0
Editorials: Point and Counterpoint |

COUNTERPOINT: Should All Patients With Idiopathic Pulmonary Fibrosis, Even Those With More Than Moderate Impairment, Be Treated With Nintedanib or Pirfenidone? No FREE TO VIEW

Kevin K. Brown, MD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST the following: K. K. B. has received multiple lung fibrosis grants from NHLBI; grants and personal fees from Actelion, Amgen, and Gilead; and personal fees from Almiral, Altitude Pharma, AstraZeneca, Bayer, Biogen/Stromedix, Boehringer Ingelheim, Celgene, Centocor, Fibrogen, Galecto, GlaxoSmithKline, MedImmune, Novartis, Pfizer, Promedior, Roche/Genentech, Sanofi/Genzyme, Aeolus, ProMetric, and Veracyte.

Department of Medicine, National Jewish Health, Denver, CO

CORRESPONDENCE TO: Kevin K. Brown, MD, FCCP, Department of Medicine, National Jewish Health, 1400 Jackson St, Denver, CO 80206


Copyright 2016, . All Rights Reserved.


Chest. 2016;150(2):276-278. doi:10.1016/j.chest.2016.04.036
Text Size: A A A
Published online

The fall of 2014 marked a new era in the management of patients with idiopathic pulmonary fibrosis (IPF), with the US Food and Drug Administration approval of not one but two therapies for its treatment. This came on the heels of a recent issue of the New England Journal of Medicine that included the results of three separate late-phase interventional trials as well as an accompanying editorial.,,, This is truly a dramatic advance in what was once considered a disease too rare to ever be adequately studied.

The study designs of the two approved therapies, pirfenidone and nintedanib, were similar and both met their primary end points, slowing the overall rate of decline in FVC, and did so with an acceptable safety profile. Although neither study was powered to show a mortality benefit, positive survival trends were noted in both trials. Pirfenidone also suggested a benefit in slowing the yearly loss of submaximal exercise capacity as measured by 6-min walk distance, whereas nintedanib suggested the possibility of a quality-of-life benefit and a lower risk of a common complication of IPF, that is, acute exacerbation. Many will note that the primary end point in these studies, the decline in FVC, is not a clinical end point (how a patient feels, how they function, or how long they live) but a surrogate end point. This distinction has been the focus of reasoned debate in the IPF community, and may be important for individual patients, as it probably should have an influence on what they and their physicians expect in response to therapy.

Should your patient be treated? This is answered by weighing risks and benefits for individuals rather than populations of patients. Large-scale, late-stage interventional treatment trials in chronic diseases are often of long duration, inefficient, resource intensive, and extremely costly. Sponsors appropriately want to focus their limited resources on a subpopulation of patients most likely to show a benefit from the intervention. A number of strategies are frequently used to enrich study populations for subjects who are likely to show a treatment response as defined by the primary end point. These might include more complex efforts to confirm the disease of interest than would otherwise be used in practice, limiting disease severity and minimizing comorbidities and other medications, particularly those that might limit the ability to see a response or might increase the risk of an adverse event. By necessity, this approach excludes significant numbers and classes of patients who have the disease of interest. Does this mean that only patients who fit the inclusion/exclusion criteria of a defining interventional trial should be treated? No, but it does demand a level of caution and weighing of individual risks and benefits that exceeds that used when a patient looks like those who were included in a definitive trial.

For example, in the recent Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF (ASCEND) trial of pirfenidone, the sponsor made a number of changes to the inclusion/exclusion criteria when compared with its predecessor trials Clinical Studies Assessing Pirfenidone in IPF: Research of Efficacy and Safety Outcomes (CAPACITY) 1 and 2. As the CAPACITY trials produced conflicting results, for the ASCEND study, the sponsor narrowed the diagnostic criteria, shortened the duration of observation, and required central rather than local review of important clinical data. Presumably this was done to increase the likelihood of identifying a subject population likely to show a clear benefit. However, there was a cost to this approach, the doubling of the screen failure rate. Thus, in this definitive trial, only a minority of the patients with IPF referred for enrollment were deemed appropriate for the study. Beyond this, even the patients with IPF referred for trial consideration likely differ in important ways from the broad population of patients now being considered for treatment.

