituations or policy decisions.

Clinicians, patients, third-party payers,and other stakeholders should never viewthese recommendations as dictates. Noguideline or recommendations can take intoaccount all of the often compelling uniqueindividual clinical circumstances. Therefore,no one charged with evaluating clinicians’actions should attempt to apply therecommendations from this guideline byrote or in a blanket fashion. Theimplications of the strength of therecommendation for various stakeholdersare described in Table 1.

This guideline does not providerecommendations for one treatmentregimen over another. With the exception ofthe recommendation against usingprednisone with azathioprine and N-acetylcysteine, the guideline does notprovide suggestions for or againstcombination regimens or sequentialtherapies. Therefore, the strong orconditional rating for eachrecommendation must be weighedindividually (i.e., two recommendationswith the same strong or conditional ratingshould not by default be consideredequivalent recommendations), factoring inall components used to determine the gradeof the recommendation, including theconfidence in effect estimates, outcomes

studies, desirable and undesirableconsequences of treatment, cost oftreatment, implications of treatment onhealth equity, and feasibility of treatment.The methods used by guideline panels toappraise the evidence are different thanthose used by regulatory agencies whenthey review applications seeking marketapproval for the use of pharmacologicagents for treatment of IPF.

The following recommendations arenew or revised from the 2011 guideline, asshown in Table 2:

1. The recommendation against the useof the following agents for thetreatment of IPF is strong:a. Anticoagulation (warfarin) (⊕⊕⊝⊝,

low confidence in effect estimates).b. Imatinib, a selective tyrosine

kinase inhibitor against platelet-derived growth factor (PDGF)receptors (⊕⊕⊕⊝, moderateconfidence in effect estimates).

c. Combination prednisone,azathioprine, and N-acetylcysteine(⊕⊕⊝⊝, low confidence in effectestimates).

d. Selective endothelin receptorantagonist (ambrisentan) (⊕⊕⊝⊝,low confidence in effect estimates).

2. The recommendation for the use of thefollowing agents for the treatment ofIPF is conditional:a. Nintedanib, a tyrosine kinase

inhibitor that targets multipletyrosine kinases, including vascularendothelial growth factor, fibroblastgrowth factor, and PDGF receptors(⊕⊕⊕⊝, moderate confidence ineffect estimates).

Table 1. Interpretation of Strong and Conditional Recommendations for Stakeholders (Patients, Clinicians, and Health Care PolicyMakers)

Implications for: Strong Recommendation Conditional Recommendation

Patients Most individuals in this situation would want therecommended course of action, and only a smallproportion would not.

The majority of individuals in this situation would want thesuggested course of action, but many would not.

Clinicians Most individuals should receive the intervention.Adherence to this recommendation according to theguideline could be used as a quality criterion orperformance indicator. Formal decision aids are notlikely to be needed to help individuals make decisionsconsistent with their values and preferences.

Recognize that different choices will be appropriate forindividual patients and that you must help each patientarrive at a management decision consistent with his orher values and preferences. Decision aids may beuseful in helping individuals to make decisionsconsistent with their values and preferences.

Policy makers The recommendation can be adopted as policy in mostsituations.

Policy making will require substantial debate andinvolvement of various stakeholders.

AMERICAN THORACIC SOCIETY DOCUMENTS

e4 American Journal of Respiratory and Critical Care Medicine Volume 192 Number 2 | July 15 2015

b. Pirfenidone (⊕⊕⊕⊝, moderateconfidence in effect estimates).

3. The recommendation against the useof the following agents for thetreatment of IPF is conditional:a. Phosphodiesterase-5 inhibitor

(sildenafil) (⊕⊕⊕⊝, moderateconfidence in effect estimates).

b. Dual endothelin receptor antagonists(macitentan, bosentan) (⊕⊕⊝⊝, lowconfidence in effect estimates).

The following recommendations areunchanged from the 2011 guideline(Table 2):

1. Updated evidence syntheses related toN-acetylcysteine monotherapy andantiacid therapy were presented to thepanel, and both recommendations wereleft unchanged from the 2011 guideline(a conditional recommendation againstN-acetylcysteine monotherapy based onlow confidence in effect estimate anda conditional recommendation forantiacid therapy based on very lowconfidence in effect estimate).

2. An updated evidence synthesis relatedto the treatment of pulmonaryhypertension associated with IPF wasalso presented to the panel, butdecisions regarding modifying the

recommendation from the 2011guideline were deferred until the nextupdate.

3. Recommendations for multiple otherinterventions that were addressed in the2011 guideline (e.g., treatment of acuteexacerbation of IPF with corticosteroids,oxygen supplementation, mechanicalventilation, pulmonary rehabilitation,and lung transplantation in general)were not prioritized for an update in thisguidelineAn evidence synthesis was also

performed for a new question about singleversus bilateral lung transplantation, butdecisions regarding a recommendation weredeferred until the next version of theguideline to gather additional informationthat was felt necessary before formulatinga recommendation. Questions regardingnewer treatments (e.g., antibiotics) were notaddressed and were deferred until the nextversion of the guideline because of resourceconstraints.

Introduction

IPF is a specific form of chronic, progressivefibrosing interstitial pneumonia of unknowncause occurring in adults. Radiologic

and/or histopathologic patterns areconsistent with usual interstitial pneumonia(1). Although the first guideline onmanagement of IPF, published in 2000,was based on the consensus of a group ofinternational experts in the field (2), the2011 guideline represented a rigorous jointeffort by the American Thoracic Society(ATS), European Respiratory Society (ERS),Japanese Respiratory Society (JRS), andLatin American Thoracic Society (ALAT).It reviewed all available evidence, clarifiedthe definition of IPF, provided precisediagnostic criteria, described the naturalcourse of the disease, and providedevidence-based recommendations fortreatment (3). The 2011 guideline alsostated that updates would be providedbased on pertinent new evidence. Althoughthe 2011 guideline provided clearrecommendations for several specifictreatment regimens, new, importantevidence for the treatment of IPF hasbecome available since 2011.

This document updates the treatmentguideline with the reappraisal of previouslyassessed treatment options and newrecommendations for novel agents.Evidence surrounding the clinicalmanagement of IPF is rapidly evolving, and

Table 2. Comparison of Recommendations in the 2015 and 2011 Idiopathic Pulmonary Fibrosis Guidelines

Agent 2015 Guideline 2011 Guideline

New and revised recommendationsAnticoagulation (warfarin) Strong recommendation against use* Conditional recommendation against use‡

Combination prednisone 1 azathioprine 1N-acetylcysteine

Strong recommendation against use† Conditional recommendation against use†

Selective endothelin receptor antagonist(ambrisentan)

Strong recommendation against use† Not addressed

Imatinib, a tyrosine kinase inhibitor withone target

Strong recommendation against use* Not addressed

Nintedanib, a tyrosine kinase inhibitorwith multiple targets

Conditional recommendation for use* Not addressed

Pirfenidone Conditional recommendation for use* Conditional recommendation against use†

Dual endothelin receptor antagonists(macitentan, bosentan)

Conditional recommendation against use† Strong recommendation against use*

Phosphodiesterase-5 inhibitor (Sildenafil) Conditional recommendation against use* Not addressedUnchanged recommendationsAntiacid therapy Conditional recommendation for use‡ Conditional recommendation for use‡

N-acetylcysteine monotherapy Conditional recommendation against use† Conditional recommendation against use†

Antipulmonary hypertension therapy foridiopathic pulmonary fibrosis-associatedpulmonary hypertension

Reassessment of the previousrecommendation was deferred

Conditional recommendation against use‡

Lung transplantation: single vs. bilaterallung transplantation

Formulation of a recommendation forsingle vs. bilateral lung transplantationwas deferred

Not addressed

*⊕⊕⊕⊝, moderate confidence in effect estimates.†⊕⊕⊝⊝, low confidence in effect estimates.‡⊕⊝⊝⊝, very low confidence in effect estimates.



it is intended that future iterations of the2011 guideline dealing with questionsrelated to diagnosis, genetics, and other newquestions will be made available promptly.The ultimate goal for this guideline is for itto be a “living document,” allowing newevidence to be incorporated as available,with periodic updates to guide clinicalmanagement based on the best availableevidence in a timely manner.

Methods

Committee CompositionThis guideline was developed bya multidisciplinary committee thatconsisted of pulmonologists withrecognized IPF expertise (n = 8; G.R., F.J.M., H.R.C., A.U.W., J.B., L.R., A.A., andM.S.), general pulmonologists (n = 3; A.T.,S.H., and H.H.), a pulmonologist-methodologist (n = 1; H.J.S.), anallergist-methodologist (n = 1; J.L.B.),a general internist (n = 1; D.R.), a chestradiologist (n = 1; T.J.), a pulmonarypathologist (n = 1; J.M.), an informationscientist (n = 1; S.L.P.), and a patient withIPF (n = 1; W.C.), who was recommendedfor participation by the Coalition forPulmonary Fibrosis and was not knownto any of the committee members. Thecommittee was chaired by G.R. and co-chaired by H.J.S. and H.H. Committeemembers represented the ATS, ERS, JRS,and ALAT.

The committee worked with theMethods Group (MG), which comprisedfive health research methodologists (B.R.,C.A.C.G., Y.Z., J.L.B., and H.J.S.) fromthe MacGRADE Centre at McMasterUniversity who had expertise in evidencesynthesis and the guideline developmentprocess. Four of these methodologists arealso clinicians (B.R., J.L.B., C.A.C.G., andH.J.S.). The MG conducted systematicreviews and prepared the systematicevidence summaries following the Gradingof Recommendations, Assessment,Development and Evaluation (GRADE)approach, as described here (4, 5).

