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Editorials: Point and Counterpoint |

POINT: Should All Patients With Idiopathic Pulmonary Fibrosis, Even Those With More Than Moderate Impairment, Be Treated With Nintedanib or Pirfenidone? Yes FREE TO VIEW

Christopher S. King, MD, FCCP; Steven D. Nathan, MD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: S. D. N. is on speaker’s bureaus and advisory boards and has received financial support for research from Roche and Boerhinger Ingelheim. None declared (C. S. K.).

Advanced Lung Disease and Transplant Clinic, Inova Fairfax Hospital, Falls Church, VA

CORRESPONDENCE TO: Christopher S. King, MD, FCCP, Inova Fairfax Hospital, Advanced Lung Disease and Transplantation Clinic, 3300 Gallows Rd, Falls Church, VA 22042


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(2):273-275. doi:10.1016/j.chest.2016.04.034
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Published online

The lack of medical options for the treatment of idiopathic pulmonary fibrosis (IPF) has long been a source of frustration and consternation for pulmonologists treating this deadly disorder. This previously led to the adoption of therapies with little supportive data, some of which have subsequently proved not only to be ineffective but also deleterious., The early 2000s heralded a new era in clinical trials for IPF, with multiple multicenter studies being successfully completed. A wealth of valuable information about the natural history of the disease, but few positive studies, emanated from these robust clinical trials. These studies also spawned a certain amount of controversy regarding suitable and acceptable end points for IPF clinical trials. The labor and commitment of many patients, physicians, principal investigators, research coordinators, pharmaceutical companies, and governmental agencies finally bore fruit with two drugs being approved for the treatment of IPF contemporaneously by the US Food and Drug Administration (FDA). This has marked a turning point and a new era in the management of these patients. Although the development of efficacious pharmacologic therapy for IPF has provided renewed hope for this deadly disease, it has also led to many questions regarding the optimal use of these agents. Who should be prescribed these medications, when should they be started, and when, if ever, should they be stopped?

All studies, not only IPF clinical trials, tend to have very specific inclusionary and exclusionary criteria. There are a number of valid reasons for this in the case of IPF studies. Exclusionary criteria are necessary to omit patients with comorbidities that are likely to impact their clinical course and “muddy the waters” with regard to the trial end point. The goals of the inclusionary criteria include ensuring, as best as possible, that patients enrolled truly have the disease. In this regard, we do believe strongly that pirfenidone and nintedanib should only be prescribed to patients with well-established IPF or “probable” IPF. Inclusionary criteria are also designed to enroll patients who are likely to deteriorate during the course of the study and who have sufficient reserve to demonstrate such deterioration. The net result is that patients with “very early” disease (more likely to stay stable) and those with “severe” disease (“the horse is out of the barn” phenomenon) are typically excluded.

Clinicians are faced with the choice of adopting a “purist” stance vs a more pragmatic approach in deciding who should be offered therapy. The former approach entails prescribing the drugs only to those patients with IPF who fall within the strict inclusionary criteria of the respective studies. As an example, patients with an FVC < 50% predicted or diffusing capacity of the lung for carbon monoxide (Dlco) < 30% predicted would not be offered the opportunity for therapy, as these values marked the lower limit of lung function in the pivotal drug trials. Indeed, it is likely that many patients with this deadly disorder would, by these or other criteria, be disqualified from receiving any therapy. Table 1 summarizes the major inclusion and exclusion criteria of the respective phase III trials of nintedanib and pirfenidone that would define candidates eligible for therapy.,,

Table Graphic Jump Location
Table 1 Major Inclusion and Exclusion Criteria of Nintedanib and Pirfenidone Phase III Trials

6MWT = 6-min walk test; CHF = congestive heart failure; CTD = connective tissue disease; Dlco = diffusing capacity of the lung for carbon monoxide; IPF = idiopathic pulmonary fibrosis; LFTs = liver function tests; MI = myocardial infarction; SLBx = surgical lung biopsy; UIP = usual interstitial pneumonia.

On the other end of the spectrum, a more pragmatic approach embraces the concept that if the drugs have demonstrated efficacy in a highly selected population of patients with IPF, they are likely to work in other patients with the same disease, including those with very early or more severe disease. It should be borne in mind that the selected cut points for FVC and Dlco are arbitrary. Certainly on a population level, worsening severity of restrictive lung disease and impairment in diffusing capacity are associated with increased mortality in IPF. However, the ability of FVC and Dlco to clearly delineate severity in individual patients is inherently flawed. One reason for this is that the current FVC % predicted fails to account for the baseline FVC predicted prior to the development of IPF. By way of example, a patient with a starting FVC of 100% predicted would likely have more severe disease and more functional impairment than a patient whose FVC started at 80% predicted prior to the development of disease. There are certainly patients with a FVC < 50% predicted who appear clinically “mild” with perhaps some oxygen requirement and exercise limitation but who do not pass the “eyeball test” for having severe disease. On the other end of the spectrum, a patient with a prior baseline FVC of 120% can have significant disease when they present with a “normal” FVC of 100%.

