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Cited by 195Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisSarcoidosis and Beryllium Toxicity ResearchOccupational exposure and asthma

Survival and course of lung function in the presence or absence of antifibrotic treatment in patients with idiopathic pulmonary fibrosis: long-term results of the INSIGHTS-IPF registry

Open access
Behr, Jürgen, Prasse, Antje, Wirtz, Hubert, Koschel, Dirk, Pittrow, David, Held, Matthias, Klotsche, Jens, Andreas, Stefan +16 more·2020·European Respiratory Journal
DOI 10.1183/13993003.02279-2019
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Abstract

Objective There is a paucity of observational data on antifibrotic therapy for idiopathic pulmonary fibrosis (IPF). We aimed to assess the course of disease of IPF patients with and without antifibrotic therapy under real-life conditions. Methods We analysed data from a non-interventional, prospective cohort study of consecutively enrolled IPF patients from 20 interstitial lung disease expert centres in Germany. Data quality was ensured by automated plausibility checks, on-site monitoring, and source data verification. Propensity scores were applied to account for known differences in baseline characteristics between patients with and without antifibrotic therapy. Results Among the 588 patients suitable for analysis, the mean±sdage was 69.8±9.1 years, and 81.0% were male. The mean±sdduration of disease since diagnosis was 1.8±3.4 years. The mean±sdvalue at baseline for forced vital capacity (FVC) and diffusion capacity (DLCO) were 68.6±18.8% predicted and 37.8±18.5% predicted, respectively. During a mean±sdfollow-up of 1.2±0.7 years, 194 (33.0%) patients died. The 1-year and 2-year survival rates were 87%versus46% and 62%versus21%, respectively, for patients withversuswithout antifibrotic therapy. The risk of death was 37% lower in patients with antifibrotic therapy (hazard ratio 0.63, 95% CI 0.45; 0.87; p=0.005). The results were robust (and remained statistically significant) on multivariable analysis. Overall decline of FVC andDLCOwas slow and did not differ significantly between patients with or without antifibrotic therapy. Conclusions Survival was significantly higher in IPF patients with antifibrotic therapy, but the course of lung function parameters was similar in patients with and without antifibrotic therapy. This suggests that in clinical practice, premature mortality of IPF patients eventually occurs despite stable measurements for FVC andDLCO.

Integrity signals

Registry

Crossref · 10.1183/13993003.02279-2019

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 11 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The antifibrotic treatments pirfenidone and nintedanib have been shown to slow disease progression as measured by the annual rate of decline in forced vital capacity.

    “The antifibrotic treatments pirfenidone and nintedanib have been shown to slow disease progression as measured by annual rate of decline in forced vital capacity (FVC) [2]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [2] source

      The Background reports that trials of novel agents showed slower IPF progression measured by FVC and discusses nintedanib and pirfenidone in relation to the rate of FVC decline. It does not establish an annual rate of decline for both drugs; it notes that FVC outcomes were reported in different ways. This paper’s own analysis focused on mortality and severe adverse events. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The observed survival difference in favour of antifibrotic therapy is in accordance with recent clinical trials showing that antifibrotic therapies are effective in progressive fibrotic interstitial lung diseases other than IPF.

    “This observation is therefore in accordance with recent clinical trials showing that antifibrotic therapies are effective in progressive fibrotic interstitial lung diseases other than IPF [20,26,27].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [20] Maher, 2020, Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial, Lancet Respir Med source
    • cites [26] source
    • cites [27] source
  • Premiseown data

    In a subset of IPF patients with long-term follow-up within the EurIPF registry, median survival on antifibrotic drugs was 123.1 months compared with 68.3 months in patients treated with any other medication including immunosuppressive therapies.

    “The analysis of this subset found that median survival on antifibrotic drugs was 123.1 months (censored cases inclusive, range 84-162 months), compared with a median survival of 68.3 months in patients treated with any other medication including immunosuppressive therapies (censored cases inclusive, range 54-83 months).”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • Findingown data

    There was no statistically significant difference in overall mortality between nintedanib and pirfenidone (HR for pirfenidone versus nintedanib 1.39, 95% CI 0.87-2.22; p=0.164).

    “Analysis for both antifibrotic drugs approved for treating IPF, nintedanib and pirfenidone, revealed no statistically significant difference in overall mortality between the two drugs (HR for pirfenidone versus nintedanib 1.39, 95% CI 0.87-2.22;p=0.164).”
    Quote in the paperSubstantial claim
  • Findingown data

    There was no significant difference in the course of D LCO % predicted between the antifibrotic-treated and untreated groups (β for time × therapy -0.40, 95% CI -2.56-1.77; p=0.721).

    “and no significant differences between the two groups (β for time × therapy -0.40, 95% CI -2.56-1.77;p=0.721).”
    Quote in the paperSubstantial claim
  • May combine two claims. 9
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingcitation

    Compared with the EurIPF registry, patients in INSIGHTS-IPF were nearly identical in total lung capacity, FVC and FEV1, while D LCO was lower in INSIGHTS-IPF.