Confidentiality Agreement andConflict-of-Interest ManagementCommittee members signeda confidentiality agreement and disclosed allpotential conflicts of interest according tothe ATS and ERS policies. Two of theco-chairs (G.R. and H.J.S.) reviewed all

potential conflicts of interest of committeemembers with the staff of the ATS conflict-of-interest and documents units.

All of the eight pulmonologists withrecognized IPF expertise (G.R., F.J.M.,H.R.C., A.U.W., J.B., L.R., A.A., and M.S.)were considered to either have majorfinancial or intellectual conflicts based ondisclosures or participation in IPF clinicaltrials/studies (6); although they werepermitted to participate in the discussionsof the evidence with the rest of thecommittee, they were instructed toabstain from discussions related tothe evidence to decision framework(described later), formulating andgrading recommendations, and votingon recommendations if necessary. Thisapproach was applied to all questions, notjust those in which they had a perceivedconflict of interest. Conflicted memberswere allowed to stay in the same roomwhile discussions among nonconflictedmembers took place to provide expertinput; however, they could do so only whenspecifically requested by nonconflictedmembers. Adherence to the rules wasstrict, with one of the co-chairs (H.J.S.)responsible for monitoring the discussionsfor adherence to these rules.

The remaining nine nonconflictedcommittee members (A.T., S.H., H.H.,H.J.S., J.L.B., D.R., T.J., J.M., andW.C.) wereallowed unrestricted participation. Two ofthe voting members were members of theMG; they are clinicians with extensiveexpertise in the guideline developmentprocess (H.J.S. and J.L.B.). The rest of theMG and the librarian also participatedin discussions, but were nonvotingparticipants.

MeetingsFace-to-face planning meetings were heldduring the 2013 ATS InternationalConference in Philadelphia, Pennsylvania,at which the committee discussed the scopeand objectives of the project, and during the2014 ATS International Conference in SanDiego, California, to go over the proceedingsof the upcoming face-to-face meeting inJune 2014 in Hamilton, Ontario, Canada(described here). Members who could notattend the actual face-to-face meetingsparticipated in person live by teleconference.Additional planning meetings were heldregularly over telephone between G.R.,H.J.S., and the MG. Conference calls and

email correspondence were used to discussspecific issues requiring input from others.

The entire guideline committee metat theMcMaster Health Forum inHamilton,Ontario, Canada, on June 9–10, 2014, atwhich the evidence summaries werepresented and discussed, and therecommendations were formulated.Three members participated throughteleconference and webinar (H.H., M.S.,and W.C.). The methodologists took notesof all matters and points discussed anddocumented all the recommendations andproceedings.

Two follow-up teleconference webinarswere held on June 23 and July 15, 2014,to complete the guideline developmentfor two of the 12 treatment questions(questions on single versus bilaterallung transplantation and treatment ofIPF-associated pulmonary hypertension[PH]). Three members (A.A., S.H., and T.J.)were not able to participate live during thefirst teleconference-webinar, and fivemembers (A.A., S.H., T.J., M.S., and H.H.)were not able to join the secondteleconference-webinar, but all providedfeedback and discussion via emails. Allmeetings were attended by staff from theATS documents unit.

McMaster University providedmeeting facilities and logistical support,and the sponsoring societies provided thefinancial support for expenses resultingfrom the meeting and conference calls. Theviews and interests of the ATS, ERS, JRS,and ALAT, as well as of any commercialentity that provided external funding forprofessional societies, had no influence onthe topics discussed and recommendationsmade.

Formulating Clinical QuestionsThe committee used the treatment section ofthe 2011 guideline document (3) asa starting point. Twelve specific questionspertinent and relevant to current clinicalpractice were addressed to update therecommendations pertinent to treatmentof IPF. Most of these questions werepreviously addressed, and formalrecommendations had been provided in the2011 document. Questions pertinent to themanagement of patients with IPF withpulmonary rehabilitation, oxygensupplementation, antibiotics, palliative care,mechanical ventilation, and specificquestions that had received a “strongagainst” or “strong for” in the 2011



guideline were not readdressed in thisupdate unless the literature search revealednew and pertinent evidence.

The committee selected outcomes ofinterest for each question, using the 2011document as a guide in addition tofollowing the approach suggested by theGRADE working group (5, 7). Alloutcomes were identified a priori, and thecommittee explicitly rated their relativeimportance (from the perspective ofa patient with IPF) from not important tocritical (7). Ranking outcomes by theirrelative importance helps focus attentionon those that are most relevant to patientsand helps resolve or clarify potentialdisagreements in decision making.Examples of critical outcomes includemortality or disease progression. Diseaseprogression, defined in the 2011 documentas increasing respiratory symptoms,worsening pulmonary function test (PFT)results, progressive fibrosis on high-resolution computed tomography scan,acute respiratory decline, or death, canbe measured using multiple outcomemeasures (3). Changes over time in FVCor diffusing capacity of the lung for carbonmonoxide (DLCO) were considered indirectmeasures of disease progression for thepurpose of this guideline. Rankings ofall outcomes were agreed on throughconsensus of the committee.

Literature SearchIn collaboration with the MG, aninformation scientist (S.L.P.) designeda search strategy using medical subjectheading keywords and text words (seeonline supplement) limited to humanstudies or nonindexed citations and articlesin English or in any language with Englishabstracts. The Ovid platform was used tosearch MEDLINE, EMBASE, CochraneRegistry of Controlled Trials, HealthTechnology Assessment, and the Databaseof Abstracts of Reviews of Affects for May2010 through May 2014. An update wasperformed in June 2014, immediatelybefore the meeting at McMaster University.Reviewers contacted experts and reviewedprevious meta-analyses for additionalarticles. The search retrieved 9,663citations, minus duplicates. On the basis ofpredefined eligibility criteria, 54 citationswere included for full text review, of which34 were excluded with reasons and 20 wereincluded in the evidence update (see onlinesupplement).

Evidence Review and Development ofClinical RecommendationsEvidence summaries for each question wereprepared by the McMaster methodologyteam, following the GRADE approach(4), using the GRADEpro GuidelineDevelopment Tool online software (8).All committee members reviewed thesummaries of evidence, and correctionswere made when appropriate. We based theevidence on the 2011 evidence summariesthat had been produced for that document.These summaries were updated, ifnecessary, with additional recentrandomized controlled trials (RCTs).Committee members were also queriedfor any additional studies not identified bythe search. If adequate outcome data werenot available from RCTs, observationalstudies were also used to supportrecommendations.

Two reviewers from the MG screenedtitles and abstracts to identify articles for fullreview and evaluated the full text of articlesdeemed potentially relevant by eitherreviewer. Disagreement was resolved byconsensus among the MG group. Dataabstraction occurred in duplicate, usingpredesigned data abstraction forms that hadbeen piloted before being used. In additionto clinical data, individual study risk ofbias was assessed independently by bothreviewers, using the Cochrane Risk of Biastool (9) for RCTs and the Ottawa-Newcastle tool (10) for observationalstudies.

Results from identified studies with thesame treatment agent were pooled, andmeta-analyses, using the CochraneCollaboration Review Manager, version 5.2(11), were reviewed. Pooling and meta-analyses of study data were independentlyperformed by the MG specifically for thisguideline document. All data fulfilling thea priori inclusion criteria were included,and pooled analysis presented in thisdocument may at times differ from otherpublished meta-analyses, dependingon inclusion or exclusion criteria.Subsequently, the overall certainty in effectestimates (also known as confidence ineffect estimate) for each outcome of interestwas assessed following the GRADEapproach (12), based on the followingcriteria: risk of bias, precision, consistency,directness of the evidence, risk forpublication bias, presence of dose-effectrelationship, magnitude of effect, and

assessment of the effect of plausible residualconfounding or bias. The confidence ineffect estimates for each outcome wascategorized into one of four levels: high,moderate, low, or very low.

The committee developedrecommendations based on the GRADEevidence profiles for each recommendation.We employed the GRADE evidence todecision frameworks in the guidelinedevelopment tool to help organizediscussion around each recommendationand ensure each of the following factorswas considered in recommendationdevelopment: the quality of the evidence, thebalance of desirable and undesirableconsequences of compared managementoptions, the assumptions about the valuesand preferences associated with thedecision, the implications for resource useand health equity, the acceptability ofintervention to stakeholders, and thefeasibility of implementation (see onlinesupplement). Recommendations and theirstrength were decided by consensus, andonly one recommendation required votingbecause of inability to achieve consensus.The committee agreed on the finalwording of recommendations andremarks with further qualifications foreach recommendation (e.g., subgroupconsiderations, justification, implementationconsiderations).

The recommendations were either“strong” or “conditional,” according to theGRADE approach (13). Conditionalrecommendations are synonymous withweak recommendations. The 2011guideline had used the nomenclature“weak,” but to improve clarity (whichconditions are relevant to implement therecommendation) and facilitate translationof guidelines to other languages, GRADEuses the term “conditional” as analternative. Factors influencing the strengthof the recommendation include thestrength of evidence, the outcomes studiesand associated importance to patients, thedesirable and undesirable consequences oftreatment, the cost of treatment, theimplications of treatment on health equity,the feasibility of treatment, the acceptabilityof treatment to important stakeholders, andpotential treatment monitoring andimplementation issues.

As suggested by GRADE, we used thephrasing “we recommend” for strongrecommendations and “we suggest” forconditional recommendations. Table 1



provides suggested interpretation ofthese recommendations by intendedstakeholders, including patients, clinicians,and health policy makers. For twoquestions, the panel decided to not offera recommendation because it was realizedthat additional evidence, mostly indirectand resource- or cost-related, should beconsidered to fully inform the panel,and we documented this as “norecommendation.”

