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      Utility of nintedanib for severe idiopathic pulmonary fibrosis: a single-center retrospective study [Letter]

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      Drug Design, Development and Therapy

      Dove Medical Press

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          Abstract

          Dear editor We read with interest the study by Abe et al on the clinical utility of nintedanib in patients with severe idiopathic pulmonary fibrosis (IPF).1 Based on the retrospective follow-up of 51 patients, the authors concluded that the survival benefit from nintedanib is reduced among patients with severe IPF (n=17) compared with those with mild-to-moderate IPF (n=34), but that the prognosis for patients with severe IPF is significantly better in those who remain on nintedanib for more than 3 months. In our opinion, the study design does not allow conclusions to be drawn about the treatment effect of nintedanib on survival in patients with severe versus mild-to-moderate IPF. First, the two study groups present clinically meaningful differences at baseline; for example, mean body weight was significantly lower in patients with severe IPF (and body weight loss is associated with decreased survival time).2 Second, a higher mortality rate among patients with severe IPF was to be expected independent of any pharmacological intervention, as lower FVC and lower diffusing capacity of the lungs for carbon monoxide (DLCO) at baseline have been associated with a worse prognosis.3 In addition, the study shows that patients with severe IPF had a greater FVC decline than those with mild-to-moderate IPF in the year before nintedanib administration. A higher decline in FVC over time has also been associated with a worse prognosis.3 In the absence of an appropriate design (ie, a prospective, randomized, and placebo-controlled study), no definite conclusions can be drawn on the survival effects of nintedanib in patients with severe IPF. The data presented by Abe et al show that initiation of nintedanib (150 mg twice daily) resulted in slower FVC decline in both mild-to-moderate and severe IPF populations, which suggest a beneficial effect of nintedanib independent of disease severity. These findings are consistent with data from the open-label extension trial INPULSIS-ON (NCT01619085)4 and the INSTAGE trial (NCT02802345),5 both of which suggest that IPF patients with more advanced functional impairment may receive the same benefit from nintedanib on reduction in FVC decline as those with less severe impairment. Furthermore, recently published real-world data from Korea6 and Greece7 also demonstrate that nintedanib reduces the rate of FVC decline in patients with more advanced IPF (FVC ≤50% or DLCO ≤35% predicted). Abe et al showed that survival was improved in patients with severe IPF who remained on nintedanib for more than 3 months, suggesting that permanence on treatment is an important therapeutic goal. As highlighted by Abe et al, management of adverse events related to nintedanib, as recommended in the prescribing information (including symptomatic treatment of diarrhea and close monitoring of liver enzyme levels), has the potential to allow patients to remain on treatment and derive long-term therapeutic benefits. Indeed, the adoption of a holistic approach to patient management, including nurse support and possible dosage adjustment, is important to maintain compliance and optimize long-term outcomes. In conclusion, findings from real-world studies, even those lacking a control group or involving relatively few patients, can provide valuable clinical insights but should be interpreted in the context of data from large, randomized controlled clinical trials. The results reported by Abe et al reinforce the need for adequate adverse event management and suggest that nintedanib slows down disease progression independent of disease severity.

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          Most cited references 5

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          Nintedanib plus Sildenafil in Patients with Idiopathic Pulmonary Fibrosis

          Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF). A subgroup analysis of a previously published trial suggested that sildenafil may provide benefits regarding oxygenation, gas exchange as measured by the diffusion capacity of the lungs for carbon monoxide (DlCO), symptoms, and quality of life in patients with IPF and severely decreased DlCO. That idea was tested in this trial.
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            Comparative efficacy, acceptability, and tolerability of lisdexamfetamine in child and adolescent ADHD: a meta-analysis of randomized, controlled trials.

             Maneeton,  DeRosa,  SE Sedykh (2015)
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              Is Open Access

              First Data on Efficacy and Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis and Forced Vital Capacity of ≤50 % of Predicted Value

              In the Phase III INPULSIS® trials, 52 weeks’ treatment with nintedanib reduced decline in forced vital capacity (FVC) versus placebo in patients with idiopathic pulmonary fibrosis (IPF). Patients who completed the INPULSIS® trials could receive nintedanib in an open-label extension trial (INPULSIS®-ON). Patients with FVC  50 % predicted at the start of INPULSIS®-ON, the absolute mean change in FVC from baseline to week 48 of INPULSIS®-ON was −62.3 and −87.9 mL, respectively (n = 24 and n = 558, respectively). No new safety signals were identified in INPULSIS®-ON compared with INPULSIS®. The decline in FVC in INPULSIS®-ON in both subgroups by baseline FVC % predicted was similar to that in INPULSIS®, suggesting that nintedanib may have a similar effect on disease progression in patients with advanced disease as in less advanced disease.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2019
                12 April 2019
                : 13
                : 1177-1178
                Affiliations
                Boehringer Ingelheim International GmbH, Ingelheim, Germany, manuel.quaresma@ 123456boehringer-ingelheim.com
                Author notes
                Correspondence: Manuel Quaresma, Boehringer Ingelheim International GmbH, Binger Str. 173, Ingelheim am Rhein 55216, Germany, Tel +49 6132 77 143 124, Email manuel.quaresma@ 123456boehringer-ingelheim.com
                Article
                dddt-13-1177
                10.2147/DDDT.S194065
                6469738
                © 2019 Orsatti et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Letter

                Pharmacology & Pharmaceutical medicine

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