Both nintedanib and pirfenidone have been demonstrated to slow progression of disease, reducing the rate of decline in FVC.,, In severe disease, it remains biologically plausible that these agents will continue to do so. The heterogeneous nature of the disease, both spatially (within the lung) and temporally (over time), results in a continuum of disease within the lung. This ranges from end-stage fibrosis (with honeycombing) and includes areas of fresh collagen deposition with fibroblast foci, as well as areas of normal lung. This spectrum of histopathologic changes is evident even in patients with the most severe disease. It would appear to make sense to consider therapy in all patients to prevent further progression of these less affected areas. However, since patients with severe disease were excluded from the major trials, evidence supporting this contention remains sparse. A recent retrospective analysis of interstitial lung disease clinics in Italy found that patients with more severe IPF as defined by a GAP index of II/III derived more benefit with respect to a reduction in decline of FVC (P = .041) in comparison with patients with GAP index 1 disease when treated with pirfenidone., In addition, subsequent subgroup analyses from the pivotal phase III studies of nintedanib and pirfenidone demonstrated that both drugs had similar treatment effects in the subgroups with more severe and milder disease., Since there is no gradient of efficacy based on disease severity within the studies, one might speculate that a similar treatment effect may be seen in those with disease severity beyond the limits of the respective studies.

On the “early” side of the spectrum, it makes sense to try and preserve lung function as long as possible with the institution of therapy. After all, any loss of lung function is irreversible and is invariably accompanied by the onset or worsening of clinical symptoms. We recognize that there is controversy regarding any mortality benefit from both available agents; however, it is well established that patients with preserved lung function are at lower risk of death. Therefore, when weighing the decision to start therapy in patients with early disease, it is important to place this in the context of the 2½- to 4-year median survival and the difficulty in predicting the course in individual patients. Granted, there is a subgroup of 5-year (and longer) survivors, who constitute about 24% of all-comers. We therefore contend that given the relative odds of early death versus late survival, one should not withhold therapy in those with even the mildest forms of the disease.

What of the downside to these agents? Certainly cost is a consideration, and although we must be cost conscious in our approach as providers, we believe efforts to limit health care costs should be focused on eliminating practices that add no value to care and in working on policy changes with the pharmaceutical industry to regulate costs rather than denying potential disease-modifying agents in a progressive and terminal condition. We do not, therefore, advocate initiation of therapy in patients with life-limiting severe comorbid conditions, very advanced disease with New York Heart Association Functional class IV, or severe hypoxemic respiratory failure (or a combination of these conditions). The other potential downside to these medications are side effects. However, discontinuation rates were fairly low in the randomized controlled trials (RCTs); 14.4% in the treatment arm (compared with 10.8% in the placebo arm of ASCEND and < 5% of study patients in INPULSIS)., Real-world data have demonstrated that both drugs maintain favorable side effect profiles and are well tolerated., We do not believe that any patient with IPF should be denied access to therapy for fear of side effects, which if they occur may be temporary and quite manageable.

Obviously, RCT data supporting the use of pirfenidone and nintedanib in severe IPF would be ideal. However, do we simply stand by while our sicker patients with IPF invariably experience disease progression while we await studies that are unlikely to ever be completed? When faced with this clinical situation, clinicians should not be handcuffed by evidence-based medicine but should be free to extrapolate the available data to arrive at an educated mutually agreeable therapeutic decision with our patients. Indeed, the FDA labeling of both drugs states quite simply “…approved for the treatment of idiopathic pulmonary fibrosis” with no mention of disease severity. This can therefore be interpreted as a tacit endorsement to use these drugs beyond the boundaries of the inclusion and exclusionary criteria of the respective studies in well-informed patients with well-established IPF.

References

Raghu G. .Anstrom K.J. . Idiopathic Pulmonary Fibrosis Clinical Research Networket al Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366:1968-1977 [PubMed]journal. [CrossRef] [PubMed]
 
Noth I. .Anstrom K.J. .Calvert S.B. .et al A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186:88-95 [PubMed]journal. [CrossRef] [PubMed]
 
Nathan S.D. .Meyer K.C. . IPF clinical trial design and endpoints. Curr Opin Pulm Med. 2014;20:463-471 [PubMed]journal. [CrossRef] [PubMed]
 
Karimi-Shah B.A. .Chowdhury B.A. . Forced vital capacity in idiopathic pulmonary fibrosis—FDA review of pirfenidone and nintedanib. N Engl J Med. 2015;372:1189-1191 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Collard H.R. .Egan J.J. .et al An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788-824 [PubMed]journal. [CrossRef] [PubMed]
 
Noble P.W. .Albera C. .Bradford W.Z. .et al Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377:1760-1769 [PubMed]journal. [CrossRef] [PubMed]
 
King T.E. Jr..Bradford W.Z. .Castro-Bernardini S. .et al A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083-2092 [PubMed]journal. [CrossRef] [PubMed]
 
Richeldi L. .du Bois R.M. .Raghu G. .et al Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071-2082 [PubMed]journal. [CrossRef] [PubMed]
 