There are two important aspectsof the recommendations to consider.First, recommendations of similarstrength should not be interpreted asequivalent recommendations. Eachrecommendation’s strength is net resultof considering the multiple factorsdescribed earlier, and therefore theremay be different reasons that tworecommendations are rated with the samestrength (e.g., one recommendation maybe conditional because it is based on verylow confidence in effect estimates, whereasanother recommendation may beconditional because the cost is so high thatit is unclear that the potential benefitsoutweigh those costs for every patient).Second, the methodology used in makingrecommendations for or against the useof therapies in guidelines considersadditional factors than those used byregulatory agencies (whose purpose is toreview data submitted to them andsubsequently consider approval of newtreatments for use in patients).

Manuscript PreparationThe writing committee (B.R., G.R., C.A.C.G.,Y.Z., and H.J.S.) drafted the guidelinedocument. The manuscript was thenreviewed by the entire committee. Feedbackwas provided primarily by electroniccommunication and, to a lesser extent,during a face-to face meeting at the ERSCongress on September 7, 2014, thatincluded some of the committee members(G.R., H.H., B.R., H.R.C., F.J.M., L.R., J.B.,A.U.W., and A.A.).

The entire committee (both conflictedand nonconflicted members) had theopportunity to correct factual errors, clarifythe presentation of backgroundinformation or evidence summaries, andsuggest changes to the rationale sections ifthey improperly captured the discussionfrom the face-to-face meetings. However,only the nonconflicted voting memberswere permitted to comment on the

recommendations. The conflicted chairand conflicted committee memberswere not permitted to comment on therecommendations and restricted theirfeedback to the presentation of theevidence and the identification of errors.The wording of recommendations(including strength and direction) was notaltered once they were finalized by thenonconflicted members during the face-to-face meeting and teleconferences. One of thenonconflicted co-chairs (H.J.S.) confirmedthat the written version of the guidelinereflected the recommendations made by thenonconflicted members. The same processwas followed for each version of thedocument. The final approved version wassubmitted to each cosponsoring professionalsociety for peer review.

Recommendations forSpecific TreatmentQuestions

Please see online supplement, whichincludes supporting evidence profiles foreach recommendation.

Question 1: Should Patients with IPFBe Treated with Anticoagulation?

Background. Studies have suggesteda procoagulant state may be involved inpromoting fibrosis via cell-surfacereceptor–mediated pathways (14, 15),providing biological plausibility fora mechanistic link between thrombosis andlung fibrosis (16, 17). It is less clear whatrole systemic anticoagulants may have inpreventing this effect in patients with IPF.

Summary of the evidence. The 2011guideline included one study, an openrandomized trial that compared oralwarfarin plus prednisolone againstprednisolone alone in 56 patients with IPF(18). Treatment with warfarin led toa reduction in the secondary outcome ofIPF acute exacerbation-associatedmortality. This trial was associated withsignificant methodological concerns,specifically, the lack of a clear descriptionof how randomization or concealment ofallocation was undertaken, the lack ofa description of how patient drop-out wasmanaged, and a failure to excludepulmonary embolus as a potential cause forclinical deterioration. For these reasons, in

addition to the absence of a placebocontrol, it was considered to have a highrisk of bias and was excluded from pooledanalysis in this treatment update.

One RCT published since the 2011guideline randomized 145 patients withIPF to oral warfarin (target internationalnormalized ratio, 2.0–3.0) versus placebocontrol (19). This study was stopped earlyafter a mean follow-up of 28 weeksbecause of a lack of benefit from warfarinand a signal for potential harm withtreatment. Despite a relatively low numberof events, a significant increase inmortality was seen with warfarin atinterim analysis (relative risk [RR], 4.73;95% confidence interval [CI], 1.42–15.77;low confidence), although this was notassociated with bleeding complications.No significant difference was seen betweengroups in terms of FVC change (lowconfidence) or percentage of patients witha greater than 10% decrease in FVC duringthe study period (low confidence). Therewas also a trend toward more seriousadverse events in patients receivingwarfarin (RR, 1.77; 95% CI, 0.94–3.33; lowconfidence).

Recommendation. We recommendthat clinicians not use warfarinanticoagulation in patients with IPF whodo not have a known alternativeindication for its use (strongrecommendation against, low confidencein estimates of effect).

Justification and implementationconsiderations. This recommendationplaces a high value on potential adverseoutcomes such as death. The committeemembers felt that the increased riskfor mortality required a strongrecommendation against using oral warfarinas a treatment for IPF in patients withIPF. However, this recommendation appliesonly to oral warfarin with a targetinternational normalized ratio of 2.0–3.0and does not include the use of otheranticoagulants for other indications.Patients who have an alternate and/orknown indication for anticoagulation,such as venous thromboembolic disease oratrial fibrillation, should follow treatmentguidelines for these conditions independentof their underlying IPF. Given that therewere no net benefits of oral warfarin costwas considered irrelevant.

Future research opportunities.Committee members considered that newtrials using oral warfarin in patients with



IPF are unlikely to be helpful, andtherefore would be difficult to develop andfund.

Question 2: Should Patients with IPFBe Treated with Imatinib, a TyrosineKinase Inhibitor?

Background. Imatinib is a potent inhibitorof lung fibroblast–myofibroblastdifferentiation and proliferation, as wellas an inhibitor of extracellular matrixproduction through inhibition of PDGFand transforming growth factor-bsignaling. For the recommendation onnintedanib, a less selective tyrosinekinase inhibitor, see Question 5. Norecommendation was offered for either ofthese medications in the 2011 guidelinedocument.

Summary of the evidence. Imatinibfor patients with IPF has been evaluatedin one placebo-controlled RCT, whichrandomized 119 patients and includeda median follow-up of 96 weeks (20). Nodifference in mortality was seen betweenthe intervention and control groups (RR,0.81; 95% CI, 0.35–1.92; low confidence).Disease progression, the study’s primaryoutcome, which was defined as a morethan 10% decline in FVC or death at 96weeks, also showed no benefit for imatinibtherapy (hazard ratio [HR], 1.05; 95% CI,0.56–1.96; moderate confidence). Therewas a statistically significant increased riskof adverse events in the imatinib groupcompared with control (RR, 1.54; 95% CI,1.25–1.90; high confidence); however,most of the undesirable effects were notconsidered bothersome enough todiscontinue the medication. There was nosignificant difference in the number ofserious adverse events between groups(low confidence).

Recommendation. We recommendthat clinicians not use imatinib inpatients with IPF (strongrecommendation, moderate confidence inestimates of effect).

Justification and implementationconsiderations. Imatinib is a relativelyexpensive drug with no current evidencesuggesting benefit in patients with IPF toprevent disease progression or mortality. Inthe context of no demonstrated clinicalbenefit, this recommendation puts a highvalue on adverse events and the cost oftreatment.

Question 3: Should Patients with IPFBe Treated with CombinationPrednisone, Azathioprine, andN-Acetylcysteine?

Background. Previously, immunesuppression was considered important inthe treatment of IPF (2). It was thoughtthat a two-drug regimen includingglucocorticoids in addition to eitherazathioprine or cyclophosphamide may besuperior to glucocorticoids alone (2).Given some early studies in favor ofN-acetylcysteine (21), clinicians andresearchers have examined the potentialbenefit of this three-drug regimen for IPF.

Summary of the evidence. The 2011guideline included one RCT that comparedN-acetylcysteine versus placebo in patientsreceiving prednisone and azathioprine (22).In this study, 12-month declines in vitalcapacity and DLCO were significantly lesswith the addition of N-acetylcysteine,although no significant effect on mortality,dyspnea scores, or quality of life wasobserved. Given the limitations of thisstudy, specifically the lack of a true placebogroup for all active therapies, a more recentRCT has been reported that randomizedpatients to combination therapy versusplacebo for all active agents (23). Thismulticenter study was stopped early aftera signal for harm was seen in patientsreceiving combination therapy comparedwith placebo, with an increase in mortality(HR, 9.26; 95% CI, 1.16–74.1; very lowconfidence) and hospitalization (P,0.001). No significant difference betweengroups was seen in FVC change (moderateconfidence), DLCO change (low confidence),or quality-of-life indices (low confidence).

Recommendation. We recommendthat clinicians not use the combinationtherapy of N-acetylcysteine, azathioprine,and prednisone in patients with IPF(strong recommendation, low confidencein estimates of effect).

Justification and implementationconsiderations. This recommendation isprimarily based on the results of a single trialthat was stopped early for harm (23).Although trials stopped early promptconcerns about the true underlying effect(24), a clear negative effect was seen formultiple patient-important outcomes afterenrolling 50% of targeted patients to thisstudy. This recommendation places a highvalue on these potential adverse effects of

the intervention. The committee felt thatthis recommendation only applies topatients with IPF treated with the dose ofagents used in the trial and may notnecessarily be generalizable to other formsof interstitial lung disease or other doses oftreatment medications. There was noconsensus on how to deal with patientswith IPF who have been receivinga combination therapy long-term withgood tolerance, as studies did notaddress stopping this treatment. Insuch circumstances, the committeerecommended that an informed discussionis necessary and should take place betweenthe individual patient and practitionerdiscussing the potential harms of treatmentin combination with considerations for thepatient’s values and preferences. Despitechallenges in judging benefit in individualpatients, with those who seemed to haveresponded to combination therapy, it isprudent to readdress the accuracy of thediagnosis of IPF and reconsider otherdisease processes that may be moreresponsive to this treatment.

Question 4: Should Patients with IPFBe Treated with Ambrisentan,a Selective ER-A Endothelin ReceptorAntagonist?