    “Compared with the recently published observational data from the EurIPF registry, patients in INSIGHTS-IPF were nearly identical in terms of total lung capacity (70.0%pred versus 71.2% pred), FVC (68.4% pred versus 68.3% pred) and FEV 1 (110% pred versus 111% pred), while D LCO was lower in our study (42.1% pred versus 37.8% pred) [18].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] source

      Table 2 (Results, “Baseline lung function in IPF patients”) supports the eurIPFreg values for TLC (70.0%), FVC (68.4%) and DLCO (42.1%). It reports FEV1 as 74.1% predicted; the approximately 110% figure is FEV1/FVC, not FEV1. The INSIGHTS-IPF values are not reported in this source. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Time to diagnosis was approximately 1 year longer in the never-treated population, which could indicate a healthy survivor effect.

    “This is especially important since time to diagnosis was ∼1 year longer in the never-treated population, which could indicate a “healthy survivor effect” [28].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] source

      Section 1.1 describes selective survival and survivor treatment selection bias, supporting the possibility of a survivor-related effect. It does not report a never-treated population or an approximately one-year difference in time to diagnosis; searches for those details found no matching passage. Page numbers were not available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Study design and conductreasoning

    Allocation to antifibrotic treatment was not randomly assigned, and a propensity score with inverse probability of treatment weighting was used so that all statistical comparisons between treated and untreated patients were weighted to balance the two groups on clinical characteristics at treatment start.

    “INSIGHTS-IPF is an observational study and thus allocation to treatment was not randomly assigned.”
    • Also stated in: § Data analysis · plain
      “All statistical comparisons between patients with and without antifibrotic therapy were weighted to balance the two groups regarding the clinical characteristics at treatment start.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [14][15][16]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [17] source

      Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    In patients with disease duration ≤12 months at enrolment, a slightly better course of FVC % predicted, D LCO % predicted and 6MWD was observed with antifibrotic therapy, but the difference was not statistically significant.

    “A slightly better course of FVC % pred, D LCO % pred and 6MWD was observed in patients with antifibrotic therapy; however, the difference was not statistically significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A number of IPF registries have been initiated in various countries to provide real-life data, but their follow-up is limited to 1-2 years only.

    “A number of registries have been initiated in various countries to provide such real-life data [3][4][5][6][7][8], but their follow-up is limited to 1-2 years only.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3][4][5][6][7][8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Unbalanced steroid medication cannot be excluded as a contributor to the observed higher mortality in the group not treated with antifibrotics.

    “Nonetheless, we cannot exclude that unbalanced steroid medication has contributed to the observed difference.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The proportional-hazards assumption of the Cox regression model was tested on the basis of Schoenfeld residuals.

    “The proportional-hazards assumption was tested on the basis of Schoenfeld residuals after fitting the Cox regression model.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The phenomenon of emphysema blunting the decline of FVC in both groups may have contributed to the similar observed course of FVC.

    “The phenomenon of emphysema blunting the decline of FVC in both groups may have contributed to this observation”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationown data

    The observed difference in survival in favour of antifibrotic therapy is an important argument for the clinical application of these drugs, even though a causative argument cannot be made from this study.

    “The observed difference in survival in favour of antifibrotic therapy is an important argument for the clinical application of these drugs, even though a causative argument cannot be made from our study.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Quality measures included automated plausibility checks at data entry, statistical checks on data quality, and on-site monitoring and source data verification performed in the majority of centres (>70%).

    “Quality measures included automated plausibility checks at data entry, statistical checks on data quality (focusing on missing values and outliers) as well as on-site monitoring and source data verification performed in the majority of centres (>70%).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The analyses follow the intention-to-treat principle, assigning each patient with at least one dose of antifibrotic therapy to the treatment group.

    “The analyses follow the intention-to-treat principle, which means that each patient with at least one dose of antifibrotic therapy is assigned to the treatment group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Stability of lung function parameters over time, especially FVC and D LCO, in untreated IPF patients may be misleading and probably does not protect from premature death.

    “our data indicate that stability of these parameters probably do not protect from premature death.”
    • Also stated in: § Abstract · hedged
      “suggesting that functional stability alone may not safeguard against premature mortality in IPF”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The statistically nonsignificant relationship between antifibrotic therapy and IPF-related deaths might be due to the low number of recorded IPF-related deaths.

    “The statistically nonsignificant relationship between antifibrotic therapy and IPF-related deaths might be due to the low number of recorded IPF-related deaths (79.4% of deaths).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hospital-based FVC measurements, compared with unsupervised daily home measurements, have been suggested to be less sensitive in detecting progression of fibrosis and in predicting subsequent prognosis.