What are the risks for your patient? The importance of this question was recently highlighted by the results of the PANTHER trial sponsored by the National Institutes of Health National Heart, Lung, and Blood Institute. In this study of the potential benefit of what was at the time considered to be conventional IPF therapy, active treatment was clearly shown to be harmful in the population studied. With this in mind, the safety profiles of both compounds suggest primarily nonserious (which should not read as unimportant) and reversible adverse reactions. For patients with IPF who do not meet the studies’ inclusion criteria, is there reason to believe that the drugs might have a different safety profile, that is, will the medicines be as safe in the broad IPF population? Although it is likely that safety will mirror that seen in the trials, definitive answers are not possible with the available data. Separate from overall safety is the question of the acceptability of adverse effects. Drug-related adverse effects were common in both studies and, like most medicines, treatment-limiting reactions occurred. What adverse effects are you and the patient willing to risk and which are you both willing to accept? For an individual patient, initiating treatment in the face of likely side effects or continuing treatment when adverse effects are present, depends on the benefits expected or hoped for and the benefits actually experienced.

Will the medication benefit your patient? This is the question that drives the initiation or continuation of treatment. This should be informed by what you and your patient expect the treatment to do and how you will decide whether or not it is working. These therapies slow the rate of disease progression; they do not cure, reverse, or permanently stabilize the debilitating clinical impact of IPF. Patients are not expected to feel better or to be able to do more. Both drugs slowed the decline in FVC in the treated population when compared with placebo. Unfortunately, you cannot confidently use the rate of FVC decline over 1 year as a measure of clinical effect in an individual patient. This would require the ability to predict an individual’s future rate of FVC decline in the absence of therapy, and this is not possible, as uncertainty about future change is the rule in IPF. In fact, in most IPF treatment trials, the FVC is stable in the majority of individual placebo-treated subjects over the course of the study. If you choose survival as the measure of benefit, recognize that the mortality rates in both trials were quite low and neither drug showed a definitive mortality benefit; in fact, those patients with IPF with the highest short-term mortality, that is, those with the most physiologically severe disease, were actively excluded from both studies. For pirfenidone, available data suggest that the treatment may not be helpful for those with severe disease. Unfortunately, the rest of the available data from these trials provides no definitive guidance on what can be used as a reliable measure of treatment response for an individual patient.

Dramatic progress has been made in our search for safe and beneficial therapy in the treatment of IPF. However, this does not mean that all patients with the disease should now be treated with one of the new medicines. Some patients and physicians will appropriately feel that the risk of important adverse events outweighs any expected or hoped-for benefits. At a minimum, those patients with long-standing stable disease, those with physiologically severe disease, those with significant comorbidities that are likely to limit long-term survival or quality of life, and those at high risk for limiting adverse effects require thoughtful consideration before initiating treatment. In those who choose not to be treated, there still is plenty to do. A formal exercise program to improve quality of life, the use of supplemental oxygen to relieve dyspnea and improve exercise capacity, vaccination against common respiratory infections, identification and treatment of known comorbidities such as OSA and gastroesophageal reflux, and appropriate antibiotic use may all provide important benefits to individuals. In the end, the decision to treat an individual patient with one of our newly approved therapies comes down to the original definition of personalized medicine, a thoughtful and reasoned discussion between a patient and the physician about hopes and expectations for the future, the goals of treatment, and the risks and benefits of any chosen course.