Background. Clinically significantendothelin receptors fall into one of a fewcategories, including endothelin type A (ET-A) receptors, which induce vasoconstrictionand are usually found on vascular smoothmuscle cells, and the endothelin type B1(ET-B1) receptors, located in the endothelialcells, which are known to stimulate therelease of nitric oxide (NO) and prostacyclinto produce a vasodilating effect (25). ET-Areceptors have also been shown topropagate epithelial-to-mesenchymaltransition through intermediary cytokines,leading to a profibrotic state (26). ET-B2receptors antagonize ET-B1 receptors andvasoconstrict through an unknownmechanism (25). Clinically availableendothelin receptor antagonists (ERAs)include selective ET-A antagonists (e.g.,ambrisentan) and dual antagonists thataffect both ET-A and ET-B receptors (e.g.,bosentan and macitentan). Increased ET-Aand ET-B receptor levels have been foundin IPF-affected fibrotic lung (27), and assuch, both selective and dual antagonistshave been investigated for potential benefitin treating patients with IPF. Given the



differential mechanism of action, thisguideline update looked at these twosubtypes separately and decided to offerindependent recommendations. Norecommendation was made in the 2011guideline for selective ERAs (see dual ERA,recommendation 9 below).

Summary of the evidence. Ambrisentanis the only selective ERA with RCT evidence,with a single study that randomized 492patients with IPF in a 2:1 ratio to either drugor placebo (28). This study also stratifiedrandomization based on the presence orabsence of PH by right heart catheterizationat baseline. Importantly, this study wasstopped early for lack of benefit and a highlikelihood of harm seen with intervention.

The HR for mortality with ambrisentanafter a median follow-up of 52 weeks was2.08 (95% CI, 0.75–5.76; low confidence).Ambrisentan increased disease progression,assessed as worsening DLCO or FVC,independent of the presence or absence of PH(HR, 1.74; 95% CI, 1.14–2.66; moderateconfidence). There was no significantdifference between groups in terms of FVC,DLCO, 6-minute-walk distance, or quality-of-life indices when assessed at week 48. Therewas no difference in adverse events (moderateconfidence) or serious adverse events (lowconfidence) between patients receivingambrisentan and those receiving placebo.

Recommendation. We recommendthat clinicians not use ambrisentan,a selective ER-A endothelin receptorantagonist, in patients with IPF,regardless of the presence or absence ofPH (strong recommendation against, lowconfidence in estimates of effect).

Justification and implementationconsiderations. Because ambrisentan isindicated for treatment of PH in patients otherthan those with IPF, the committeerecommends against the use of ambrisentan inpatients with IPF manifesting PH. It isreasonable for patients with IPF who are takingambrisentan to discontinue treatment, giventhe lack of benefit and potential for harm. Thecommittee did not suggest subgroupconsiderations or future research opportunities.

Question 5: Should Patients with IPFBe Treated with Nintedanib,a Tyrosine Kinase Inhibitor?

Background. Nintedanib (previously knownas molecule BIBF 1120) is an intracellularinhibitor of several tyrosine kinases thattargets multiple growth factor receptors,

including vascular endothelial growthfactor, fibroblast growth factor, and PDGF.

Summary of the evidence. Nintedanibtreatment in patients with IPF was evaluatedin three RCTs published in two separatereports (29, 30). The first was a phase 2safety and efficacy trial that studied fourdifferent doses of nintedanib (50 mg oncedaily, 50 mg twice daily, 100 mg twice daily,and 150 mg twice daily) versus placebo(29). No significant difference betweengroups was seen in terms of mortality. Thepercentage of patients with more than 10%FVC decline during the 12 month follow-up period was lower with the highest doseof nintedanib (P = 0.004) but was notsignificantly different at the other doseswhen compared with placebo. Patientstreated with any dose of nintedanib didhave fewer IPF acute exacerbationscompared with controls (HR, 0.16; 95% CI,0.04–0.70). There were more adverse eventsand serious adverse events in the patientsreceiving nintedanib; however, neither ofthese was statistically significant.

INPULSIS-1 (Safety and Efficacy ofBIBF 1120 at High Dose in IdiopathicPulmonary Fibrosis Patients) and INPULSIS-2(Safety and Efficacy of BIBF 1120 at HighDose in Idiopathic Pulmonary FibrosisPatients II) were replicate phase 3 RCTs thatenrolled a total of 1,066 patients in a 3:2 ratioto receive 150 mg of nintedanib twice dailyversus placebo (30). Follow-up for both ofthese studies was 52 weeks. Consideringthese trials as one, there was no significantbenefit of nintedanib on mortality (RR, 0.70;95% CI, 0.44–1.11) or acute exacerbation ofIPF (HR, 0.64; 95% CI, 0.39–1.05). However,fewer patients treated with nintedanib hada more than 10% absolute decline in FVCduring the study period (RR, 1.16; 95% CI,1.06–1.27). Also, the adjusted annual rate ofchange in FVC was 2114.7 ml withnintedanib therapy versus 2239.9 ml withplacebo (difference, 125.2 ml; 95% CI,77.7–172.8). Significantly more patientstreated with nintedanib reported an adverseevent (RR, 1.07; 95% CI, 1.03–1.11);however, there was no significant increase inserious adverse events. Patients treated withnintedanib did report significantly morediarrhea and nausea compared with thosereceiving placebo.

Pooled analysis of these three trials(29, 30) showed an RR of 0.70 (95% CI,0.47–1.03; moderate confidence) formortality and a HR of 0.47 (95% CI,0.17–1.29; low confidence) for acute

exacerbations. A benefit was seen withnintedanib for the outcome number ofpatients with more than 10% absolutedecline in FVC (RR, 1.15; 95% CI,1.06–1.25; moderate confidence).Significantly more patients treated withnintedanib reported adverse events (highconfidence), but not serious adverse events(high confidence).

Recommendation. We suggest thatclinicians use nintedanib in patients withIPF (conditional recommendation,moderate confidence in estimates ofeffect).

Justification and implementationconsiderations. This recommendation putsa high value on the potential benefit ofnintedanib on patient-important outcomessuch as disease progression as measured byrate of FVC decline and mortality anda lower value on potentially significantadverse effects and the expected cost oftreatment. As opposed to more selectivetyrosine kinase inhibitors, nintedanibappears to have some benefit in terms ofpatient-important outcomes in patients withIPF, although no significant effect on overallmortality was seen. The concerns based oncurrent costs may limit feasibility and use.These considerations are important, werediscussed by the committee as part of therecommendation, and must be factored intoany decision for treatment. Adverse effectswere commonly reported with nintedanibtherapy, specifically diarrhea, and patientsmust be informed of this when deciding ontreatment. As noted earlier, there was noincrease in serious adverse events withnintedanib, and relatively few patientsdiscontinued the study drug secondary toadverse effects. Of note, one committeemember felt that the recommendationshould be strong in favor; all other membersagreed with a conditional recommendation.As with other interventions, the availableevidence focuses on patients with IPF withmild to moderate impairment in PFTs. It isunknown whether the therapeutic benefitswould differ in patients with a more severeimpairment in pulmonary function testingor those with other comorbidities. Some ofthe patients enrolled in the clinical trialsincluded patients with a high-resolutioncomputed tomography image pattern thatwas suggestive of the usual interstitialpneumonia (UIP) pattern (and wasdesignated as “probable UIP” pattern),rather than those with definite UIP pattern(i.e., without confirmation of UIP on



surgical lung biopsy in patients whose high-resolution computed tomography scan hadnot demonstrated a pattern consistent withdefinite UIP [3]). The evidence does notallow suggestions about the optimalduration of therapy, and it is unknown howlong the treatment effect endures withongoing drug therapy.

Future research opportunities. Futurenintedanib trials should focus on patientswith IPF with impairment in PFTs moresevere than mild to moderate. Moreinformation on proper duration oftreatment is also needed.

Question 6: Should Patients with IPFBe Treated with Pirfenidone?

Background. Pirfenidone is an oralantifibrotic drug with pleiotropic effects. Ithas been shown to regulate importantprofibrotic and proinflammatory cytokinecascades in vitro (31) while reducingfibroblast proliferation and collagensynthesis in animal models of lung fibrosis(32–34).

Summary of the evidence. The 2011guideline document reported on tworelatively small RCTs that comparedpirfenidone with placebo in Japanesepatients with IPF who had mild to moderateimpairment in PFTs (35, 36). One of thesetrials (35) was stopped early for potentialbenefit, as acute exacerbation, a secondaryoutcome, was found to occur morefrequently in the placebo group. Similarly,and despite an incomplete data set,a benefit with pirfenidone was seen whenevaluating the frequency of oxygendesaturation during 6-minute-walk test andthe decline in vital capacity (VC) over time.The second trial (36) had significantmethodological concerns, includinga highly selected enrolment and alterationof the primary endpoint midstudy.Understanding this, it also demonstrateda benefit to pirfenidone treatment in termsof a reduction in the rate of decline in VC(290 ml vs. 2160 ml; P = 0.04) andimproved progression-free survival (P =0.03). The CAPACITY trial (37), thecombined results of two large-scale RCTs(Safety and Efficacy of Pirfenidone inPatients With Idiopathic PulmonaryFibrosis, and Three-Arm Study of theSafety and Efficacy of Pirfenidone inPatients With Idiopathic PulmonaryFibrosis) considering pirfenidone for IPF,had not been published. However,

preliminary results were available, and wereconsidered in the last iteration of theguideline.