Ley B. .Ryerson C.J. .Vittinghoff E. .et al A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156:684-691 [PubMed]journal. [CrossRef] [PubMed]
 
Harari S. .Caminati A. .Albera C. .et al Efficacy of pirfenidone for idiopathic pulmonary fibrosis: an Italian real life study. Respir Med. 2015;109:904-913 [PubMed]journal. [CrossRef] [PubMed]
 
Kolb M. .Richeldi L. .Kimura T. .et al Effect of baseline FVC on decline in lung function with nintedanib in patients with IPF: Results from the INPULSIS trials. Am J Respir Crit Care Med. 2015;191:A1021- [PubMed]journal
 
Albera C. .Bradford W.Z. .Costabel U. .et al Pirfenidone is efficacious in patients with idiopathic pulmonary fibrosis (IPF) and mild or more pronounced physiological impairment. Am J Respir Crit Care Med. 2015;191:A1018- [PubMed]journal
 
Nathan S.D. .Shlobin O.A. .Weir N. .et al Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest. 2011;140:221-229 [PubMed]journal. [CrossRef] [PubMed]
 
Cottin V. .Maher T. . Long-term clinical and real-world experience with pirfenidone in the treatment of idiopathic pulmonary fibrosis. Eur Respir Rev. 2015;24:58-64 [PubMed]journal. [CrossRef] [PubMed]
 
Crestani B. .Ogura M. .Pelling K. .et al Safety and Tolerability of nintedanib in patients with IPF: interim analysis from an open-label extension of the Inpulsis trials (Inpulsis-On). Am J Respir Crit Care Med. 2015;191:A1020- [PubMed]journal
 

Figures

Tables

Table Graphic Jump Location
Table 1 Major Inclusion and Exclusion Criteria of Nintedanib and Pirfenidone Phase III Trials

6MWT = 6-min walk test; CHF = congestive heart failure; CTD = connective tissue disease; Dlco = diffusing capacity of the lung for carbon monoxide; IPF = idiopathic pulmonary fibrosis; LFTs = liver function tests; MI = myocardial infarction; SLBx = surgical lung biopsy; UIP = usual interstitial pneumonia.

References

Raghu G. .Anstrom K.J. . Idiopathic Pulmonary Fibrosis Clinical Research Networket al Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366:1968-1977 [PubMed]journal. [CrossRef] [PubMed]
 
Noth I. .Anstrom K.J. .Calvert S.B. .et al A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186:88-95 [PubMed]journal. [CrossRef] [PubMed]
 
Nathan S.D. .Meyer K.C. . IPF clinical trial design and endpoints. Curr Opin Pulm Med. 2014;20:463-471 [PubMed]journal. [CrossRef] [PubMed]
 
Karimi-Shah B.A. .Chowdhury B.A. . Forced vital capacity in idiopathic pulmonary fibrosis—FDA review of pirfenidone and nintedanib. N Engl J Med. 2015;372:1189-1191 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Collard H.R. .Egan J.J. .et al An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788-824 [PubMed]journal. [CrossRef] [PubMed]
 
Noble P.W. .Albera C. .Bradford W.Z. .et al Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377:1760-1769 [PubMed]journal. [CrossRef] [PubMed]
 
King T.E. Jr..Bradford W.Z. .Castro-Bernardini S. .et al A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083-2092 [PubMed]journal. [CrossRef] [PubMed]
 
Richeldi L. .du Bois R.M. .Raghu G. .et al Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071-2082 [PubMed]journal. [CrossRef] [PubMed]
 
Ley B. .Ryerson C.J. .Vittinghoff E. .et al A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156:684-691 [PubMed]journal. [CrossRef] [PubMed]
 
Harari S. .Caminati A. .Albera C. .et al Efficacy of pirfenidone for idiopathic pulmonary fibrosis: an Italian real life study. Respir Med. 2015;109:904-913 [PubMed]journal. [CrossRef] [PubMed]
 
Kolb M. .Richeldi L. .Kimura T. .et al Effect of baseline FVC on decline in lung function with nintedanib in patients with IPF: Results from the INPULSIS trials. Am J Respir Crit Care Med. 2015;191:A1021- [PubMed]journal
 
Albera C. .Bradford W.Z. .Costabel U. .et al Pirfenidone is efficacious in patients with idiopathic pulmonary fibrosis (IPF) and mild or more pronounced physiological impairment. Am J Respir Crit Care Med. 2015;191:A1018- [PubMed]journal
 
Nathan S.D. .Shlobin O.A. .Weir N. .et al Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest. 2011;140:221-229 [PubMed]journal. [CrossRef] [PubMed]
 
Cottin V. .Maher T. . Long-term clinical and real-world experience with pirfenidone in the treatment of idiopathic pulmonary fibrosis. Eur Respir Rev. 2015;24:58-64 [PubMed]journal. [CrossRef] [PubMed]
 
Crestani B. .Ogura M. .Pelling K. .et al Safety and Tolerability of nintedanib in patients with IPF: interim analysis from an open-label extension of the Inpulsis trials (Inpulsis-On). Am J Respir Crit Care Med. 2015;191:A1020- [PubMed]journal
 
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