References

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]
 
King T.E. Jr..Bradford W.Z. .Castro-Bernadini 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]
 
The Idiopathic Pulmonary Fibrosis Clinical Research Network Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2093-2101 [PubMed]journal. [CrossRef] [PubMed]
 
Hunninghake G.M. . A new hope for idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2142-2143 [PubMed]journal. [CrossRef] [PubMed]
 
Silverman J.J. .Talbot T.J. . Diffuse interstitial pulmonary fibrosis camouflaged by hypermetabolism and cardiac failure; antemortem diagnosis with biopsy and catheterization studies. Ann Intern Med. 1953;38:1326-1338 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Collard H.R. .Anstrom K.J. .et al Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med. 2012;185:1044-1048 [PubMed]journal. [CrossRef] [PubMed]
 
Wells A.U. .Behr J. .Costabel U. .et al Hot off the breath: mortality as a primary end-point in IPF treatment trials: the best is the enemy of the good. Thorax. 2012;67:938-940 [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]
 
Wells A.U. .Latsi P. .McCune W.J. . Daily cyclophosphamide for scleroderma: Are patients with the most to gain underrepresented in this trial? Am J Respir Crit Care Med. 2007;176:952-953 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Anstrom K.J. .King T.E. Jr..Lasky J.A. .Martinez F.J. . Idiopathic Pulmonary Fibrosis Clinical Research Network Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366:1968-1977 [PubMed]journal. [CrossRef] [PubMed]
 
Schmidt S.L. .Tayob N. .Han M.K. .et al Predicting pulmonary fibrosis disease course from past trends in pulmonary function. Chest. 2014;145:579-585 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Johnson W.C. .Lockhart D. .Mageto Y. . Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study. Am J Respir Crit Care Med. 1999;159:1061-1069 [PubMed]journal. [CrossRef] [PubMed]
 
Dowman L. .Hill C.J. .Holland A.E. . Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev. 2014;10:CD006322- [PubMed]journal. [PubMed]
 
Lee J.S. .Collard H.R. .Anstrom K.J. . IPFnet Investigatorset al Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med. 2013;1:369-376 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

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]
 
King T.E. Jr..Bradford W.Z. .Castro-Bernadini 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]
 
The Idiopathic Pulmonary Fibrosis Clinical Research Network Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2093-2101 [PubMed]journal. [CrossRef] [PubMed]
 
Hunninghake G.M. . A new hope for idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2142-2143 [PubMed]journal. [CrossRef] [PubMed]
 
Silverman J.J. .Talbot T.J. . Diffuse interstitial pulmonary fibrosis camouflaged by hypermetabolism and cardiac failure; antemortem diagnosis with biopsy and catheterization studies. Ann Intern Med. 1953;38:1326-1338 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Collard H.R. .Anstrom K.J. .et al Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med. 2012;185:1044-1048 [PubMed]journal. [CrossRef] [PubMed]
 
Wells A.U. .Behr J. .Costabel U. .et al Hot off the breath: mortality as a primary end-point in IPF treatment trials: the best is the enemy of the good. Thorax. 2012;67:938-940 [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]
 
Wells A.U. .Latsi P. .McCune W.J. . Daily cyclophosphamide for scleroderma: Are patients with the most to gain underrepresented in this trial? Am J Respir Crit Care Med. 2007;176:952-953 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Anstrom K.J. .King T.E. Jr..Lasky J.A. .Martinez F.J. . Idiopathic Pulmonary Fibrosis Clinical Research Network Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366:1968-1977 [PubMed]journal. [CrossRef] [PubMed]
 
Schmidt S.L. .Tayob N. .Han M.K. .et al Predicting pulmonary fibrosis disease course from past trends in pulmonary function. Chest. 2014;145:579-585 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Johnson W.C. .Lockhart D. .Mageto Y. . Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study. Am J Respir Crit Care Med. 1999;159:1061-1069 [PubMed]journal. [CrossRef] [PubMed]
 
Dowman L. .Hill C.J. .Holland A.E. . Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev. 2014;10:CD006322- [PubMed]journal. [PubMed]
 
Lee J.S. .Collard H.R. .Anstrom K.J. . IPFnet Investigatorset al Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med. 2013;1:369-376 [PubMed]journal. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543