The CAPACITY trial reported on twoindependent study protocols: study 004included 435 patients randomized to oneof three treatment groups (high-dosepirfenidone [2,403 mg/d], low-dosepirfenidone [1,197 mg/d], and placebo),whereas study 006 had 344 patientsrandomized to only two treatment groups(high-dose pirfenidone [2,403 mg/d] andplacebo). The results of the low-dosepirfenidone group were intermediate to thehigher dose, and to avoid heterogeneity ofintervention, we chose to focus on theresults of the high-dose pirfenidone groupversus those of the placebo group acrossboth studies. In study 004, pirfenidoneshowed a reduction in decline of FVCduring the 72-week treatment period. Study006 did not show a benefit in the sameoutcome during the same period.Importantly, patients from both studies whowere assigned to receive high-dosepirfenidone reported increased rates ofnausea, dyspepsia, vomiting, anorexia,photosensitivity, and rash comparedwith placebo. The ASCEND trial (ARandomized, Double-Blind, PlaceboControlled Trial of Pirfenidone in Patientswith Idiopathic Pulmonary Fibrosis)randomized 555 patients with IPF to eitherhigh-dose pirfenidone (2,403 mg/d) orplacebo (38). As opposed to theCAPACITY trials, the ASCEND trial hadstricter patient selection criteria, such asa FEV1/FVC ratio below 0.8. Of 1,562screened patients, 1,007 were excludedbecause of these predefined exclusioncriteria. Pirfenidone significantly reducedthe proportion of patients who had a morethan 10% decline in their FVC during the52-week follow-up period. Pirfenidonetreatment increased 6-minute-walkdistance and progression-free survival whencompared with placebo. Mortality ordyspnea scores did not differ. Consistentwith previous studies, patients randomizedto pirfenidone reported more treatment-related adverse effects.

Pooled results from these trials (35–38)suggested improved mortality withpirfenidone (RR, 0.70; 95% CI, 0.47–1.02;moderate confidence). Pirfenidone reducedthe rate of FVC decline (standardized meandifference, 0.23; 95% CI, 0.06–0.41; highconfidence). This pooled estimate did notinclude the positive results from one study

(38) because of heterogeneity in reporting,which made pooling including this trialimpossible. Pooled analysis showedincreased rates of photosensitivity (highconfidence), fatigue (moderate confidence),stomach discomfort (moderate confidence),and anorexia (high confidence) in patientstreated with pirfenidone.

Recommendation. We suggest thatclinicians use pirfenidone in patients withIPF (conditional recommendation,moderate confidence in estimates ofeffect).

Justification and implementationconsiderations. New evidence that hasbecome available since the prior edition ofthis guideline has led to a conditionalrecommendation in favor of treatment.Only one committee member felt thatthe recommendation should be strongin favor; all other nonconflictedmembers agreed with a conditionalrecommendation. This recommendationputs a high value on the potential benefitof pirfenidone on patient-importantoutcomes such as disease progression asmeasured by rate of FVC decline andmortality and a lower value on potentiallysignificant adverse effects and the cost oftreatment. Quality-of-life data weresporadically reported across pirfenidonetrials. The adverse effects of pirfenidonetreatment fall on a spectrum, and somepatients may not be willing to toleratecertain adverse effects even in the settingof treatment benefit, as assessed bymeasurement of FVC. Shared decision-making should be used, and patientsstarting this treatment must be educatedon all potential adverse effects. Inaddition, pirfenidone is currently a verycostly intervention, and this must befactored into the decision-making process,especially when patients directly carrythe financial burden of treatment. Giventhe different inclusion criteria for thepirfenidone trials, these results cannotnecessarily be generalized to patients withIPF with more severe impairment in PFTsor for patients with other significantcomorbidities. The evidence does notallow suggestions about the optimalduration of therapy, and it is unknownhow long the treatment effect endureswith ongoing drug therapy.

Future research opportunities. Futureresearch should focus on duration oftreatment and the effect of pirfenidone inpatients with IPF with more impairment in



PFTs and in patients with coexisting airflowobstruction less than the FEV1/FVC of 0.8or those with comorbid emphysema.

Question 7: Should Patients with IPFBe Treated with Antiacid Medication?

Background. Abnormal gastroesophagealreflux (GER), including clinically silentacid (or at least untreated acid), has beenobserved in up to 90% of patients with IPF(39). GER is a risk factor for aspirationand microaspiration, which couldsubsequently cause pneumonitis,a mechanism that has been postulated tocause or worsen IPF. Antiacid treatments,used on a regular basis, such as protonpump inhibitors (PPIs) or histamine-2 blocker receptor antagonists(H2RAs), may decrease this risk formicroaspiration-associated lung injuryor damage (40, 41).

Summary of the evidence.Observational studies have attempted tolook at the role of regular PPI and H2RA usein decreasing the progression of disease inpatients with IPF (40, 42–44). Oneretrospective analysis of longitudinalcohorts suggested a survival benefit forpatients receiving antiacid medication (HR,0.47; 95% CI, 0.24–0.93; adjusted analysis),of whom 86 used PPIs and 12 used H2RAs(42, 43). Another aggregate analysisexamined all the patients who wererandomized to the placebo groups fromthree RCTs of different pharmacologictherapies on patients with IPF (40). Onehundred twenty-four patients receivinga PPI or H2 blocker at baseline (91% PPI,9% H2RA) were compared with 118patients not receiving antiacid treatmentand not receiving other study medications.This analysis showed a significantly smallerdecrease in FVC during the study periodfor those receiving antiacid treatment atbaseline (mean difference, 0.07 L; 95% CI,0–0.14; P = 0.05) There were no episodes ofadjudicated acute exacerbations in patientstreated with antiacid treatment comparedwith placebo. However, this study showedno differences in all-cause mortality or all-cause hospitalization.

Recommendation. We suggest thatclinicians use regular antiacid treatmentfor patients with IPF (conditionalrecommendation, very low confidence inestimates of effect).

Justification and implementationconsiderations. This recommendation

places a higher value on possibleimproved lung function and survival andthe low cost of therapy and a lower valueon the potential increased risk forpneumonia with antiacid therapy.Although the individual studies appear tohave been well conducted, the nature ofobservational studies suggests that theindication for antiacid treatment wasbased on the individual physician’sdecision, which may introduce bias. Inaddition, it is unclear how wellinvestigators controlled for co-interventions, although the effects of suchtreatments are also unknown. Theevidence presented mostly focused onPPIs, as a very small proportion ofincluded patients were receivingH2RAs; other antiacid treatments mayneed to be considered differently. Itis important to note that thisrecommendation applies to all patientswith IPF, as it is based on IPF beingthe treatment indication, rather thanabnormal GER. It is unclear whetherthe benefit of antiacid therapy in IPFwould be different in symptomaticversus asymptomatic patients. However,it is recognized that patients withclinically abnormal GER/GER disease(GERD) should receive best availabletreatment according to appropriateguidelines for GERD. The safety of PPItherapy was also considered in thisrecommendation. Despite some studiesshowing association, a recent meta-analysis of observational studiesshowed PPIs did not increase the riskfor hospitalization for community-acquired pneumonia in the generalpopulation (45). The potential druginteraction of PPIs with other IPFmedications and the long-term effect oftreatment in patients with IPF areunknown.

Future research opportunities. FurtherRCTs are needed to compare antiacidtreatment versus placebo in patients withIPF. Also, further research should focuson the drug interaction of PPIs with otherIPF medical treatment, the long-termsafety of PPI treatment for patients withIPF with or without symptoms ofGER/GERD, the role of therapy innonacid reflux, and the role of abnormalGER and microaspiration in thepathogenesis, progression, and/orexacerbation of IPF. Further studies arewarranted to determine safety and efficacy

of decreasing risks for GER andmicroaspiration by surgical interventions inpatients with IPF.

Question 8: Should Patients withIPF Be Treated with Sildenafil,a Phosphodiesterase-5 Inhibitor?

Background. Sildenafil, an oralphosphodiesterase-5 inhibitor, has beenstudied in two RCTs that enrolled patientswith IPF (46, 47). This evidence wasincluded in the 2011 guideline; however,one of the studies (47) only becameavailable after the guideline committeehad met, and therefore no formalrecommendation on phosphodiesteraseinhibitor use in patients with IPF wasprovided.

Summary of the evidence. STEP-IPF(Sildenafil Trial of Exercise Performance inIdiopathic Pulmonary Fibrosis) was a phase 3study that randomized 180 patients withadvanced IPF (DLCO, 35% predicted) toeither sildenafil (20 mg three times daily)or placebo for 12 weeks, with a subsequent12-week open-label phase during whichall patients received active drug (47). Therewas no significant benefit of sildenafil on theprimary outcome, which was the proportionof patients who showed more than 20%improvement in their 6-minute-walkdistance after the initial 12-week period(10.1% vs. 6.6%; P = 0.39). There were smallbenefits seen with sildenafil on the secondaryoutcomes, with improved shortness ofbreath, improved quality of life, improvedDLCO, and improved arterial oxygensaturation, all at the end of the 12-weekrandomized period. There was no differencein serious adverse events between the groupsreceiving sildenafil versus those receivingplacebo. A predefined subgroup analysis wasperformed in the 119 patients with availableechocardiograms to see whether there wasa differential effect of sildenafil on patientswith IPF with documented right ventricularhypertrophy or right ventricular systolicdysfunction (RVSD) (48). In patients withechocardiogram-documented RVSD,sildenafil treatment was found to result ina significant improvement in the primaryoutcome of 6-minute-walk distance (meandistance, 99.3 m; 95% CI, 22.3–176.2 m)Similar results to patients without RVdysfunction were seen in the othersecondary outcomes.

The second, smaller studyrandomized 29 patients with mild or



moderate disease (average DLCO, 42%predicted) to receive either sildenafil(20 mg three times daily) or placebo fora 6-month treatment period (46). Patientswith known PH or RV dysfunction wereexcluded. In this small study, nosignificant benefit of sildenafil treatmentwas seen on 6-minute-walk test distance,Borg dyspnea scores, FVC, DLCO, orarterial oxygen saturation. More adverseevents occurred in the sildenafil group;however, these were not serious.

