Advertisement

Impact of reduction in antifibrotic treatment on mortality in idiopathic pulmonary fibrosis

Published:October 24, 2022DOI:https://doi.org/10.1016/j.rmed.2022.107015

      Highlights

      • A remarkably high number of patients with IPF receive reduced antifibrotic treatment.
      • Low antifibrotic treatment adherence in IPF despite best-case scenario conditions.
      • Antifibrotics seem superior in improving survival in IPF.
      • Survival benefits of antifibrotics remain even after treatment reduction in IPF.

      Abstract

      Introduction

      Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease for which two effective antifibrotics, nintedanib and pirfenidone, are available. However, many patients receive a reduced dosage or pause treatment due to side effects although the impact of antifibrotic treatment reduction is uncertain.

      Methods

      We retrospectively investigated the impact of antifibrotic treatment reduction on death in a large real-life IPF cohort. The primary endpoint of the analyses was time until death by any cause. Five patient groups were defined based on treatment intensity (full, reduced or no treatment) and the antifibrotic drug type (pirfenidone or nintedanib). Between group survival was compared using Cox proportional hazards analysis adjusted for age, sex, smoking status, and lung function at baseline.

      Results

      375 patients from the Danish PFBIO-cohort were followed from April 2016 until November 2021 with a median follow-up time of 1.84 years. Of patients receiving nintedanib and pirfenidone, 80.19% and 67.42% had reduced treatment, respectively, when considering the entire follow-up period.
      Treatment with nintedanib and pirfenidone was associated with improved survival compared to no antifibrotic treatment independent of treatment intensity (nintedanib: HR: 0.31, 95%-CI: 0.19–0.53, p < 0.001 & pirfenidone: HR: 0.26, 95%-CI: 0.16–0.42, p < 0.001). Nintedanib and pirfenidone in lower intensities were not associated with worse survival outcomes.

      Conclusion

      A substantial proportion of patients with IPF receive reduced antifibrotic treatment to ameliorate the side effects associated with a full dosage regime. Treatment with nintedanib and pirfenidone, independent of treatment intensity, was preferable over no antifibrotic treatment in improving survival and reduced dose appears to be a good alternative if full dose is not tolerated.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Respiratory Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Raghu G.
        • Chen S.-Y.
        • Yeh W.-S.
        • Maroni B.
        • Li Q.
        • Lee Y.-C.
        • et al.
        Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11.
        Lancet Respir. Med. 2014 Jul; 2: 566-572
        • American Thoracic Society
        Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS).
        Am. J. Respir. Crit. Care Med. 2000 Feb; 161: 646-664
      1. EMA. Esbriet | European Medicines Agency [Internet]. [cited 2021 Mar 14]. Available from:.https://www.ema.europa.eu/en/medicines/human/EPAR/esbriet.

      2. EMA. Ofev | European Medicines Agency [Internet]. [cited 2021 Mar 14]. Available from:.https://www.ema.europa.eu/en/medicines/human/EPAR/ofev#authorisation-details-section.

        • Cerri S.
        • Monari M.
        • Guerrieri A.
        • Donatelli P.
        • Bassi I.
        • Garuti M.
        • et al.
        Real-life comparison of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis: a 24-month assessment.
        Respir. Med. 2019 Nov 1; 159105803
        • Dempsey T.M.
        • Sangaralingham L.R.
        • Yao X.
        • Sanghavi D.
        • Shah N.D.
        • Limper A.H.
        Clinical effectiveness of antifibrotic medications for idiopathic pulmonary fibrosis.
        Am. J. Respir. Crit. Care Med. 2019; 200: 168-174
        • Nathan S.D.
        • Albera C.
        • Bradford W.Z.
        • Costabel U.
        • Glaspole I.
        • Glassberg M.K.
        • et al.
        Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis.
        Lancet Respir. Med. 2017; 5: 33-41
        • Margaritopoulos G.A.
        • Trachalaki A.
        • Wells A.U.
        • Vasarmidi E.
        • Bibaki E.
        • Papastratigakis G.
        • et al.
        Pirfenidone improves survival in IPF: results from a real-life study.
        BMC Pulm. Med. 2018; 18: 1-7
      3. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet [Internet]. 2011 May 21 [cited 2021 Mar 13];377(9779):1760–9. Available from: https://doi.org/10.1016/S0140-6736(11)60405-4.

      4. Lancaster L, Crestani B, Hernandez P, Inoue Y, Wachtlin D, Loaiza L, et al. Safety and survival data in patients with idiopathic pulmonary fibrosis treated with nintedanib: pooled data from six clinical trials. Available from:.http://bmjopenrespres.bmj.com/.