    “it is noteworthy that hospital-based FVC measurements, compared with unsupervised daily home measurements, have been suggested to be less sensitive in detecting progression of fibrosis and in predicting subsequent prognosis [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Russell, 2016, Daily home spirometry: an effective tool for detecting progression in idiopathic pulmonary fibrosis, Am J Respir Crit Care Med source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Because of substantial missing values in lung function tests and 6MWD, multiple imputation was applied to estimate missing values as sensitivity analyses.

    “Since the number of missing values in lung function tests (FVC baseline 4.5%, follow-up 20.7%; D LCO baseline 16.2%, follow-up 31.9%) and 6MWD (baseline 14.1%, follow-up 57.3%) were substantial, we applied the technique of multiple imputation for those variables to estimate the missing values as sensitivity analyses.”
    Quote in the paperNot a substantial claim
15 of 15

  • The paper relies on this without support.

    Randomised controlled studies on antifibrotic treatments have limitations in generalisability due to patient selection/exclusion and duration of follow-up, so observational data in unselected IPF patients are needed.

    “As randomised controlled studies on antifibrotic treatments have limitations in terms of their generalisability due to patient selection/exclusion and duration of follow-up, observational data in unselected IPF patients are needed to provide a more comprehensive picture.”
1 of 1

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Mortality reduction does not match the hazard ratio

    Major

    A hazard ratio of 0.44 corresponds to a 56% lower risk, not the reported 64%. The discrepancy affects the stated size of the survival benefit in this subgroup.

    Reported 0.64 · recomputed 0.56

  • Oxygen-therapy percentage uses an inconsistent denominator

    Minor

    The table reports 71 oxygen-therapy patients among 298 treated patients. That is 23.8% to one decimal place, not 23.3%.

    Reported 23.3 · recomputed 23.825503

  • Baseline 6MWD availability differs between sections

    Minor

    The stated baseline missing rate of 14.1% implies 85.9% availability, rather than the 89% reported in the results.

  • Recent-duration patients receive opposing cohort labels

    Minor

    Patients with disease duration of approximately 12 months or less are called prevalent in the lung-function analysis but incident in the mortality analysis.

  • Conflicting percentages for IPF-related deaths

    Minor

    The results identify 79 IPF-related deaths as 41% of deaths, whereas the discussion calls them 79.4% of deaths.

5 of 5

Cites

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Authors
Behr, J., Prasse, A., Wirtz, H., Koschel, D., Pittrow, D., Held, M., Klotsche, J., Andreas, S., Claussen, M., Grohé, C., Wilkens, H., Hagmeyer, L., Skowasch, D., Meyer, J. F., Kirschner, J., Gläser, S., Kahn, N., Welte, T., Neurohr, C., Schwaiblmair, M., Bahmer, T., Oqueka, T., Frankenberger, M., & Kreuter, M.
Affiliations
  • Helmholtz Munich (DE)
  • Medizinische Hochschule Hannover (DE)
  • University Hospital Leipzig (DE)
  • GWT-TUD (Germany) (DE)
  • Medical Mission Institute (DE)
  • German Rheumatism Research Centre (DE)
  • Universitätsmedizin Göttingen (DE)
  • German Center for Lung Research (DE)
  • University of Cologne (DE)
  • University Hospital Bonn (DE)
  • München Klinik Bogenhausen (DE)
  • University of Bamberg (DE)
  • Universitätsmedizin Greifswald (DE)
  • Heidelberg University (DE)
  • Klinik Schillerhöhe (DE)
  • University Hospital Augsburg (DE)
  • University Hospital Schleswig-Holstein (DE)
  • University Medical Center Hamburg-Eppendorf (DE)
ORCID
Venue
European Respiratory Journal
Publisher
European Respiratory Society (ERS)
Published
2020-05-07
Volume
56
Issue
2
Pages
1902279
ISSN
  • 0903-1936 (ISSN-L)
  • 1399-3003
DOI
10.1183/13993003.02279-2019
OpenAlex
W3023534540
Cited by
195
References
28
Citations by year
2026: 16 · 2025: 22 · 2024: 32 · 2023: 35 · 2022: 37 · 2021: 42 · 2020: 4
FWCI
13.16
Type
journal article
Language
en
Open access
Licence
www.ersjournals.com/user-licence (vor)
Locations
  • European Respiratory Journal (publishedVersion)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • Publikationsdatenbank der Fraunhofer-Gesellschaft (Fraunhofer-Gesellschaft) (submittedVersion)
  • Site cant be reached (submittedVersion, other-oa)
  • Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
  • OPUS (Augsburg University) (submittedVersion)
Funders
Boehringer Ingelheim
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Health Sciences › Medicine › Physiology › Sarcoidosis and Beryllium Toxicity Research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Occupational exposure and asthma
Keywords
idiopathic pulmonary fibrosis, antifibrotic therapy, survival, lung function decline, forced vital capacity, diffusing capacity for carbon monoxide, mortality, real-world outcomes
MeSH terms
Aged, Female, Germany, Humans, Lung, Male, Middle Aged, Prospective Studies, Registries

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