Pooled analysis of these two trials (46,47) showed no significant benefit ofsildenafil treatment on mortality (RR, 0.51;95% CI, 0.1–2.72; low confidence) or acuteexacerbation (RR, 0.34; 95% CI, 0.04–3.22;low confidence). There was a significantimprovement in quality of life withsildenafil when assessed by the St GeorgeRespiratory Questionnaire (moderateconfidence). Similar to the individualtrials, no significant benefit with treatmentwas seen on the other outcomes ofFVC (moderate confidence), DLCO

(low confidence), Borg dyspnea score(moderate confidence), oxygen saturation(low confidence), or 6-minute-walkdistance (low confidence).

Recommendation. We suggestthat clinicians not use sildenafil,a phosphodiesterase-5 inhibitor, fortreatment of IPF (conditionalrecommendation against, moderateconfidence in estimates of effect).

Justification and implementationconsiderations. Although there was a slightimprovement in quality of life withsildenafil, given the lack of benefit in anyother outcomes, including mortality, acuteexacerbations, or dyspnea scores, there wasfelt to be net harm. In addition to potentialdrug-related adverse effects, the cost ofsildenafil treatment was considereda potential barrier for patients who wouldhave to pay out of pocket for sildenafil.This recommendation puts a higher valueon the mortality, acute exacerbation, anddyspnea (which did not improve) adverseevents and the cost of treatment, anda relatively lower value on quality of life.This recommendation required a vote by thecommittee: two panel members voted fora conditional recommendation in favor, fivevoted for a conditional recommendationagainst treatment, and two abstained. Thisrecommendation does not apply to patientsreceiving phosphodiesterase inhibitors forother indications such as PH or other RV

dysfunction. Given that echocardiogram isnot the gold standard for diagnosing RVdysfunction or PH, and that only subgroupevidence was available, the committee madeno specific subgroup recommendation inpatients with IPF with documented PH.

Future research opportunities.Randomized trials focusing onphosphodiesterase inhibitor treatment ofpatients with IPF with RV-catheterdocumented PH are needed, as it is possiblebenefit could be seen in this subgroup ofpatients. In addition, further studies areneeded to address this potential benefit onquality of life seen with sildenafil treatment.

Question 9: Should Patients with IPFBe Treated with Bosentan orMacitentan, Dual Endothelin ReceptorAntagonists (ER-A and ER-B)?

Background. One small study looking atthe effect of a dual ERA (bosentan) wasavailable at the time of the 2011 guideline,and given the lack of benefits, a strongrecommendation against therapy was made.

Summary of the evidence. Two RCTsexamined the effect of bosentan versusplacebo (49, 50), whereas a single RCTtested macitentan versus placebo (51).BUILD-1 (Bosentan Use in Interstitial LungDisease) randomized 158 patients to eitherbosentan or placebo and followed patientsfor 12 months (50). No significant benefitwas seen in mortality (RR, 1.14; 95% CI,0.24–5.54), although the data suggested animprovement in the composite outcome ofmortality and disease progression (RR, 0.62;95% CI, 0.37–1.05), as measured byworsening PFTs or clinical status. Therewas no statistically significant increase inadverse events or serious adverse eventswith bosentan therapy. The follow-upstudy, BUILD-3, attempted to clarify thispotential beneficial effect of bosentan byincluding a larger sample (n = 616) and bybeing more specific, including only patientswith biopsy-proven usual interstitialpneumonia, a pathologic diagnosisconsistent with IPF (49). Despite thesemodifications in study design, bosentan didnot show a conclusive effect on mortality(RR, 1.25; 95% CI, 0.53–2.96) or diseaseprogression (RR, 0.86; 95% CI, 0.71–1.05).Differences were also not seen in FVC,health-related quality of life (assessed by 36-Item Short Form Health Survey), dyspneascores, reported adverse events, or seriousadverse events in the bosentan group.

Macitentan, a novel dual-receptor ERA,was compared with placebo in a phase 2study of 178 patients with lung biopsy-proven IPF (51). Similar to bosentan, nosignificant difference was seen in patientstreated with macitentan versus thosereceiving placebo for the outcomesmortality (RR, 0.74; 95% CI, 0.13–4.33),mortality or disease progression (RR 1.02;95% CI, 0.63–1.66), or change in FVC(mean difference, 0.00; 95% CI, 20.16 to0.16). No difference in rates of reportedadverse or serious adverse events was seen.

Given the relatively similar mechanismof action between these two dual ERAsand the homogenous results, these threestudies were pooled for analysis (49–51). Nooverall effect on mortality was seen usingdual ERAs for patients with IPF (RR, 1.13;95% CI, 0.57–2.27; low confidence). Thecomposite outcome of death or diseaseprogression appeared improved, with theupper confidence interval just crossingunity (RR, 0.85; 95% CI, 0.71–1.00; lowconfidence). No important differencebetween groups was seen in FVC change(moderate confidence) or in the rates ofadverse events (high confidence) or seriousadverse events (high confidence).

Recommendation. We suggestthat clinicians not use bosentan ormacitentan, both dual ER-A and ER-Bendothelin receptor antagonists, forthe treatment of IPF (conditionalrecommendation against, low confidencein estimates of effect).

Justification and implementationconsiderations. This recommendationplaces a relatively higher value on thereported patient-important outcomes andthe high cost of this medication anda relatively lower value on possiblereduction of the risk of mortality or diseaseprogression. Given the inconsistency ofa composite outcome (mortality or diseaseprogression) across trials and theimprecision in the estimate of the effect, thecommittee recommended against thistherapy. The increased cost of dual-receptorERAs was also considered, especially in thecontext of unclear desirable effects. It isimportant to mention that only studiesexamining bosentan or macitentan wereconsidered, and that other dual ERAs maybe beneficial in patients with IPF. Thecommittee felt that patients with PHsecondary to IPF might benefit from dualERAs more than patients without; however,the evidence did not allow a specific



subgroup recommendation. A recentlypublished study, not considered by thecommittee, showed no benefit of bosentantherapy on pulmonary hemodynamics inpatients with IPF with right heart catheter-diagnosed PH (52).

Future research opportunities. Furtherstudies, including assessment of treatmentresponse of patient-important outcomessuch as mortality and quality of life, areneeded to determine the efficacy of dualERAs in patients with IPF with PH.

Question 10: Should Patients with IPFBe Treated with N-AcetylcysteineMonotherapy?

Background. The only RCT that wasincluded in the 2011 guideline documentrandomized 30 patients to receive eitheraerosolized N-acetylcysteine or bromhexinehydrochloride for 12 months anddocumented significant improvement in theextent of ground glass on computedtomography and reduction in KL-6 levels(21). No differences in physiologicmeasurements or walk distance were found.

Summary of the evidence. Two newRCTs have been performed examiningN-acetylcysteine monotherapy and havebeen included in this update. A multicenter,prospective RCT done in Japan randomlyassigned 76 patients to receive 352.4 mginhaled N-acetylcysteine twice daily versuscontrol during a period of 48 weeks (53). Nosignificant difference was seen in theprimary outcome of change in FVC betweengroups. The other RCT enrolled 264 patientswho were subsequently randomized toreceive 600 mg oral N-acetylcysteine threetimes a day or placebo (54). The originalintent of this study was to compare threeintervention groups, including one groupof a combination therapy that consistedof oral prednisone, azathioprine, andN-acetylcysteine (23). Because ofsafety concerns encountered afterinterim analysis, the combinationtherapy group was dropped midstudy,and randomization continued with thetwo-group study design, including onlyN-acetylcysteine monotherapy and placebogroups. Results of this two-group analysis(including both pre- and poststudy designchange) showed no significant differencein the FVC change with N-acetylcysteinemonotherapy. Also, there were nosignificant differences seen in the ratesof death or acute exacerbation.

After pooling the results of these threeRCTs (21, 53, 54), no significant benefiton mortality was seen using N-acetylcysteine monotherapy for patientswith IPF (RR, 1.97; 95% CI, 0.50–7.71; lowconfidence). There were no significantdifferences in FVC change (highconfidence), quality of life (moderateconfidence), or adverse outcomes (lowconfidence). Two studies (21, 54) reportedon 6-minute-walk test distance, anda significant improvement was seen usingN-acetylcysteine monotherapy (meandifference, 44.33 m; 95% CI, 2.92–85.75;very low confidence).

Recommendation. We suggest thatclinicians not use N-acetylcysteinemonotherapy in patients with IPF(conditional recommendation, lowconfidence in estimates of effect).

Justification and implementationconsiderations. This recommendationplaces a higher value on the potential risks,inconvenience, and cost of therapy anda low value on possible improvement ofoutcomes with unclear patient importance.This recommendation generatedconsiderable debate among committeemembers. The available evidence focused onpatients with IPF with mild to moderateimpairment in PFTs, and as for otherrecommendations, it was acknowledged thatgeneralization to patients with more severeimpairment of PFTs should be done withcaution. The committee did not findsufficient evidence for differences inoutcomes between inhaled versus oraladministration of N-acetylcysteine, andtherefore the recommendation applies toboth interventions. No evidence ofsignificant harm was found, and therefore,no suggestion related to discontinuation inpatients already receiving N-acetylcysteinemonotherapy was made, although if there isno benefit from starting therapy, it isunlikely that there is benefit fromcontinuing.

Future research opportunities. It isunclear whether a subset of patients withIPF with a higher burden of oxidative stressmay benefit from N-acetylcysteinemonotherapy. Future trials should identifywhether there is a subgroup of patientsmore likely to benefit from therapy thanothers. It is possible that one route ofadministration may be more beneficial thananother, and studies assessing differentdelivery of N-acetylcysteine in patients withIPF could be considered.

Question 11: Should Patients with IPFBe Treated with Bilateral LungTransplantation versus Single-LungTransplantation?