        • Richeldi L.
        • du Bois R.M.
        • Raghu G.
        • Azuma A.
        • Brown K.K.
        • Costabel U.
        • et al.
        Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.
        N. Engl. J. Med. 2014 May 29; 370: 2071-2082
      5. Antoniou K, Markopoulou K, Tzouvelekis A, Trachalaki A, Vasarmidi E, Organtzis J, et al. Efficacy and safety of nintedanib in a Greek multicentre idiopathic pulmonary fibrosis registry: a retrospective, observational, cohort study. Available from: https://doi.org/10.1183/23120541.00172-2019].

      6. Wuyts WA, Dahlqvist C, Slabbynck H, Schlesser M, Gusbin N, Compere C, et al. Longitudinal clinical outcomes in a real-world population of patients with idiopathic pulmonary fibrosis: the PROOF registry. Available from:.https://doi.org/10.1186/s12931-019-1182-z.

        • Agrawal N.
        • Vaidya P.J.
        • Chavhan V.B.
        • Lele T.T.
        • Leuppi-Taegtmeyer A.
        • Leuppi J.D.
        • et al.
        Best tolerated dose of Pirfenidone in patients with idiopathic pulmonary fibrosis.
        ([Internet])in: European Respiratory Journal. European Respiratory Society (ERS), 2019 ([cited 2021 Apr 5]. p. PA4707. Available from:)
        • Toi Y.
        • Kimura Y.
        • Domeki Y.
        • Kawana S.
        • Aiba T.
        • Ono H.
        • et al.
        Association of low body surface area with dose reduction and/or discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: a pilot study.
        Sarcoidosis, Vasc Diffus lung Dis Off J WASOG. 2019; 36: 74-78
        • Song M.J.
        • Moon S.W.
        • Choi J.S.
        • Lee S.H.S.H.
        • Lee S.H.S.H.
        • Chung K.S.
        • et al.
        Efficacy of low dose pirfenidone in idiopathic pulmonary fibrosis: real world experience from a tertiary university hospital.
        Sci. Rep. 2020 Dec 1; 10
        • Toellner H.
        • Hughes G.
        • Beswick W.
        • Crooks M.G.
        • Donaldson C.
        • Forrest I.
        • et al.
        Early clinical experiences with nintedanib in three UK tertiary interstitial lung disease centres.
        Clin. Transl. Med. 2017; 6: 41
        • Bonella F.
        • Kreuter M.
        • Hagmeyer L.
        • Neurohr C.
        • Keller C.
        • Kohlhaeufl M.J.
        • et al.
        Insights from the German compassionate use program of nintedanib for the treatment of idiopathic pulmonary fibrosis.
        Respiration. 2016; 92: 98-106
        • Hoyer N.
        • Prior T.S.
        • Bendstrup E.
        • Wilcke T.
        • Shaker S.B.
        Risk factors for diagnostic delay in idiopathic pulmonary fibrosis.
        Respir. Res. 2019 May; 20: 103
        • Raghu G.
        • Collard H.R.
        • Egan J.J.
        • Martinez F.J.
        • Behr J.
        • Brown K.K.
        • 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
        • Raghu G.
        • Remy-Jardin M.
        • Myers J.L.
        • Richeldi L.
        • Ryerson C.J.
        • Lederer D.J.
        • et al.
        Diagnosis of idiopathic pulmonary fibrosis an Official ATS/ERS/JRS/ALAT Clinical practice guideline.
        Am. J. Respir. Crit. Care Med. 2018 Sep 1; 198: e44-e68
        • Richeldi L.
        • Costabel U.
        • Selman M.
        • Soon Kim D.
        • Hansell D.M.
        • Nicholson A.G.
        • et al.
        Efficacy of a Tyrosine Kinase Inhibitor in Idiopathic Pulmonary Fibrosis. vol. 12. 2011 (n engl j med)
        • Flaherty K.R.
        • Wells A.U.
        • Cottin V.
        • Devaraj A.
        • Walsh S.L.F.
        • Inoue Y.
        • et al.
        Nintedanib in progressive fibrosing interstitial lung diseases.
        N. Engl. J. Med. 2019 Oct; 381: 1718-1727
        • Distler O.
        • Highland K.B.
        • Gahlemann M.
        • Azuma A.
        • Fischer A.
        • Mayes M.D.
        • et al.
        Nintedanib for systemic sclerosis-associated interstitial lung disease.
        N. Engl. J. Med. 2019 Jun 27; 380: 2518-2528
        • Kolb M.
        • Collard H.R.
        Staging of idiopathic pulmonary fibrosis: past, present and future.
        Eur. Respir. Rev. 2014; 23: 220-224