Background. Given the progressiveand incurable nature of IPF, lungtransplantation is commonly considered forpatients with moderate to severe disease.It is unclear whether bilateral lungtransplantation is superior to single-lungtransplantation in patients with underlyingIPF. Lacking RCT evidence to guide thisrecommendation, we consideredobservational studies that assessed thesurvival of patients with IPF, acceptingbilateral lung transplantation versus single-lung transplantation (55–61).

Summary of the evidence. Pooledsurvival analysis of three observationalstudies showed no difference betweenpatients who received single versus bilaterallung transplantation (HR, 0.47; 95% CI,0.19–1.17) (56–58). Four additionalstudies were not included in the pooledanalysis, as they did not report hazardratios; however, consistent with the otherstudies, patients accepting bilateral lungtransplantation showed no significantdifference in terms of survival from thoseaccepting single-lung transplantation (55,59–61). A subsequent meta-analysis waspublished after the guideline committeehad met, and therefore was not considered,although results presented in this reviewwere consistent with previous studies andwould not have changed the overallconclusion (62).

Recommendation. The committeedid not make a recommendationregarding single versus bilateral lungtransplantation in patients with IPF.

Justification. The committeeacknowledged that additional evidenceshould be evaluated to guide this clinicaldecision. The shortage of organs isa universal problem, and the decision to givebilateral lung transplantation to a singlepatient rather than give single-lungtransplantation to two patients, includingthe effect on health inequity, must beconsidered.

Future research opportunities. RCTsare needed to properly address this question.Also, future guidelines regarding thisquestion need to be addressed bycommittees that include members withexpertise in lung transplantation to betteraddress this clinical question.



Question 12: Should PH Be Treated inPatients with IPF?

Background. Comorbid PH is commonlyseen in patients with IPF and contributes toa worsened clinical prognosis (63, 64).

Summary of the evidence. The 2011guideline considered the very limited availableevidence at the time (65–69) in suggestingagainst treatment of PH in patients with IPF.The studies included in this initial guidelinedocument were limited by focusing on short-term hemodynamics rather than long-termpatient important outcomes (65–67, 69), notrandomizing patients to treatment or control(65, 67, 68), not including an adequateplacebo (66, 68, 69), analyzing dataretrospectively (68), or a combination ofthese methodologic concerns.

Subsequent RCTs, already described inthis document, which examined thetreatment of patients with IPF withambrisentan (28) and sildenafil (47),included a priori subgroup analysis forpatients with comorbid PH. Ambrisentantreatment, stratified in the ARTEMIS-IPF(Randomized, Placebo-Controlled Studyto Evaluate Safety and Effectiveness ofAmbrisentan in IPF) trial based on PHstatus, as assessed by right-sided heartcatheterization, showed no significantsubgroup effect in patients withdocumented mean pulmonary arterypressures higher than 25 mm Hg. Giventhe similar results, namely, an increase indisease progression and respiratoryhospitalization in patients treated withambrisentan, the strong recommendationagainst treatment above also applies to thissubgroup of patients.

Within the STEP-IPF trial, investigatorsexamined the effect of sildenafil treatment onthe subgroup of patients withechocardiogram-documented rightventricular hypertrophy or RVSD (48). Asdescribed earlier, in patients with RVSD,but not right ventricular hypertrophy,sildenafil was found to have a significantimprovement on the primary outcome of6-minute-walk distance. Given that no otheroutcomes were significantly different, thelack of gold standard in diagnosing PH, andthe exploratory nature of the analysis, nosubgroup recommendation forphosphodiesterase inhibitor treatment inpatients with IPF with documented PH wasmade.

Finally, a small, open-label,noncontrolled, pulmonary hemodynamic

study has shown an acceptable safety profilefor riociguat, a soluble guanylate cyclasestimulator, when used in patients with PHand associated interstitial lung disease of anycause (70). Further investigation, includinglarge phase 3 and 4 trials specificallyexamining the effect of this medication inpatients with documented IPF, will beneeded before serious consideration ofwidespread use.

Recommendation. The committee didnot make a recommendation regardingtreatment of PH in patients with IPF.

Justification. The committeeacknowledged that further evidence isneeded and should be evaluated to guide thisclinical decision.

Future research opportunities. NovelPH agents are increasingly becomingavailable, and future research should focuson their effect on PH in patients withunderlying IPF. Future clinical trials inpatients with IPF manifesting PH shouldconsider studies with agents indicated fortreatment of PH, especially the ones thathave demonstrated an acceptable safetyprofile in patients with IPF (e.g., dual ERAs,phosphodiesterase-5 inhibitor), but not theones with documented harmful effects (e.g.,selective ERA, ambrisentan). Clinical trialsshould consider treatment with vasoactivemedications stratified or subgroup analysisfocusing on patients with known PH toassess for differential effect.

Conclusions

Significant advances have been made inthe clinical management of IPF since the2011 evidence-based guideline. Newevidence for treatment recommendationsthat had received conditional (i.e., weak)recommendations by the committeedeveloping the 2011 guideline have beenreviewed carefully, and updatedrecommendations have been provided.Although there are no pharmacologicinterventions that received strongrecommendations for treatment,conditional recommendations have beenmade for treatment with novel agentssuch as pirfenidone and nintedanib, aswell as antiacid treatment for patientswith IPF.

Clinicians confronted with treatingpatients with IPF should individualizedecisions with their patients, as suggestedby the conditional recommendations, and

they should be cautious in comparingthe relative net benefit of one interventionwith another. Significant variations ininclusion criteria, based on physiologic andanatomic variables between studies includedin these evidence summaries, as well asvariability in the level of confidence of theoverall certainty in effect estimates available,are important factors that need to beconsidered by the clinician when confrontedwith treating a patient with IPF.

The potential of combined, sequential, oradjunctive treatment regimens with agentsincluded in this guideline document havenot been studied to date, and thereforerecommendations have not beenmade. Futurehead-to-head RCTs of treatment interventionsare necessary to address these importantquestions. Also, the duration of benefitseen with these newer agents is not clear.Further research is required to better informoptimal duration of therapy. It is hoped thatthe results of such anticipated research andongoing research will clarify this soon.

Some treatment options with potentialclinical benefit (e.g., clotrimazole) in IPFwere not addressed in this update. This andother treatment interventions such astreatment for acute exacerbation,pulmonary rehabilitation, oxygensupplementation, mechanical ventilation,palliative care, and so on, as well otherpertinent new evidence that may becomeavailable, will be addressed in anotherupdate focused on treatment in the nearfuture by the committee.

Future Directions

There is an absolute need for further andlong-term studies to determine the safety andefficacy of treatment options for IPF inpatients with all spectrums of functionalimpairment. This is especially true fortreatment with drugs that receivedconditional recommendations, includingpirfenidone and nintedanib. Although it isclear that treatment with warfarin for IPF inpatients without other indications is notbeneficial, studies using other anticoagulantssuch as the new oral agents may beworthwhile. Triple therapy with prednisone,azathioprine, and N-acetylcysteine isharmful, although it is unknown whichspecific component or combination and whatdoses of the individual components causeharm. The feasibility of conducting anothertrial examining triple therapy is questionable,



especially in the context of the knownadverse effects associated with prednisoneand azathioprine and the encouraging resultswith the newer antifibrotic agents. Treatmentwith different formulation of N-acetylcysteineor other antioxidants, stratified on the basisof the burden of oxidant stress, are worthwhileconsiderations.

Although there is no benefit of endothelinreceptor antagonists for the treatment of IPF inpatients without PH, the safety profile of dualERAs in patients with IPF and their knowntherapeutic benefits for treatment of PH,especially macitentan, are worthwhileconsiderations and should dictate futurestudies looking at their role in patients with IPFwith documented PH. Pursuing treatmentwith ambrisentan, a selective ERA, is notappropriate, given the documented decline inrespiratory status seen in the context of a largeclinical trial. Future clinical studies mustaddress the potential treatment with otheragents of PH in patients with IPF.

Although the strong association ofabnormal acid GER with IPF and the veryhigh prevalence of abnormal acid GER inpatients with IPF is well known, it is lessclear whether the abnormal acid GER is thecause or the effect of IPF. Further studies arewarranted to determine the safety andefficacy of antiacid treatment, the adherenceof conservative measures to prevent or

decrease the risks of insults to the lung bymicroaspiration, and the role for surgicalcorrection to eliminate or decrease GER.

Treatment studies looking at combinationinterventions and multiple targets implicatedin the pathogenesis of IPF are needed. In thisregard, the promising results that have beenseen (and reported in this guideline document)using novel individual agents may lead toa cumulative benefit, or even a synergisticeffect, when given in combination. Indeed,drug–drug interactions, pharmacokinetics,and safety profiles will need to be delineatedbefore embarking on such clinical trials.Future clinical trials should include allconsecutive patients with IPF and stratify theextent of disease by functional impairmentand/or anatomic extent.

Importantly, the vast majority ofpatients with IPF are older than 60 years andare considered elderly, and they manifest anincreasing number of comorbidities thatwarrant prompt detection and treatmentstrategies. This includes conditions such asPH, emphysema, airflow obstruction,GERD, sleep apnea, coronary arterydiseases, and obesity.

Palliative care for symptoms, such asshortness of breath, cough, and fatigue, aswell as comfort care for the terminally ill, isessential for patients with IPF at the end oflife. Future studies need to address these as

endpoints in assessing response to newtreatment strategies.

Lung transplantation is indicated fora subgroup of patients with IPF who meetcriteria; however, it is unclear whether singleor bilateral lung transplantation ispreferential for long-term outcomes. Becauseseveral confounding and seemingly arbitraryfactors determine the clinical decision ofsingle versus bilateral lung transplantation atmost centers, future multicenter studies areneeded to determine the most appropriateuse of donor lungs to maximize availableorgans in an efficacious manner.

Finally, approaches to personalizedmedicine such as treatment stratified byanatomic, clinical, or physiologic biomarkersfound in the peripheral circulation or in thelung (tissue or bronchoalveolar lavage), andstudies with pharmacogenomics andpharmacoeconomics, are worthy of futureinvestigation. This will allow physicianstreating patients with IPF to betterunderstand the role of increasingly complexand costly treatment interventions aimed atimproving the outcomes of those with thisdisease. Most important, with continuedhigh-level and collaborative clinical and basicscience research, dedicated efforts, andadequate resources and funds, the hopes ofaborting disease progression and ultimatelycuring this disease will be met. n

Editor’s Note (Kevin Wilson, M.D.): An important aspect of this guideline was the intense effort to balance the need to minimize bias with the need forexpertise to inform decisions. According to international standards for guideline development, the strategy was to compose a panel in which the majority of co-chairs and members had no conflicts of interest. The nonconflicted members were able to participate without restrictions, whereas the conflicted memberswere allowed to discuss the evidence, but were prohibited from discussing the recommendations, formulating and grading the recommendations, and votingon the recommendations. Having observed the deliberations, I can attest that adherence to this strategy was strict, without a single violation. A commonquestion that was subsequently posed by the peer reviewers, however, is whether or not the recommendations would have differed if the conflicted expertshad been allowed unrestricted participation. I had the privilege of corresponding with the conflicted experts at the conclusion of the project, and therefore, Ican answer this question. In general, the conflicted experts would have made the same recommendations as this guideline, with one exception: there werevarying opinions regarding the antiacid recommendation. Many of the conflicted experts would have made no recommendation, citing a lack of randomizedtrials and concern that the antiacid recommendation would be perceived as equivalent to other conditional recommendations based on better evidence.

This Clinical Practice Guideline was prepared by the ATS/ERS/JRS/ALAT Committee on Treatment of IPF.

Members of the subcommittee are asfollows:

GANESH RAGHU, M.D. (Chair)HENK HOOGSTEDEN, M.D. (Co-Chair)HOLGER J. SCHUNEMANN, M.D., PH.D. (Co-Chair)BRAM ROCHWERG, M.D., M.SC.YUAN ZHANG, M.SC.CARLOS A. CUELLO GARCIA, M.D., M.SC.ARATA AZUMA, M.D., PH.D.JUERGEN BEHR, M.D.JAN L. BROZEK, M.D., PH.D.HAROLD R. COLLARD, M.D.WILLIAM CUNNINGHAM*SAKAE HOMMA, M.D.

TAKESHI JOHKOH, M.D.FERNANDO J. MARTINEZ, M.D., M.S.JEFFREY MYERS, M.D.SHANDRA L. PROTZKOLUCA RICHELDI, M.D., PH.D.DAVID RIND, M.D.MOISES SELMAN, M.D.ARTHUR THEODORE, M.D.ATHOL U. WELLS, M.D.

*The ATS, ERS, JRS, and ALAT, includingthe IPF guideline committee, are deeplyindebted to Mr. William Cunningham forhis active participation and the invaluableinput he provided in support of this

document. Sadly, he passed away October 23,2014.

Mr. Cunningham actively participated in every oneof the guideline meetings without reservation, andwhenever he spoke to offer input, other memberslistened with great care. His comments werealways objective, balanced, to the point, insightful,and respectful of other patients and the communityof healthcare providers caring for patients with IPF.The entire committee held him in the highestregard. His most meaningful input surrounded hisown experiences with IPF from the perspective ofsomeone living with this disease and havingencountered problems and frustrations directly.His ability to endure the very long hours of



teleconference-webinars and of intensediscussions over 2 consecutive days, including lateevenings, is proof of his commitment. His diligentreview of the evidence and documents circulatedand his comments were commendable and simplyincredible. His understanding of the evidence wasastounding and was reflected in his remarks.

He was very aware of the evolving knowledgeand updates concerning the management of IPFand the clinical and political landscape includingpatient advocacy groups, decisions ofregulatory agencies, and available medicationsand their relevant adverse effects. Thiscommitment was very evident up until the end,as his last communication to the group was justa few days before he sadly passed away. Mr.Cunningham’s ability to be objective with factsand figures studies in the midst of his ownillness and what he was experiencing is one ofa kind.

In essence, Mr. Cunningham was a truegentleman, scholar, and intellect, and a remarkablywise man whose input was greatly respected andappreciated by this committee and strengthenedthe significance of this document. The IPFcommunity at large is truly fortunate to have hadhisinvaluable input.

His voice was heard, loud and clear, and will beringing in the authors’ ears and minds. Theauthors offer their most sincere respects to hisfamily. May his soul rest in peace.

Author Disclosures: G.R. consulted forActelion ($1–4,999), Bayer (USA) ($1–4,999),Biogen ($1–4,999), Boehringer Ingelheim($1–4,999), Centocor/Johnson & Johnson/Janssen ($1–4,999), Celgene ($1–4,999),FibroGen ($5,000–24,999), GlaxoSmithKline($1–4,999), GeNO ($1–4,999), Gilead ($1–4,999), InterMune International (EU) ($1–4,999), Promedior ($1–4,999), Sanofi-Aventis($5,000–24,999), Stromedix ($1–4,999),Takeda ($1–4,999), Kadmon ($5,000–24,999),Roche Genentech (anticipated $5,000–24,999), UCB Celltech ($1–4,999), andVeracyte ($5,000–24,999); he served on a dataand safety monitoring board of MedImmune

($5,000–24,999) and an adjudicationcommittee of Degge ($1–4,999); and heprovided expert testimony for the U.S.Department of Justice. A.A. was on advisorycommittees of Boehringer Ingelheim($5,000–24,999), InterMune (UK) ($1–4,999),and Shionogi & Co. ($5,000–24,999), anda data and safety monitoring board of Pfizer($1–4,999). J.B. was a speaker for Actelion($5,000–24,999), Bayer Schering Pharma($5,000–24,999), Boehringer Ingelheim($5,000–24,999), and InterMune1; he receivedresearch support paid to his institution fromActelion ($25,000–49,999), BoehringerIngelheim ($25,000–49,999), and InterMune1;he was on advisory committees of Actelion($5,000–24,999), Bayer Schering Pharma($1–4,999), Boehringer Ingelheim($5,000–24,999), and InterMune1, and a dataand safety monitoring board of Actelion($5,000–24,999). H.R.C. consulted forAstraZeneca ($1–4,999), Bayer (USA)($1–4,999), Biogen ($5,000–24,999), Gilead($5,000–24,999), InterMune/Genentech($25,000–49,999), Mesoblast ($1–4,999),Pfizer ($1–4,999), Promedior ($1–4,999), andthe Pulmonary Fibrosis Foundation (paid tohis institution [$25,000–49,999]); he wasa coordinating investigator for BoehringerIngelheim1. F.J.M. consulted for AbleAssociates1, Cory Path1, CSA Medical($1–4,999), Grey Healthcare1, Ikaria ($5,000–24,999), Novartis (no payments or otherfinancial benefits), Nycomed1, Pearl1, Sudlerand Hennessey ($1–4,999), and Veracyte($1–4,999); he was on advisory committees ofBoehringer Ingelheim ($5,000–24,999),Carden Jennings ($1–4,999), Genentech1,GlaxoSmithKline1, Ikaria ($5,000–24,999),Janssen ($1–4,999), MedImmune ($5,000–24,999), Merck ($5,000–24,999), Nycomed($50,000–99,999), Pearl ($1–4,999), Pfizer($1–4,999), Roche1, and Vertex ($1–4,999),and a data and safety monitoring board ofStromedix (no payments or other financialbenefits); he was a speaker for Bayer (USA)($5,000–24,999), CME Incite ($5,000–24,999),Forest ($5,000–24,999), Foundation forImproving Patient Care1, GlaxoSmithKline1,

Haymarket1, Medscape/WebMD1, MillerCommunications ($5,000–24,999), NationalAssociation for Continuing Education($1–4,999), NCME1, Nycomed ($5,000–24,999), Paradigm1, Peer Voice1, Projects inKnowledge1, Spectrum Health1, andUpToDate1; he received research support fromBayer (USA) (no payments or other financialbenefits), Forest (no payments or otherfinancial benefits), Gilead (no payments orother financial benefits), GlaxoSmithKline($5,000–24,999), Janssen1, and Nycomed($5,000–24,999); and he received bookroyalties from Informa ($1–4,999). L.R.consulted for UCB ($5,000–24,999) and wason advisory committees of AstraZeneca($5,000–24,999), Boehringer Ingelheim($5,000–24,999), GlaxoSmithKline ($5,000–24,999), Promedior ($1–4,999), RocheGenentech ($5,000–24,999), and Sanofi-Aventis ($5,000–24,999); he was a speaker forBoehringer Ingelheim ($5,000–24,999), CiplaPharmaceuticals ($1–4,999), and InterMune($5,000–24,999), and received researchsupport paid to his institution from InterMune1.D.R. is an employee of UpToDate. B.R., Y.Z.,C.A.C.G., J.L.B., W.C., S.H., T.J., J.M., S.L.P.,M.S., A.T., A.U.W., H.H., and H.J.S. reportedno relevant commercial interests.

Acknowledgment: The authors are grateful topatients participating in clinical studies andinvestigators and sponsors of publishedreports of clinical studies; Ms. Teresa Barnes,from the Coalition for Pulmonary Fibrosis,for introducing Mr. Cunningham asa representative of patients with IPF who gavethem a strong voice in this committee; ATS,ERS, JRS, and ALAT; Kevin Wilson, M.D.,editor, ATS documents; peers and externalreviewers for providing useful input; Ms. JudyCorn, Mr. John Harmon, and the ATSDocumentation and ImplementationCommittee, ATS; and Ms. Charmaine Frazer,McMaster University, Hamilton, Ontario,Canada.

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